A synthetic method for darolamide intermediate

Abstract

The invention discloses a preparation method of 2-chloro-4-(1H-pyrazol-5-yl)benzonitrile, a key intermediate of darolamide. The method comprises the following steps: using a halogenated pyrazole as a raw material, performing functional group protection, performing Suzuki coupling, and then deprotecting to obtain 2-chloro-4-(1H-pyrazol-5-yl)benzonitrile. The reaction is a one-pot reaction with mild conditions and readily available reagents. Compared with conventional, existing, disclosed, or in-use methods for synthesizing darolamide intermediates, the preparation method of the invention requires cheap and readily available raw materials and reagents, has a high yield, is simple to operate, and has low time cost, and is suitable for industrial production and promotion.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical substance synthesis and preparation, and particularly relates to a method for synthesizing a darolutamide intermediate. Background Art

[0002] Darolutamide is a second-generation, oral, non-steroidal androgen receptor antagonist used to treat patients with non-metastatic, castration-resistant prostate cancer. On March 11, 2019, Bayer submitted a new drug application for darolutamide film-coated tablets to the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Ministry of Health, Labor, and Welfare (MHLW) of Japan. The FDA granted priority review on April 29, 2019, and Darolutamide was approved for marketing on July 29, 2019. Its chemical structure is as follows:

[0003]

[0004] CN111116476A provides a method for synthesizing darolamide intermediate 6, and the route is as follows:

[0005]

[0006] (1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)boronic acid was coupled with 4-bromo-2-chlorobenzonitrile, followed by acid-catalyzed deprotection to obtain intermediate 6. The raw material (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)boronic acid used in this coupling step is in short supply, and post-processing requires column chromatography purification, making it unsuitable for industrial production.

[0007] CN110669049A provides a method for synthesizing darolamide intermediate 6, and the route is as follows:

[0008]

[0009] 1-(2-Tetrahydropyranyl)-1H-pyrazole-5-boronic acid pinacol ester is coupled with 4-bromo-2-chlorobenzonitrile, followed by acid-catalyzed deprotection to obtain intermediate 6. The deprotection step requires a long reflux reaction in a hydrochloric acid-ethanol solution, resulting in a high number of byproducts. Furthermore, column chromatography purification is required, making it unsuitable for industrial production. Summary of the Invention

[0010] The present invention aims to provide a method for preparing a novel darolutamide intermediate compound. This method utilizes readily available raw materials and reagents, avoids column chromatography purification during post-treatment, and utilizes a one-pot process for the coupling and deprotection steps. This method is simple to operate, low-cost, and suitable for industrial production.

[0011] The specific synthetic route is as follows:

[0012]

[0013] In the formula, X=Cl, Br, I; PG=Trt, Boc, EE;

[0014] Trt is triphenylmethyl, Boc is tert-butyloxycarbonyl, and EE is 1-ethoxyethyl;

[0015] The synthetic route comprises the following steps:

[0016] a. Compound 1 is dissolved or dispersed in an organic solvent, protected by protective gas, in the presence of a palladium catalyst and an organic base, and the reaction temperature is controlled to synthesize compound 2 with pinacol diborate;

[0017] b. Compound 3 reacts with an amine protecting reagent to generate compound 4;

[0018] c. Compound 2 and compound 4 are dissolved or dispersed in an organic solvent under protective gas protection, in the presence of a palladium catalyst and an inorganic base, while controlling the reaction temperature, undergoing Suzuki coupling, and removing the protecting group to obtain compound 6, a darolamide intermediate.

[0019] Preferably, X is Br or I;

[0020] Preferably, in step a, the organic base is potassium acetate, and the reaction temperature is 50°C to 110°C, preferably 90°C.

[0021] Preferably, in step a, the organic solvent is toluene, dioxane, acetonitrile or DMF; the palladium catalyst includes Pd(dppf)Cl2, Pd(OAc)2 / PPh3, Pd2(dba)3 / PCy3 or Pd(PPh3)4, preferably at least one of Pd(dppf)Cl2; the equivalent ratio of diboronic acid pinacol ester to compound 1 is 1:0.8~3.0, preferably 1:1.1.

