An N-(3-benzene) 10 Preparation method of boric acid-L-aspartic acid intermediate

Abstract

This invention relates to the field of boron neutron capture therapy (BNCT), specifically to an N-(3-benzene) 10 A method for preparing an intermediate of N-(3-benzene)-L-aspartic acid. This intermediate has the structure of Formula I, as defined herein. The method for preparing the Formula I compound includes the following steps: under an inert gas atmosphere, in the presence of a palladium catalyst and a base, a Formula II compound reacts with a borizing agent in an organic solvent to obtain the Formula I compound. The yield of the Formula I compound obtained by this method is as high as 95.71%, avoiding the Grignard low-temperature reaction, reducing the process difficulty, and enabling the realization of N-(3-benzene)-L-aspartic acid. 10 Industrial production of boric acid-L-aspartic acid.

Description

Technical Field

[0001] This invention relates to the field of boron neutron capture therapy (BNCT), specifically to an N-(3-benzene) 10 Method for preparing intermediates of boric acid-L-aspartic acid. Background Technology

[0002] In recent years, boron neutron capture therapy (BNCT) has become an attractive treatment option for cancer, particularly for malignant tumors, as it selectively kills tumor cells using boron-containing drugs while preserving normal cells. Specifically, BNCT is a novel radiotherapy based on neutron capture and boron fission reactions. This treatment method consists of two independent steps: first, the boron-containing drug is externally injected and enriched in tumor cells; then, through neutron irradiation, boron captures neutrons and undergoes nuclear fission, producing high-energy... 4 He 2 +(alpha particles) and 7 Li 3 +, thereby releasing gamma rays within a killing range (5-9µm) of tumor cells. Compared with traditional chemotherapy and radiotherapy, BNCT has several advantages: 1) The gamma ray range is small (5-9µm), killing only boron-containing cells without damaging surrounding tissues; 2) There is no radiation resistance effect on hypoxic cells; 3) It avoids the multidrug resistance phenomenon of chemotherapy and targeted drugs.

[0003] Although the concept of BNCT (Bipolar Noncompatibility Therapy) is well-known, technological limitations associated with this type of treatment have slowed its development, with the primary barrier being the lack of ideal boron-containing reagents. Ideal boron-containing reagents should possess the following characteristics: high intratumoral enrichment concentration, high selectivity (biodistribution in vivo with a tumor tissue / blood (T / B) concentration ratio ≥3 and a tumor tissue / normal tissue (T / N) concentration ratio ≥3), and low systemic toxicity, among others. Looking at the current development history of boron-containing reagents, there are mainly three generations. The first generation of boron-containing reagents consisted of boric acid and its derivatives, which were first used in clinical trials in the 1950s and 1960s. These were basic compounds, but lacked tumor differentiation and had low specificity. Subsequently, second-generation boron-containing reagents were developed, mainly including low-molecular-weight boron compounds such as undecylhydrazine disodium dodecoboride (BSH) and boron p-dihydroxyphenylalanine (BPA). Although their performance has been greatly improved compared with the first-generation boron-containing reagents, and BPA has been approved for marketing and BSH has been approved for clinical trials, they still cannot meet the requirements of BNCT. Their retention time in tumor cells is short and their selectivity is low (T / B and T / N concentration ratios can only reach >1), so the effect of treating tumors is not very ideal.

[0004] The applicant has successfully developed a series of novel ASCT2-targeting compounds. 10 Boron compounds exhibit high targeting specificity for ASCT2-directed therapy and show efficacy in tumors. 10 The high concentration of boron enhances the therapeutic effect of BNCT. This series contains... 10 Boron compounds include N-(3-benzene) 10 Boric acid)-L-aspartic acid, as shown in Formula III, the present invention aims to provide an N-(3-phenyl) 10 Preparation method of boric acid-L-aspartic acid intermediate.

[0005] Summary of the Invention

[0006] This invention provides an N-(3-benzene) 10 A method for preparing a boric acid-L-aspartic acid intermediate, which has the structure of formula I.

[0007] The preparation method includes the following steps: in an inert gas atmosphere, under the action of a palladium catalyst and a base, the compound of formula II reacts with a boriding agent in an organic solvent to obtain the compound of formula I;

[0008]

[0009] in:

[0010] Hal is either I or Br;

[0011] Boring agent Boring agent is for R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 Each is independently selected from hydrogen or C1-C4 alkyl; R 11 It is a C1-C5 alkyl group, such as methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, isobutyl, pentyl, etc.

[0012] In some implementation schemes, for R1, R2, R3, and R4 are each independently selected from hydrogen or methyl, with R1, R2, R3, and R4 preferably being methyl.

