A 5H-dibenzo[a,d]cycloheptatrien-5-one intermediate compound

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a 5H-dibenzo[a,d]cycloheptatriene-5-ketone intermediate compound and a method for preparing 5H-dibenzo[a,d]cycloheptatriene-5-ketone. The method uses SM-1 as a starting material, reacts with ethanethiol first, and then is coupled with SM-2 to obtain the intermediate compound I-2, and the compound I-2 can be reacted for one step under the action of a catalyst to obtain 5H-dibenzo[a,d]cycloheptatriene-5-ketone. The preparation method solves the problems of complex operation and high toxicity in the prior art, is simple to operate, the obtained product has high yield and purity, the reaction period is short, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a 5H-dibenzo[a,d]cycloheptatrien-5-one intermediate compound. Background Technology

[0002] Cyclobenzaprine hydrochloride, chemically named 5-(3-dimethylaminopropylidene)dibenzo[a,d]cycloheptene hydrochloride, is a muscle relaxant developed by Merck & Co., Inc. It is now marketed in many countries under the brand name Flexeril and is clinically used to relieve muscle spasms and associated severe skeletal muscle pain. This product has a rapid onset of action, good antispasmodic effect, and few adverse reactions, making it the first-line drug for this type of pain. Its chemical structural formula is:

[0003]

[0004] Patents US3454643A, 387CHE2005, 171MUM2011, WO2012098563A2, CN102942489A, CN103242170B and literature Acta. Chemical Scandinavica, 1963, 17, 2437-2443, Journal of Medicinal and Pharmaceutical Chemistry, 1962, 5, 2, 373-383, "Study on the Synthesis of Cyclobenzaline", Journal of Mudanjiang Medical College, 2008, 29(2), 18-20, "Synthesis of Cyclobenzaline Hydrochloride", China Pharmaceutical Industry Journal, 2008, 39(8), 569-570, "Simple Synthesis of Cyclobenzaline", Contemporary Medicine, 2009, 15(3), 15-16, "Improved Synthesis Process of Cyclobenzaline Hydrochloride", Chinese Journal of Medicinal Chemistry, 2015, 25(2), 115-117. The preparation methods of cyclobenzaline hydrochloride are disclosed in these articles.

[0005] 5H-Dibenzo[a,d]cycloheptatrien-5-one is a key intermediate in the synthesis of cyclobenzaline hydrochloride, directly affecting the production, market supply, and quality of this drug. Its structural formula is as follows:

[0006]

[0007] In addition, 5H-dibenzo[a,d]cycloheptatrien-5-one can also be used to further synthesize cyproheptadine hydrochloride, amitriptyline hydrochloride and its metabolite nortriptyline, with the relevant structural formulas as follows:

[0008]

[0009] The currently reported methods for preparing 5H-dibenzo[a,d]cycloheptatrien-5-one are as follows:

[0010] The literature "Research on the Synthesis of Cyclobenzaline", Journal of Mudanjiang Medical College, 2008, 29(2) and "Simple Synthesis of Cyclobenzaline", Contemporary Medicine, 2009, 15(3), 15-16, uses dibenzo[a,d]cyclohepta-5-one as the starting material. The reaction involves bromination with bromine in CCl4 under reflux for 18 hours, followed by the addition of triethylamine and another 16 hours of reflux. The target product is then obtained after post-treatment. However, this reaction requires highly toxic carbon tetrachloride and bromine, resulting in low operational safety and a long reaction cycle, making it unsuitable for scale-up. US Patent 3409640A uses NBS for bromination followed by treatment with a tertiary amine to obtain the product.

[0011]

[0012] In addition, US Patent 3409640A also uses the Friedel-Crafts acylation reaction to prepare the target product with AlCl3 as a catalyst. However, the application of anhydrous AlCl3 is quite dangerous and can easily introduce aluminum ions into the product.

[0013]

[0014] The literature ACS Catal. 2014, 4, 11, 4034-4039 describes the preparation of the target product using trans-dibromo derivatives as substrates under argon protection and with the aid of α-selenothiophene and tetramethylethylenediamine in a Schlenk tube apparatus under light radiation. However, the relevant substrates still require substitution with highly toxic bromine, and organoselenium catalysts are not readily available. Furthermore, the target product is prepared at the milligram level, requiring column chromatography purification, making mass production difficult. The literature Bull. Korean Chem. Soc. 34 (2013) 7, 1951-1952 describes the selective debromination of vic-dibromine to olefins using an NbCl5 / In system, but this catalyst is costly.