[0022] Preferably, in step b, the amine protecting agent comprises at least one of Boc anhydride, vinyl ethyl ether, or triphenylmethane, preferably vinyl ethyl ether.

[0023] Preferably, in step c, the organic solvent is selected from at least one of dioxane, acetonitrile, or DMF; the palladium catalyst is selected from at least one of Pd(dppf)Cl2, Pd(OAc)2 / PPh3, Pd2(dba)3 / PCy3, Pd(amphos)2Cl2, or Pd(PPh3)4, preferably Pd(amphos)2Cl2. The equivalent ratio of compound 2 to compound 4 is 0.8 to 3.0:1, preferably 0.8:1.

[0024] As a further embodiment of the present invention: in step c, the inorganic base is K2CO3, K3PO4, Na2CO3, CsF or Cs2CO3, preferably K2CO3; the reaction temperature is 50°C to 110°C, preferably 80°C.

[0025] Beneficial effects of the present invention:

[0026] First, the raw materials and reagents used in the preparation method disclosed in the present invention are simple and easy to obtain, and there is no problem of inconvenient purchase or insufficient reagent production capacity that cannot be used for mass production;

[0027] Second, the post-treatment of the present invention avoids the column chromatography purification process of the prior art and uses a one-pot method to complete the coupling and deprotection steps, which is simple to operate, low in cost, and suitable for industrial production;

[0028] In summary, the preparation method of the present invention is easy to operate, the reagents are readily available, the yield of the compounds obtained in each stage is high, and it is suitable for mass production. DETAILED DESCRIPTION

[0029] The present invention is further described below by means of specific examples, which are not intended to limit the scope of the present invention.

[0030] The reagents used in the above and following examples are all commercially available conventional reagents and can be purchased through normal channels.

[0031] Example 1:

[0032] Preparation of compound 2:

[0033] To a 500mL three-necked flask were added 20g (92.4mmol) of 4-bromo-2-chlorobenzonitrile, 25.8g (101.6mmol) of pinacol diboronate, 27.3g (278.0mmol) of potassium acetate, 0.5g (0.7mmol) of Pd(dppf)2Cl2, and dioxane. After nitrogen substitution three times, the temperature was raised to 90°C and kept for 3h. The temperature was then lowered to 20-30°C, 150mL of saturated brine was added, and the mixture was stirred for 5 minutes. The stratification was allowed to proceed. The organic phase was distilled under reduced pressure at 50°C, and the residue was evaporated to dryness. 60mL of ethanol was added, and the mixture was stirred and heated until the solution became clear. The temperature was then lowered to 20-30°C, stirred for 10h, and then lowered to 0-10°C, stirred, and crystallized for 2h. The mixture was filtered, and the filter cake was rinsed with a small amount of ethanol and dried under reduced pressure to yield 17.8g of a tan solid (72.6% yield).

[0034] Preparation of compound 4:

[0035] To a 250 mL three-necked flask, add 8.0 g, 41.2 mmol, and 80 mL of dichloromethane. Stir under nitrogen. Add 3.6 g, 49.9 mmol of ethyl vinyl ether and dropwise add 0.3 mL of 4M dioxane hydrochloride. Stir and react at 20-30°C for 4 h. Add 20 mL of saturated sodium bicarbonate solution, stir for 5 minutes, and allow to stand for stratification. The organic phase is distilled under reduced pressure to yield 10.3 g of a light yellow liquid (94.0% yield).

[0036] Preparation of compound 6:

[0037] To a 250 mL three-necked flask, add 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (10 g, 38.0 mmol), 1-(1-ethoxyethyl)-3-iodo-1H-pyrazole (10.1 g, 38.0 mmol), Pd(amphos)2Cl2 (1.3 g, 1.9 mmol), K2CO3 (15.7 g, 113.7 mmol), 60 mL of dioxane, and 40 mL of purified water. Replace the atmosphere with nitrogen three times, using a nitrogen blanket. Heat to reflux for 3 hours. Cool to 60°C, and remove the lower aqueous phase. Add 2 g of activated carbon to the organic phase and stir for 20 minutes. Filter, add 10 mL of concentrated hydrochloric acid to the organic phase, and stir at 25-30°C for 4 hours. Adjust the pH to 8-9 with 3M sodium hydroxide aqueous solution, add 10 mL of purified water, cool to 0-10°C, and crystallize for 2 h. Filter and dry the filter cake under reduced pressure to obtain 7.0 g of a white solid with a yield of 90.6%.