[0013] The alkali used in the preparation method of the present invention is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium acetate, sodium methoxide, sodium acetate, cesium acetate, cesium carbonate, or potassium carbonate; in some embodiments, cesium carbonate is preferred.

[0014] In some embodiments, the molar ratio of the strong base to the compound of formula II is (2-5):1, preferably 3:1.

[0015] The palladium catalyst used in the preparation method of this invention is selected from any one of Pd2(dba)3, Pd(PPh3)4, PdCl2(PPh3)2, PdCl2, Pd(OAc)2, and Pd(dppf)Cl2; in some embodiments, Pd(dppf)Cl2 is preferred.

[0016] In some embodiments, the molar ratio of the palladium catalyst to the compound of formula II is (0.01-0.1):1; preferably 0.03:1.

[0017] The organic solvent used in the preparation method of this invention is a single solvent or a mixed solvent, and the volume-to-mass ratio of the organic solvent to the compound of formula II is 5-20 mL / g. The single solvent is selected from methanol, toluene, dimethyl sulfoxide, tetrahydrofuran, dioxane, and N,N-dimethylformamide; the mixed solvent is selected from toluene-dimethyl sulfoxide, toluene-dioxane, and toluene-N,N-dimethylformamide, and the volume ratio of toluene to the other solvent in the mixed solvent is (500-100):1, preferably (100-300):1, and more preferably 200:1. In some embodiments, the organic solvent is preferably a toluene-dimethyl sulfoxide mixed solvent.

[0018] The reaction temperature in the preparation method of the present invention is 90-120℃ and the reaction time is 3-8h; in some embodiments, the reaction temperature is preferably 100℃ and the reaction time is 5h.

[0019] In some embodiments, the compound of formula I has the following structure:

[0020]

[0021] In some embodiments, the boriding agent has the following structure:

[0022]

[0023]

[0024]

[0025] The following structure is preferred:

[0026]

[0027]

[0028] The compound of formula I obtained by the preparation method of this invention can be condensed with aspartic acid compound IV under the action of onium salt condensing agents (such as HBTU, TBTU, HATU, etc.) and organic bases (triethylamine, diisopropylethylamine, N-methylmorpholine, etc.) to obtain compound V. Compound V is then deprotected to obtain compound III, namely N-(3-benzene) 10 Boric acid)-L-aspartic acid.

[0029]

[0030] Compared with the prior art, the present invention has the following beneficial effects: The N-(3-benzene) provided by the present invention 10 The method for preparing the boric acid-L-aspartic acid intermediate features high yield, avoids Grignard low-temperature reactions, reduces process difficulty, and enables the realization of N-(3-phenylene)-L-aspartic acid intermediates. 10 Industrial production of boric acid-L-aspartic acid. Detailed Implementation

[0031] To better understand the technical solution of the present invention, the technical solution of the present invention will be further described below with reference to specific embodiments. The embodiments are only for the purpose of helping to understand the present invention and should not be regarded as specific limitations of the present invention.

[0032] All boron in the boron-containing compounds involved in this invention are... 10 boron.

[0033] Unless otherwise specified, other reagents and solvents used in this invention can be prepared by conventional methods or purchased commercially.

[0034] Boring agent It can be prepared by using BF3·OEt2 as a raw material through a series of reactions as shown below:

[0035]

[0036] in, The definition is the same as the one described above.

[0037] Boring agent It can be obtained by esterification and transesterification of boric acid, as shown in the following preparation method:

[0038]

[0039] in, The definition is the same as the one described above.

[0040] Example 1: Preparation of Compound 5

[0041]

[0042] 4.80 g m-bromoaniline, 18.52 g cesium carbonate, 7.92 g pinacol diborate, 0.60 g Pd(dppf)Cl2, 50 mL toluene, and 0.1 mL DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was then purified by preparative chromatography (column: WelFlash C18-I (20-40 μm); methanol and water gradient elution) to give 5.29 g of compound 5 (ESI-MS: [M+H)). + =219.14), yield 86.85%.

[0043] Example 2: Preparation of Compound 5

[0044] 4.80 g m-bromoaniline, 18.52 g cesium carbonate, 7.92 g pinacol diborate, 0.60 g Pd(dppf)Cl2, 50 mL toluene, and 0.25 mL DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was purified by preparative chromatography to obtain 5.65 g of compound 5, with a yield of 92.76%.

[0045] Example 3: Preparation of Compound 5

[0046] 4.80 g m-bromoaniline, 18.52 g cesium carbonate, 7.92 g pinacol diborate, 0.60 g Pd(dppf)Cl2, 50 mL toluene, and 0.5 mL DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The product was purified by preparative chromatography to obtain 5.41 g of compound 5, with a yield of 88.81%.