[0015]

[0016] The literature ACS Catal. 2018, 8, 4, 3030-3034 uses an alcohol oxidation strategy to prepare the target product. This reaction requires a CO2 environment at 90℃ for 48 hours. This process must be carried out in a glove box under strict anhydrous conditions, and the reaction cycle is long. The target product also requires column chromatography purification, making it difficult to mass-produce. The literature Tetrahedron Letters, 55 (2014), 6895-6898 uses Swern-type oxidation, but this reaction requires a temperature of -30℃, which places high demands on the equipment. In addition, the reaction easily produces toxic dimethyl sulfide gas with a foul odor, and the prepared product is also in the millimolecular range, making it difficult to mass-produce. The literature Nat. Commun. 10, 2796 (2019) uses a microchannel continuous flow reactor for preparation, but the production cost is high.

[0017]

[0018] In summary, current methods for preparing 5H-dibenzo[a,d]cycloheptatrien-5-one suffer from high technological risks, cumbersome operations, low yields, and high costs. Therefore, finding a reaction route suitable for industrial-scale production of 5H-dibenzo[a,d]cycloheptatrien-5-one that is simple to operate, yields high-purity products, and has low production costs remains a problem to be solved. Summary of the Invention

[0019] To address the problems existing in current techniques for preparing 5H-dibenzo[a,d]cycloheptatrien-5-one, this invention provides a novel intermediate compound I-2 and a new method for preparing 5H-dibenzo[a,d]cycloheptatrien-5-one using this intermediate. The 5H-dibenzo[a,d]cycloheptatrien-5-one prepared by this method exhibits high purity and yield, and is produced at low cost with high operational safety.

[0020] The specific technical solution of the present invention is as follows:

[0021] The first aspect of this invention provides a 5H-dibenzo[a,d]cycloheptatrien-5-one intermediate compound, the structure of which is shown in Formula I-2:

[0022]

[0023] A second aspect of this invention provides a method for preparing a 5H-dibenzo[a,d]cycloheptatrien-5-one intermediate compound, comprising the following steps:

[0024]

[0025] Step 1: Dissolve SM-1 and ethanethiol in anhydrous organic solvent A, add catalyst, and control the temperature T. AThe reaction was stirred to prepare compound I-1;

[0026] Step 2: Under inert gas protection, I-1, SM-2, CuTC, catalyst, and ligand are added to reaction solvent B, and the temperature is controlled at T. B The reaction was continued with stirring to obtain compound I-2.

[0027] Preferably, the organic solvent A in step 1 is selected from acetonitrile and tetrahydrofuran, with acetonitrile being the preferred choice.

[0028] Preferably, the catalyst in step 1 is selected from trifluoroacetic acid, p-toluenesulfonic acid, and p-toluenesulfonic anhydride, with trifluoroacetic acid being the most preferred.

[0029] Preferably, the molar ratio of SM-1 to ethanethiol and catalyst in step 1 is 1:1.0-1.25:0.2-0.5, more preferably 1:1.05:0.3.

[0030] Preferably, the reaction temperature T in step 1 A The temperature range is 40–65℃, with 55–60℃ being preferred.

[0031] Preferably, the anhydrous organic solvent in step 1 can be prepared by conventional methods in the art, such as redistillation and drying, or can be purchased directly.

[0032] In a preferred embodiment, after the reaction in step 1, a post-processing operation is required. Specifically, the steps are as follows: add a saturated sodium carbonate solution to the reaction solution until the pH reaches 8-9, stir, extract with an organic solvent, combine the organic phases, wash with saturated brine, and concentrate the organic phase to dryness under reduced pressure to obtain compound I-1. Preferably, the extractant is selected from one or a combination of dichloromethane, chloroform, ethyl acetate, and methyl tert-butyl ether, with ethyl acetate and dichloromethane being preferred.