[0038] Example 2:

[0039] Preparation of compound 2:

[0040] To a 500mL three-necked flask, add 20g (92.4mmol) of 4-bromo-2-chlorobenzonitrile, 70.4g (277.2mmol) of pinacol diboron, 27.3g (278.0mmol) of potassium acetate, 0.7mmol of Pd(OAc)2 / PPh3, and acetonitrile. After nitrogen substitution three times, the mixture was heated to 90°C and kept warm for 3h. The temperature was then lowered to 20-30°C, 150mL of saturated brine was added, the mixture was stirred for 5 minutes, and the stratification was allowed to proceed. The organic phase was distilled under reduced pressure at 50°C, the residue evaporated to dryness, 60mL of ethanol was added, the mixture was heated with stirring until the solution became clear, the temperature was lowered to 20-30°C, and the mixture was stirred for 10h. The temperature was then lowered to 0-10°C and stirred for 2h to allow crystallization. The mixture was filtered, the filter cake was rinsed with a small amount of ethanol, and dried under reduced pressure to obtain 17.6g of a tan solid (yield 71.9%).

[0041] Preparation of compound 4:

[0042] To a 250 mL three-necked flask, add 3-iodopyrazole (5.0 g, 25.8 mmol) and acetonitrile (50 mL). Stir and then add triethylamine (6.8 g, 67.0 mmol), DMAP (0.3 g, 2.6 mmol), and Boc anhydride (5.9 g, 27.0 mmol). React at 20-30°C for 2 h. Distill under reduced pressure to remove most of the acetonitrile. Extract the mixture three times with 50 mL of water and 50 mL of ethyl acetate. Combine the organic phases and wash with saturated brine. Distill the organic phase under reduced pressure to obtain 7.5 g of the product as a gray solid, with a yield of 98.9%.

[0043] Preparation of compound 6:

[0044] To a 250 mL three-necked flask, add 7.21 g (27.4 mmol) of 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile, 7.3 g (27.4 mmol) of 1-(1-ethoxyethyl)-3-iodo-1H-pyrazole, 0.9 g (1.37 mmol) of Pd(amphos)2Cl2, 11.3 g (82.0 mmol) of Na2CO3, 60 mL of acetonitrile, and 40 mL of purified water. Replace the atmosphere with nitrogen three times, then heat to reflux for 3 hours. Cool to 60°C and remove the lower aqueous phase. Add 2 g of activated carbon to the organic phase and stir for 20 minutes. Filter the organic phase, add 10 mL of concentrated hydrochloric acid, and stir at 25-30°C for 4 hours. Adjust the pH to 8-9 with 3M sodium hydroxide aqueous solution, add 10 mL of purified water, cool to 0-10°C, and crystallize for 2 h. Filter and dry the filter cake under reduced pressure to obtain 5.1 g of a white solid, with a yield of 91.3%.

[0045] Example 3:

[0046] Preparation of compound 2:

[0047] To a 500mL three-necked flask, add 20g (92.4mmol) of 4-bromo-2-chlorobenzonitrile, 25.8g (101.6mmol) of pinacol diboronate, 27.3g (278.0mmol) of potassium acetate, 0.7mmol of Pd2(dba)3 / PCy3, and toluene. After nitrogen substitution three times, the mixture was heated to 90°C and kept for 3h. The mixture was cooled to 20-30°C, 150mL of purified water was added, and the mixture was stirred for 5 minutes. The organic phase was then allowed to stand for stratification. The organic phase was washed once with 150mL of purified water. The organic phase was then distilled under reduced pressure at 50°C, and the residue was evaporated to dryness. 60mL of ethanol was added, and the mixture was stirred and heated until the solution became clear. The mixture was cooled to 20-30°C and stirred for 10h. The mixture was then cooled to 0-10°C and stirred for 2h to allow crystallization. The mixture was filtered, the filter cake was rinsed with a small amount of ethanol, and dried under reduced pressure to obtain 17.7g of a tan solid (72.5% yield).