[0047] Example 4: Preparation of Compound 5

[0048] 4.80 g m-bromoaniline, 18.52 g cesium carbonate, 7.92 g pinacol diborate, 0.60 g Pd(dppf)Cl2, 50 mL toluene, and 0.17 mL DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. Preparative chromatography and purification yielded 5.52 g solid compound 5, with a yield of 90.62%.

[0049] Example 5: Preparation of Compound 5

[0050] 4.80 g m-bromoaniline, 18.52 g cesium carbonate, 7.92 g pinacol diborate, 2.00 g Pd(dppf)Cl2, 50 mL toluene, and 0.25 mL DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The product was purified by preparative chromatography to obtain 5.59 g of compound 5, with a yield of 91.77%.

[0051] Example 6: Preparation of Compound 5

[0052] 4.80 g of m-bromoaniline, 18.52 g of cesium carbonate, 7.92 g of pinacol diborate, 0.24 g of Pd(dppf)Cl2, 50 mL of toluene, and 0.25 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was purified by preparative chromatography to obtain 5.46 g of compound 5, with a yield of 89.64%.

[0053] Example 7: Preparation of Compound 5

[0054] 4.80 g m-bromoaniline, 44.85 g cesium carbonate, 7.92 g pinacol diborate, 0.60 g Pd(dppf)Cl2, 50 mL toluene, and 0.25 mL DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was purified by preparative chromatography to obtain 5.32 g of compound 5, with a yield of 87.34%.

[0055] Example 8: Preparation of Compound 5

[0056] 4.80 g m-bromoaniline, 27.50 g cesium carbonate, 7.92 g pinacol diborate, 0.60 g Pd(dppf)Cl2, 50 mL toluene, and 0.25 mL DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was purified by preparative chromatography to obtain 5.83 g of compound 5, with a yield of 95.71%.

[0057] Example 9: Preparation of Compound 5

[0058] 4.80 g of m-bromoaniline, 27.50 g of cesium carbonate, 7.92 g of pinacol diborate, 0.60 g of Pd(dppf)Cl2, and 50 mL of toluene were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The product was purified by preparative chromatography to obtain 4.92 g of compound 5, with a yield of 80.77%.

[0059] Example 10: Preparation of Compound 5

[0060] 4.80 g of m-bromoaniline, 8.15 g of potassium acetate, 7.92 g of pinacol diborate, 0.60 g of Pd(dppf)Cl2, and 50 mL of toluene were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was purified by preparative chromatography to obtain 5.08 g of compound 5, with a yield of 83.40%.

[0061] Example 11: Preparation of Compound 5

[0062] 4.80 g m-bromoaniline, 8.15 g potassium acetate, 7.92 g pinacol diboronate, 0.60 g Pd(dppf)Cl2, 50 mL toluene, and 0.25 mL DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was purified by preparative chromatography to obtain 5.64 g of compound 5, with a yield of 92.59%.

[0063] Example 12: Preparation of Compound 5

[0064] 4.80 g m-bromoaniline, 16.3 g cesium acetate, 7.92 g pinacol diborate, 0.60 g Pd(dppf)Cl2, 50 mL toluene, and 0.25 mL DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The product was purified by preparative chromatography to obtain 5.47 g of compound 5, with a yield of 89.80%.

[0065] Example 13: Preparation of Compound 5

[0066] 4.80 g of m-bromoaniline, 16.3 g of cesium acetate, 7.92 g of pinacol diborate, 0.60 g of Pd(dppf)Cl2, and 50 mL of toluene were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The product was purified by preparative chromatography to obtain 4.40 g of compound 5, with a yield of 72.24%.

[0067] Example 14: Preparation of Compound 5

[0068] 4.80 g of m-bromoaniline, 27.5 g of cesium carbonate, 7.92 g of pinacol diborate, 0.60 g of Pd(dppf)Cl2, 25 mL of toluene, and 0.12 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was purified by preparative chromatography to obtain 5.45 g of compound 5, with a yield of 89.48%.

[0069] Example 15: Preparation of Compound 5

[0070] 4.80 g m-bromoaniline, 27.5 g cesium carbonate, 7.92 g pinacol diborate, 0.60 g Pd(dppf)Cl2, 100 mL toluene, and 0.5 mL DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The product was purified by preparative chromatography to obtain 5.63 g of compound 5, with a yield of 92.43%.