[0033] Preferably, the catalyst in step 2 is selected from palladium dichloride (PdCl2), palladium acetate [Pd(OAc)2], and tris(dibenzylideneacetone)palladium [Pd2(dba)3], with PdCl2 being the most preferred.

[0034] Preferably, the ligand in step 2 is selected from one of triphenylphosphine (PPh3), tri-tert-butylphosphine [P(t-Bu)3], tricyclohexylphosphine (PCy3), tri-o-tolylphosphine [P(o-tol)3], and tri(2-furanyl)phosphine (TFP), with triphenylphosphine being the most preferred.

[0035] Preferably, the molar ratio of compound I-1 to SM-2, CuTC, catalyst, and ligand in step 2 is 1:1.0-1.3:1.2-1.8:0.5%-4.0%:0.5%-5.0%, more preferably 1:1.1:1.6:1.0%:2.0%, wherein the catalyst is calculated as Pd.

[0036] Preferably, the reaction temperature T in step 2 B The temperature range is 40–78℃, with 50–55℃ being preferred.

[0037] Preferably, the reaction solvent B in step 2 is selected from one or a combination of tetrahydrofuran, ethanol, and isopropanol, with tetrahydrofuran being the most preferred.

[0038] Preferably, the inert gas in step 2 is either argon or nitrogen.

[0039] In a preferred embodiment, after the reaction in step 2, a post-processing operation is required. The specific steps are as follows: the reaction solution is poured into dilute hydrochloric acid, filtered, the filtrate is adjusted to pH 10-11 with an alkali, extracted with an organic solvent, the organic phases are combined, washed with saturated brine, and concentrated to dryness under reduced pressure to obtain the target compound I-2. Preferably, the concentration of the dilute hydrochloric acid is 0.5-2 mol / L, preferably 1 mol / L. Preferably, the alkali includes sodium hydroxide and potassium hydroxide. Preferably, the extractant is selected from dichloromethane, ethyl acetate, chloroform, and methyl tert-butyl ether, preferably dichloromethane.

[0040] On the other hand, the present invention provides a method for preparing 5H-dibenzo[a,d]cycloheptatrien-5-one from compound I-2, the specific steps of which are as follows: under inert gas protection, compound I-2, catalyst, and base are added to reaction solvent C, and the temperature is controlled at T. C Continue stirring the reaction to obtain compound I, as shown in the following reaction formula:

[0041]

[0042] Preferably, the catalyst is selected from one or a combination of Pd(PPh3)4, Pd(PPh3)2Cl2, and Pd(dppf)Cl2, with Pd(PPh3)2Cl2 being the most preferred.

[0043] Preferably, the reaction solvent C is one or a combination of acetonitrile, 1,4-dioxane, toluene, N,N-dimethylformamide, and dimethyl sulfoxide.

[0044] Preferably, the alkali is one or a combination of Na2CO3, K3PO4, CH3COONa, CH3COOK, and t-BuONa, with CH3COOK being the most preferred.

[0045] Preferably, the molar ratio of compound I-2 to alkali and catalyst is 1:2 to 6:3% to 7%, more preferably 1:4:5%.

[0046] Preferably, the reaction temperature T C The temperature range is 82–110℃, with 90–95℃ being preferred.

[0047] In a preferred embodiment, a post-processing operation is required after the reaction is complete. The specific steps are as follows: the reaction solution is filtered, the filtrate is poured into purified water, extracted with an organic solvent, the organic phases are combined, washed with saturated brine, and concentrated to dryness under reduced pressure to obtain compound I. Preferably, the extractant is selected from one or a combination of dichloromethane, chloroform, ethyl acetate, and methyl tert-butyl ether, with dichloromethane being preferred.

[0048] Preferably, the inert gas is either argon or nitrogen, with argon being the preferred gas.

[0049] The beneficial effects of this invention are:

[0050] This invention provides a novel 5H-dibenzo[a,d]cycloheptatrien-5-one intermediate compound I-2, and a novel method for preparing 5H-dibenzo[a,d]cycloheptatrien-5-one from compound I-2. This preparation method uses SM-1 as the starting material, first reacting it with ethanethiol to obtain a methyl thioester, and then proceeding to obtain 5H-dibenzo[a,d]cycloheptatrien-5-one via a two-step coupling reaction. This method solves the problems of complex operation and high toxicity in existing technologies. The 5H-dibenzo[a,d]cycloheptatrien-5-one prepared by the intermediate compound I-2 of this invention has high yield and purity, is simple to operate, has a short reaction cycle, and is suitable for industrial production. Detailed Implementation

[0051] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection of the present invention.