[0048] Preparation of compound 4:

[0049] To a 250 mL three-necked flask, add 5.0 g, 34.0 mmol, and 70 mL of dichloromethane. Stir under nitrogen. Then, add 3.0 g, 41.6 mmol of ethyl vinyl ether and 0.25 mL of 4M dioxane hydrochloride dropwise. Stir at room temperature for 4 hours. Add 20 mL of saturated sodium bicarbonate solution, stir, and allow to stand for stratification. The organic phase is distilled under reduced pressure to yield 7.15 g of a brown oil (95.9% yield).

[0050] Preparation of compound 6:

[0051] To a 250 mL three-necked flask, add 8.4 g (32.0 mmol) of 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile, 7.0 g (32.0 mmol) of 1-(1-ethoxyethyl)-3-bromo-1H-pyrazole, 1.1 g (1.6 mmol) of Pd(amphos)2Cl2, 13.2 g (95.7 mmol) of potassium carbonate, 60 mL of dioxane, and 40 mL of purified water. Replace the atmosphere with nitrogen three times, then heat to reflux and react for 3 hours. Cool to 60°C and remove the lower aqueous phase. Add 2 g of activated carbon to the organic phase and stir for 20 minutes. Filter the organic phase, add 10 mL of concentrated hydrochloric acid, and stir at 25-30°C for 4 hours. Adjust the pH to 8-9 with 3M sodium hydroxide aqueous solution, add 10 mL of purified water, cool to 0-10°C, and crystallize for 2 h. Filter and dry the filter cake under reduced pressure to obtain 4.8 g of a white solid, with a yield of 90.4%.

[0052] Example 4:

[0053] Preparation of compound 2:

[0054] To a 500mL three-necked flask, add 20g (92.4mmol) of 4-bromo-2-chlorobenzonitrile, 70.4g (277.2mmol) of pinacol diboron, 27.3g (278.0mmol) of potassium acetate, 0.8g (0.7mmol) of Pd(PPh3)4, and DMF. After nitrogen substitution three times, the temperature was raised to 50°C and kept for 3h. The temperature was then lowered to 20-30°C, 150mL of saturated brine was added, and the mixture was stirred and allowed to stand for separation. The organic phase was distilled under reduced pressure at 70°C, and the residue was evaporated to dryness. 80mL of ethanol was added, and the mixture was stirred and heated until the solution became clear. The temperature was then lowered to 20-30°C, stirred for 10h, and then cooled to 0-10°C, stirred, and crystallized for 2h. The mixture was filtered, the filter cake was rinsed with a small amount of ethanol, and dried under reduced pressure to obtain 17.6g of a tan solid (71.8% yield).

[0055] Preparation of compound 4:

[0056] To a 250 mL three-necked flask, add 4.2 g (41.2 mmol) of 3-chloro-1H-pyrazole and 80 mL of dichloromethane, stir under nitrogen. Add 13.9 g (49.9 mmol) of triphenylmethane, and dropwise add 0.3 mL of 4M dioxane hydrochloride. Stir and react at 20-30°C for 4 h. Add 20 mL of saturated sodium bicarbonate solution, stir for 5 minutes, and allow to stand for stratification. The organic phase is distilled under reduced pressure to yield 14.9 g of a light yellow liquid (95.3% yield).

[0057] Preparation of compound 6:

[0058] To a 250 mL three-necked flask, add 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzonitrile (12.1 g, 45.9 mmol), 1-(1-ethoxyethyl)-3-chloro-1H-pyrazole (10.1 g, 57.3 mmol), Pd(PPh3)4 (3.4 g, 2.9 mmol), Cs2CO3 (55.8 g, 171.4 mmol), 60 mL of DMF, and 40 mL of purified water. Replace the atmosphere with nitrogen three times, using a nitrogen blanket. Heat to reflux for 3 hours. Cool to 60°C, and remove the lower aqueous phase. Add 2 g of activated carbon to the organic phase and stir for 20 minutes. Filter, add 10 mL of concentrated hydrochloric acid to the organic phase, and stir at 25-30°C for 4 hours. Adjust the pH to 8-9 with 3M sodium hydroxide aqueous solution, add 10 mL of purified water, cool to 0-10°C, and crystallize for 2 h. Filter and dry the filter cake under reduced pressure to obtain 5.7 g of a white solid with a yield of 92.1%.