[0052] This invention uses HPLC to determine the purity of 5H-dibenzo[a,d]cycloheptatrien-5-one. The chromatographic conditions are as follows:

[0053] Column: Hypersil BDS-C 18 Column (4.6 mm × 250 mm, 5 μm) or equivalent chromatographic column;

[0054] Mobile phase: Acetonitrile-0.085% phosphoric acid aqueous solution (adjusted to pH 6.5 with triethylamine) (65:35)

[0055] Column temperature: 30℃;

[0056] Detection wavelength: 210nm;

[0057] Flow rate: 1.0 ml / min;

[0058] Injection volume: 20 μl;

[0059] The retention time of 5H-dibenzo[a,d]cycloheptatrien-5-one is approximately 41.913 min.

[0060] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art, and the reagents used, unless otherwise specified, are commercially available analytical grade or chemically pure.

[0061] Synthesis of compound I-1

[0062] Example 1

[0063] Trifluoroacetic acid (2.23 ml, 0.03 mol) was added dropwise to an anhydrous acetonitrile (100 ml) solution of SM-1 (16.22 g, 0.1 mol) and ethanethiol (6.52 g, 0.105 mol). The reaction was carried out at 55–60 °C with stirring. After the reaction was completed, saturated sodium carbonate solution was added to the reaction solution to adjust the pH to 8–9. The mixture was stirred and extracted with ethyl acetate (30 ml × 3). The organic phases were combined and washed with saturated brine (30 ml × 2). The organic phase was concentrated to dryness under reduced pressure to obtain compound I-1 with a yield of 98.6% and a purity of 99.37%. ESI-HRMS (m / z): 193.0517 [M+H]; 1 H-NMR (600MHz, CDCl3) δ: 7.80 (d, J=7.6Hz, 1H), 7.62 (td, J=7.6, 2.3Hz, 1H), 7.36~7.42 (m ,3H),5.54(dd,J=13.4,1.6Hz,1H),5.50(dd,J=8.0,1.7Hz,1H),2.98(q,2H),1.28(t,3H); 13 C-NMR (151MHz, CDCl3) δ: 188.57, 138.29, 135.62, 133.48, 132.68, 131.49, 129.08, 127.43, 118.37, 22.75, 12.62.

[0064] Example 2

[0065] Toluenesulfonic acid (5.17 g, 0.03 mol) was added dropwise to an anhydrous acetonitrile (100 ml) solution of SM-1 (16.22 g, 0.1 mol) and ethanethiol (6.21 g, 0.1 mol). The mixture was stirred at 50–55 °C. After the reaction was complete, saturated sodium carbonate solution was added to the reaction solution to bring the pH to 8–9. The mixture was stirred and extracted with methyl tert-butyl ether (30 ml × 3). The organic phases were combined and washed with saturated brine (30 ml × 2). The organic phases were concentrated to dryness under reduced pressure to obtain compound I-1 with a yield of 94.5% and a purity of 99.04%.

[0066] Example 3

[0067] Toluenesulfonic anhydride (9.79 g, 0.03 mol) was added dropwise to an anhydrous tetrahydrofuran (100 ml) solution of SM-1 (16.22 g, 0.1 mol) and ethanethiol (5.59 g, 0.09 mol). The reaction was carried out at 60–65 °C with stirring. After the reaction was completed, saturated sodium carbonate solution was added to the reaction solution to bring the pH to 8–9. The mixture was stirred and extracted with chloroform (30 ml × 3). The organic phases were combined and washed with saturated brine (30 ml × 2). The organic phase was concentrated to dryness under reduced pressure to obtain compound I-1 with a yield of 91.2% and a purity of 98.55%.

[0068] Example 4

[0069] Trifluoroacetic acid (2.23 ml, 0.03 mol) was added dropwise to an anhydrous acetonitrile (100 ml) solution of SM-1 (16.22 g, 0.1 mol) and ethanethiol (7.77 g, 0.125 mol). The reaction was carried out at 45–50 °C with stirring. After the reaction was completed, saturated sodium carbonate solution was added to the reaction solution to bring the pH to 8–9. The mixture was stirred and extracted with dichloromethane (30 ml × 3). The organic phases were combined and washed with saturated brine (30 ml × 2). The organic phase was concentrated to dryness under reduced pressure to obtain compound I-1 with a yield of 97.0% and a purity of 98.83%.

[0070] Example 5

[0071] Trifluoroacetic acid (2.23 ml, 0.03 mol) was added dropwise to an anhydrous acetonitrile (100 ml) solution of SM-1 (16.22 g, 0.1 mol) and ethanethiol (8.07 g, 0.130 mol). The mixture was stirred at 40–45 °C. After the reaction was complete, saturated sodium carbonate solution was added to the reaction solution to bring the pH to 8–9. The mixture was stirred and extracted with dichloromethane (30 ml × 3). The organic phases were combined and washed with saturated brine (30 ml × 2). The organic phase was concentrated to dryness under reduced pressure to obtain compound I-1 with a yield of 92.9% and a purity of 98.31%.

[0072] Example 6

[0073] Trifluoroacetic acid (1.49 ml, 0.02 mol) was added dropwise to an anhydrous acetonitrile (100 ml) solution of SM-1 (16.22 g, 0.1 mol) and ethanethiol (6.52 g, 0.105 mol). The mixture was stirred at 55–60 °C. After the reaction was complete, saturated sodium carbonate solution was added to the reaction solution to bring the pH to 8–9. The mixture was stirred and extracted with ethyl acetate (30 ml × 3). The organic phases were combined and washed with saturated brine (30 ml × 2). The organic phase was concentrated to dryness under reduced pressure to obtain compound I-1 with a yield of 95.3% and a purity of 99.19%.

[0074] Example 7

[0075] Trifluoroacetic acid (3.72 ml, 0.05 mol) was added dropwise to an anhydrous acetonitrile (100 ml) solution of SM-1 (16.22 g, 0.1 mol) and ethanethiol (6.52 g, 0.105 mol). The mixture was stirred at 55–60 °C. After the reaction was complete, saturated sodium carbonate solution was added to the reaction solution to bring the pH to 8–9. The mixture was stirred and extracted with dichloromethane (30 ml × 3). The organic phases were combined and washed with saturated brine (30 ml × 2). The organic phases were concentrated to dryness under reduced pressure to obtain compound I-1 with a yield of 97.8% and a purity of 99.06%.

[0076] Synthesis of compound I-2

[0077] Example 8

[0078] Under argon protection, I-1 (19.20 g, 0.1 mol), SM-2 (22.09 g, 0.11 mol), CuTC (30.51 g, 0.16 mol), PdCl2 (0.18 g, 1.0 mmol), and triphenylphosphine (0.52 g, 2.0 mmol) were added to tetrahydrofuran (200 ml). The reaction was carried out at 50–55 °C. After the reaction was detected to be complete, the reaction solution was poured into 1 mol / L dilute hydrochloric acid (200 ml), filtered, and the filtrate was adjusted to pH 10–11 with sodium hydroxide. The solution was extracted with dichloromethane (100 ml × 3), the organic phases were combined, washed with saturated brine (100 ml × 2), and the organic phase was concentrated to dryness under reduced pressure to obtain compound I-2 with a yield of 94.6% and a purity of 99.42%. ESI-HRMS(m / z):287.0068, 289.0032[M+H]; 1H-NMR(600MHz, CDCl3)δ:7.74~7.80(m,2H),7.61~7.63(m,2H),7.49~7.53(m,1H),7.44~7 .46(m,2H),7.34~7.40(m,3H),5.63(dd,J=13.5,1.6Hz,1H),5.56(dd,J=8.0,1.7Hz,1H); 13 C-NMR(151MHz, CDCl3)δ:193.26,139.17,138.42,136.83,133.58,132.95, 131.77,131.09,120.02,129.33,127.46,127.38,127.06,124.46,117.03.