[0059] Example 5:

[0060] Preparation of compound 2:

[0061] To a 500mL three-necked flask, add 20g (92.4mmol) of 4-bromo-2-chlorobenzonitrile, 25.8g (73.92mmol) of pinacol diboron, 27.3g (278.0mmol) of potassium acetate, 0.7mmol of Pd(OAc)2 / PPh3, and DMF. After nitrogen substitution three times, the mixture was heated to 110°C and kept warm for 3h. The temperature was then lowered to 20-30°C, 150mL of saturated brine was added, the mixture was stirred for 5 minutes, and the stratification was allowed to proceed. The organic phase was distilled under reduced pressure at 70°C, the residue evaporated to dryness, 60mL of ethanol was added, the mixture was heated with stirring until the solution became clear, the temperature was lowered to 20-30°C, and the mixture was stirred for 10h. The temperature was then lowered to 0-10°C and stirred for 2h to allow crystallization. The mixture was filtered, the filter cake was rinsed with a small amount of ethanol, and dried under reduced pressure to obtain 13.8g of a tan solid (70.5% yield).

[0062] Preparation of compound 4:

[0063] To a 250 mL three-necked flask, add 8.0 g, 41.2 mmol, and 80 mL of dichloromethane. Stir under nitrogen. Add 3.6 g, 49.9 mmol of ethyl vinyl ether and dropwise add 0.3 mL of 4M dioxane hydrochloride. Stir and react at 20-30°C for 4 h. Add 20 mL of saturated sodium bicarbonate solution, stir for 5 minutes, and allow to stand for stratification. The organic phase is distilled under reduced pressure to yield 10.1 g of a light yellow liquid (92.0% yield).

[0064] Preparation of compound 6:

[0065] To a 250 mL three-necked flask, add 29.1 g (110.7 mmol) of 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzonitrile, 9.8 g (36.9 mmol) of 1-(1-ethoxyethyl)-3-iodo-1H-pyrazole, 1.8 mmol of Pd(OAc)2 / PPh3, 123.4 g (110.4 mmol) of K3PO4, 60 mL of acetonitrile, and 40 mL of purified water. Replace the atmosphere with nitrogen three times, then heat to reflux for 3 hours. Cool to 60°C and remove the lower aqueous phase. Add 2 g of activated carbon to the organic phase and stir for 20 minutes. Filter the organic phase, add 10 mL of concentrated hydrochloric acid, and stir at 25-30°C for 4 hours. Adjust the pH to 8-9 with 3M sodium hydroxide aqueous solution, add 10 mL of purified water, cool to 0-10°C, and crystallize for 2 h. Filter and dry the filter cake under reduced pressure to obtain 6.7 g of a white solid with a yield of 89.9%.

[0066] Example 6:

[0067] Preparation of compound 2:

[0068] To a 500mL three-necked flask, add 20g (92.4mmol) of 4-bromo-2-chlorobenzonitrile, 25.8g (101.6mmol) of pinacol diboronate, 27.3g (278.0mmol) of potassium acetate, 0.7mmol of Pd2(dba)3 / PCy3, and acetonitrile. After nitrogen substitution three times, the mixture was heated to 90°C and kept warm for 3h. The temperature was then lowered to 20-30°C, 150mL of saturated brine was added, and the mixture was stirred for 5 minutes. The mixture was then allowed to stand for stratification. The organic phase was distilled under reduced pressure at 50°C, and the residue was evaporated to dryness. 60mL of ethanol was added, and the mixture was stirred and heated until the solution became clear. The temperature was then lowered to 20-30°C, stirred for 10h, and then cooled to 0-10°C, where it was stirred and crystallized for 2h. The mixture was filtered, the filter cake was rinsed with a small amount of ethanol, and dried under reduced pressure to obtain 18.43g of a tan solid (75.2% yield).