[0079] Example 9

[0080] Under argon protection, I-1 (19.20 g, 0.1 mol), SM-2 (21.09 g, 0.105 mol), CuTC (30.51 g, 0.16 mol), Pd(OAc)2 (0.22 g, 1.0 mmol), and triphenylphosphine (0.52 g, 2.0 mmol) were added to tetrahydrofuran (200 ml). The reaction was carried out at a controlled temperature of 55–60 °C. After the reaction was detected to be complete, the reaction solution was poured into 1 mol / L dilute hydrochloric acid (200 ml), filtered, and the filtrate was adjusted to pH 10–11 with potassium hydroxide. The solution was extracted with dichloromethane (100 ml × 3), the organic phases were combined, washed with saturated brine (100 ml × 2), and the organic phase was concentrated to dryness under reduced pressure to obtain compound I-2 with a yield of 90.7% and a purity of 99.16%.

[0081] Example 10

[0082] Under argon protection, I-1 (19.20 g, 0.1 mol), SM-2 (20.09 g, 0.10 mol), CuTC (30.51 g, 0.16 mol), PdCl2 (0.18 g, 1.0 mmol), and tri-o-tolylphosphine [P(o-tol)3, 0.61 g, 2.0 mmol] were added to ethanol (200 ml) and refluxed at 45–50 °C. After the reaction was confirmed to be complete, the reaction solution was poured into 1 mol / L dilute hydrochloric acid (200 ml), filtered, and the filtrate was adjusted to pH 10–11 with sodium hydroxide. The solution was extracted with dichloromethane (100 ml × 3), washed with saturated brine (100 ml × 2), and the organic phase was concentrated to dryness under reduced pressure to obtain compound I-2 with a yield of 85.8% and a purity of 98.60%.

[0083] Example 11

[0084] Under nitrogen protection, I-1 (19.20 g, 0.1 mol), SM-2 (26.11 g, 0.13 mol), CuTC (30.51 g, 0.16 mol), Pd2(dba)3 (0.92 g, 1.0 mmol), and triphenylphosphine (0.52 g, 2.0 mmol) were added to tetrahydrofuran (200 ml). The reaction was carried out at 40–45 °C. After the reaction was detected to be complete, the reaction solution was poured into 2 mol / L dilute hydrochloric acid (150 ml), filtered, and the filtrate was adjusted to pH 10–11 with sodium hydroxide. The solution was extracted with dichloromethane (100 ml × 3), the organic phases were combined, washed with saturated brine (100 ml × 2), and the organic phase was concentrated to dryness under reduced pressure to obtain compound I-2 with a yield of 93.2% and a purity of 98.91%.

[0085] Example 12

[0086] Under argon protection, I-1 (19.20 g, 0.1 mol), SM-2 (27.11 g, 0.11 mol), CuTC (30.51 g, 0.16 mol), PdCl2 (0.18 g, 1.0 mmol), and tris(2-furanyl)phosphine (TFP, 0.46 g, 2.0 mmol) were added to tetrahydrofuran (200 ml). The reaction was carried out at a controlled temperature of 55–60 °C. After the reaction was detected to be complete, the reaction solution was poured into 1 mol / L dilute hydrochloric acid (200 ml), filtered, and the filtrate was adjusted to pH 10–11 with sodium hydroxide. The solution was extracted with methyl tert-butyl ether (100 ml × 3), the organic phases were combined, washed with saturated brine (100 ml × 2), and the organic phase was concentrated to dryness under reduced pressure to obtain compound I-2 with a yield of 87.6% and a purity of 98.43%.

[0087] Example 13

[0088] Under argon protection, I-1 (19.20 g, 0.1 mol), SM-2 (22.09 g, 0.11 mol), CuTC (22.84 g, 0.12 mol), PdCl2 (0.18 g, 1.0 mmol), and tri-tert-butylphosphine [P(t-Bu)3, 0.40 g, 2.0 mmol] were added to isopropanol (200 ml) and refluxed at 75–78 °C. After the reaction was confirmed to be complete, the reaction solution was poured into 0.5 mol / L dilute hydrochloric acid (250 ml), filtered, and the filtrate was adjusted to pH 10–11 with sodium hydroxide. The solution was extracted with dichloromethane (100 ml × 3), washed with saturated brine (100 ml × 2), and the organic phase was concentrated to dryness under reduced pressure to obtain compound I-2 with a yield of 91.5% and a purity of 99.26%.

[0089] Example 14

[0090] Under argon protection, I-1 (19.20 g, 0.1 mol), SM-2 (22.09 g, 0.11 mol), CuTC (34.27 g, 0.18 mol), PdCl2 (0.18 g, 1.0 mmol), and tricyclohexylphosphine (PCy3, 0.56 g, 2.0 mmol) were added to tetrahydrofuran (200 ml). The reaction was carried out at 50–55 °C. After the reaction was detected to be complete, the reaction solution was poured into 1 mol / L dilute hydrochloric acid (200 ml), filtered, and the filtrate was adjusted to pH 10–11 with sodium hydroxide. The solution was extracted with dichloromethane (100 ml × 3), washed with saturated brine (100 ml × 2), and the organic phase was concentrated to dryness under reduced pressure to obtain compound I-2 with a yield of 93.8% and a purity of 99.04%.

[0091] Example 15

[0092] Under argon protection, I-1 (19.20 g, 0.1 mol), SM-2 (22.09 g, 0.11 mol), CuTC (30.51 g, 0.16 mol), PdCl2 (0.09 g, 0.5 mmol), and triphenylphosphine (0.13 g, 0.5 mmol) were added to isopropanol (200 ml) and reacted at a controlled temperature of 65–70 °C. After the reaction was confirmed to be complete, the reaction solution was poured into 1 mol / L dilute hydrochloric acid (200 ml), filtered, and the filtrate was adjusted to pH 10–11 with sodium hydroxide. The solution was extracted with ethyl acetate (100 ml × 3), washed with saturated brine (100 ml × 2), and the organic phase was concentrated to dryness under reduced pressure to obtain compound I-2 with a yield of 91.2% and a purity of 99.12%.

[0093] Example 16

[0094] Under argon protection, I-1 (19.20 g, 0.1 mol), SM-2 (22.09 g, 0.11 mol), CuTC (30.51 g, 0.16 mol), PdCl2 (0.53 g, 3.0 mmol), and triphenylphosphine (1.05 g, 4.0 mmol) were added to isopropanol (200 ml) and reacted at 70–75 °C. After the reaction was confirmed to be complete, the reaction solution was poured into 1 mol / L dilute hydrochloric acid (200 ml), filtered, and the filtrate was adjusted to pH 10–11 with sodium hydroxide. The solution was extracted with chloroform (100 ml × 3), washed with saturated brine (100 ml × 2), and the organic phase was concentrated to dryness under reduced pressure to obtain compound I-2 with a yield of 93.3% and a purity of 99.01%.

[0095] Synthesis of Compound I

[0096] Example 17

[0097] Under argon protection, intermediate I-2 (14.36 g, 0.05 mol), Pd(PPh3)2Cl2 (1.75 g, 2.5 mmol), and CH3COOK (19.63 g, 0.2 mol) were added to dimethyl sulfoxide (150 ml) and reacted at 90–95 °C. After the reaction was detected to be complete, the reaction solution was filtered, and the filtrate was poured into purified water (1200 ml). The solution was extracted with dichloromethane (400 ml × 3), and the organic phases were combined. The solutions were washed with saturated brine (400 ml × 2), and the organic phases were concentrated to dryness under reduced pressure to obtain the target compound I with a yield of 97.7% and a purity of 99.19%. ESI-HRMS (m / z): 207.0802 [M+H]; 1 H-NMR (600MHz, DMSO-d6) δ: 8.11 (dd, J = 8.64, 1.02Hz, 2H), 7.74~7.79 (m, 4H), 7.63~7.66 (m, 2H), 7.24 (s, 2H); 13 C-NMR(151MHz,DMSO-d6)δ:191.92,137.78,134.42,132.35,131.37,130.96,129.52,129.03.

[0098] Example 18

[0099] Under argon protection, intermediate I-2 (14.36 g, 0.05 mol), Pd(PPh3)4 (1.73 g, 1.5 mmol), and K3PO4 (42.45 g, 0.2 mol) were added to toluene (150 ml) and reacted at a controlled temperature of 105–110 °C. After the reaction was detected to be complete, the reaction solution was filtered, and the filtrate was washed with purified water (50 ml × 3) and saturated brine (50 ml × 2). The organic phase was concentrated to dryness under reduced pressure to obtain target compound I with a yield of 93.2% and a purity of 98.62%.