[0069] Preparation of compound 4:

[0070] To a 250 mL three-necked flask, add 5.0 g, 34.0 mmol, and 70 mL of dichloromethane. Stir under nitrogen. Then, add 3.0 g, 41.6 mmol of ethyl vinyl ether and 0.25 mL of 4M dioxane hydrochloride dropwise. Stir at room temperature for 4 hours. Add 20 mL of saturated sodium bicarbonate solution, stir, and allow to stand for stratification. The organic phase is distilled under reduced pressure to yield 7.04 g of a brown oil (94.8% yield).

[0071] Preparation of compound 6:

[0072] To a 250 mL three-necked flask, add 18.04 g (68.6 mmol) of 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzonitrile, 5.0 g (22.85 mmol) of 1-(1-ethoxyethyl)-3-bromo-1H-pyrazole, 1.1 mmol of Pd2(dba)3 / PCy3, 7.3 g (113.7 mmol) of CsF1, 60 mL of acetonitrile, and 40 mL of purified water. Replace the atmosphere with nitrogen three times, then heat to reflux and react for 3 hours. Cool to 60°C and remove the lower aqueous phase. Add 2 g of activated carbon to the organic phase and stir for 20 minutes. Filter the organic phase, add 10 mL of concentrated hydrochloric acid, and stir at 25-30°C for 4 hours. Adjust the pH to 8-9 with 3M sodium hydroxide solution, add 10 mL of purified water, cool to 0-10°C, and crystallize for 2 h. Filter and dry the filter cake under reduced pressure to obtain 3.48 g of a white solid, with a yield of 91.2%.

[0073] Conclusion: The reagents used in the above-mentioned groups of examples are all conventional commercially available reagents and can be purchased through normal channels. From the recorded experimental operating conditions, the preparation method has mild conditions, the high temperature does not exceed 150°C, and is highly safe; it does not involve high pressure and is easy to operate; in all the crude product Primrose separation processes, only water washing and separation and low-temperature crystallization are required, which simplifies the traditional synthesis route, abandons column chromatography, a separation method that depends on the polarity of the substance, saves waiting time for column passing, and reduces process costs; the yields of the several routes involved are quite considerable, and are suitable for large-scale industrial production.

Claims

1. A method for synthesizing a darolamide intermediate, characterized in that: The synthetic route of this intermediate is as follows: X = Cl, Br, I; PG=Trt, Boc, EE The synthetic route comprises the following steps: a. Compound 1 is dissolved or dispersed in an organic solvent, protected by protective gas, in the presence of a palladium catalyst and an organic base, and the reaction temperature is controlled to synthesize compound 2 with pinacol diborate; b. Compound 3 reacts with an amine protecting reagent to generate compound 4; c. Compound 2 and compound 4 are dissolved or dispersed in an organic solvent under protective gas protection, in the presence of a palladium catalyst and an inorganic base, while controlling the reaction temperature, undergoing Suzuki coupling, and removing the protecting group to obtain compound 6, a darolamide intermediate.

2. The method for synthesizing the darolamide intermediate according to claim 1, wherein in step a, the organic base is potassium acetate and the reaction temperature is 50°C to 110°C.

3. The method for synthesizing a darolamide intermediate according to claim 1, wherein in step a, the organic solvent is toluene, dioxane, acetonitrile or DMF; the palladium catalyst comprises at least one of Pd(dppf)Cl2, Pd(OAc)2 / PPh3, Pd2(dba)3 / PCy3 or Pd(PPh3)4; and the equivalent ratio of diboronic acid pinacol ester to compound 1 is 0.8 to 3.0:

1.

4. The method for synthesizing the darolamide intermediate according to claim 1, wherein in step b, the amine protecting reagent is at least one of Boc anhydride, vinyl ethyl ether or triphenylmethane.

5. The method for synthesizing the darolamide intermediate according to claim 1, wherein in step c, the organic solvent comprises at least one of dioxane, acetonitrile or DMF; the palladium catalyst comprises at least one of Pd(dppf)Cl2, Pd(OAc)2 / PPh3, Pd2(dba)3 / PCy3, Pd(amphos)2Cl2 or Pd(PPh3)4; and the equivalent ratio of compound 2 to compound 4 is 0.8~3.0:

1.

6. The method for synthesizing the darolamide intermediate according to claim 1, wherein in step c, the inorganic base is K2CO3, K3PO4, Na2CO3, CsF or Cs2CO3, and the reaction temperature is 50°C to 110°C.

Images