[0100] Example 19

[0101] Under nitrogen protection, intermediate I-2 (14.36 g, 0.05 mol), Pd(dppf)Cl2 (2.56 g, 3.5 mmol), and CH3COONa (16.41 g, 0.2 mol) were added to acetonitrile (150 ml) and refluxed at 82–87 °C. After the reaction was confirmed to be complete, the reaction solution was filtered, and the filtrate was poured into purified water (1200 ml) and extracted with methyl tert-butyl ether (400 ml × 3). The organic phases were combined, washed with saturated brine (400 ml × 2), and concentrated to dryness under reduced pressure to obtain target compound I with a yield of 96.0% and a purity of 98.80%.

[0102] Example 20

[0103] Under argon protection, intermediate I-2 (14.36 g, 0.05 mol), Pd(PPh3)2Cl2 (1.75 g, 2.5 mmol), and Na2CO3 (21.20 g, 0.2 mol) were added to N,N-dimethylformamide (150 ml). The reaction was carried out at 100–105 °C. After the reaction was detected to be complete, the reaction solution was filtered, and the filtrate was poured into purified water (1200 ml). The solution was extracted with chloroform (400 ml × 3), and the organic phases were combined. The solution was washed with saturated brine (400 ml × 2), and the organic phase was concentrated to dryness under reduced pressure to obtain the target compound I with a yield of 94.6% and a purity of 98.91%.

[0104] Example 21

[0105] Under argon protection, intermediate I-2 (14.36 g, 0.05 mol), Pd(PPh3)2Cl2 (1.75 g, 2.5 mmol), and t-BuONa (19.22 g, 0.2 mol) were added to 1,4-dioxane (150 ml) and reacted at a controlled temperature of 95–100 °C. After the reaction was detected to be complete, the reaction solution was filtered, and the filtrate was poured into purified water (1200 ml). The solution was extracted with ethyl acetate (400 ml × 3), and the organic phases were combined. The solutions were washed with saturated brine (400 ml × 2), and the organic phases were concentrated to dryness under reduced pressure to obtain the target compound I with a yield of 97.1% and a purity of 98.83%.

Claims

1. A 5H-dibenzo[a,d]cycloheptatrien-5-one intermediate compound, characterized in that, The structure of the compound is shown as formula I-2: 。 2. A process for the preparation of an intermediate compound according to claim 1, characterized in that, The steps are as follows: ； Step 1: SM-1 is dissolved in anhydrous organic solvent A, a catalyst is added, and temperature TA is controlled for stirring reaction to prepare compound I-1; Step 2: Under inert gas protection, I-1, SM-2, CuTC, a catalyst, and a ligand are added to reaction solvent B, and temperature TB is controlled for continuous stirring reaction to prepare compound I-2; The catalyst in step 1 is selected from one of trifluoroacetic acid, p-toluenesulfonic acid, and p-toluenesulfonic anhydride; The reaction temperature TA is 40-65℃, and the reaction temperature TB is 40-78℃; The catalyst in step 2 is selected from one of dichloropalladium, palladium acetate, and tris(dibenzylideneacetone)dipalladium, and the ligand is selected from one of triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, tri-o-tolylphosphine, and tris(2-furyl)phosphine; The molar ratio of compound I-1 to SM-2, CuTC, a catalyst, and a ligand in step 2 is 1:1.0-1.3:1.2-1.8:0.5%-4.0%:0.5%-5.0%.

3. Use of the intermediate compound I-2 in claim 1 for preparing 5H-dibenzo[a,d]cycloheptatriene-5-one.

4. Use according to claim 3, characterized in that, The preparation procedure is as follows: under inert gas protection, compound I-2, catalyst, base are added into reaction solvent C, and temperature T is controlled C The reaction is continued to prepare compound I, and the reaction formula is as follows: ； wherein the catalyst is selected from one or a combination of Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(dppf)Cl2; the base is selected from one or a combination of Na2CO3, K3PO4, CH3COONa, CH3COOK, t-BuONa; the reaction temperature T is 82-110 °C. C is 82-110 °C.

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