[0071] Example 16: Preparation of Compound 5

[0072] 4.80 g m-bromoaniline, 27.5 g cesium carbonate, 7.92 g pinacol diborate, 0.60 g Pd(dppf)Cl2, 50 mL toluene, and 0.25 mL DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 90 °C for 8 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The product was purified by preparative chromatography to obtain 5.42 g of compound 5, with a yield of 88.98%.

[0073] Example 17: Preparation of Compound 5

[0074] 4.80 g m-bromoaniline, 27.5 g cesium carbonate, 7.92 g pinacol diborate, 0.60 g Pd(dppf)Cl2, 50 mL toluene, and 0.25 mL DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 120 °C for 3 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was purified by preparative chromatography to obtain 5.34 g of compound 5, with a yield of 87.67%.

[0075] Example 18: Preparation of Compound 5

[0076] 4.80 g of m-bromoaniline, 27.5 g of cesium carbonate, 7.92 g of pinacol diborate, 0.6 g of Pd(dppf)Cl2, 50 mL of toluene, and 0.25 mL of DMF were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was purified by preparative chromatography to obtain 5.58 g of compound 5, with a yield of 91.61%.

[0077] Example 19: Preparation of Compound 5

[0078] 4.80 g of m-bromoaniline, 27.5 g of cesium carbonate, 7.92 g of pinacol diborate, 0.60 g of Pd(dppf)Cl2, 50 mL of toluene, and 0.25 mL of 1,4-dioxane were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was purified by preparative chromatography to obtain 5.40 g of compound 5, with a yield of 88.65%.

[0079] Example 20: Preparation of Compound 5

[0080] 6.14 g of m-iodoaniline, 27.5 g of cesium carbonate, 7.92 g of pinacol diborate, 0.60 g of Pd(dppf)Cl2, 60 mL of toluene, and 0.3 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 60 mL of water was added, and the mixture was extracted with ethyl acetate (60 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was purified by preparative chromatography to obtain 5.66 g of compound 5, with a yield of 92.49%.

[0081] Example 21: Preparation of Compound 2

[0082]

[0083] 4.80 g m-bromoaniline, 27.5 g cesium carbonate, 7.01 g neopentyl glycol diboronate, 0.60 g Pd(dppf)Cl2, 50 mL toluene, and 0.25 mL DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was then purified by preparative chromatography (column: WelFlash C18-I (20-40 μm); methanol and water gradient elution) to give 5.31 g of compound 2 (ESI-MS: [M+H)). + =205.13), yield 93.16%.

[0084] Example 22: Preparation of Compound 7

[0085]

[0086] 4.80 g of m-bromoaniline, 27.5 g of cesium carbonate, 4.47 g of 1,3-propanediol isopropylboronic acid, 0.60 g of Pd(dppf)Cl2, 50 mL of toluene, and 0.25 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was then purified by preparative chromatography (column: WelFlash C18-I (20-40 μm); methanol and water gradient elution) to obtain 4.50 g of compound 7 (ESI-MS: [M+H)). + =177.10), yield 91.52%.

[0087] Example 23: Preparation of Compound 6

[0088]

[0089] 4.80 g m-bromoaniline, 27.5 g cesium carbonate, 4.03 g 2-isopropoxy-1,3,2-dioxaborane, 0.60 g Pd(dppf)Cl2, 50 mL toluene, and 0.25 mL DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was then purified by preparative chromatography (column: WelFlash C18-I (20-40 μm); methanol and water gradient elution) to give 4.14 g of compound 6 (ESI-MS: [M+H)). + =163.08), yield 91.48%.

[0090] Example 24: Preparation of Compound 1

[0091]

[0092] 4.80 g of m-bromoaniline, 27.5 g of cesium carbonate, 6.14 g of 4,4',5,5'-tetramethyl-2,2'-bi-1,3,2-dioxoboronylcyclopentane, 0.60 g of Pd(dppf)Cl2, 50 mL of toluene, and 0.25 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was then purified by preparative chromatography (column: WelFlash C18-I (20-40 μm); methanol and water gradient elution) to obtain 4.98 g of compound 1 (ESI-MS: [M+H)). + =191.11), yield 93.81%.

[0093] Example 25: Preparation of Compound 3

[0094]

[0095] 4.80 g m-bromoaniline, 27.5 g cesium carbonate, 7.88 g bis(2-methyl-2,4-pentanediol)borate, 0.60 g Pd(dppf)Cl2, 50 mL toluene, and 0.25 mL DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was then purified by preparative chromatography (column: WelFlash C18-I (20-40 μm); methanol and water gradient elution) to give 5.53 g of compound 3 (ESI-MS: [M+H)). + =219.14), yield 90.79%.

[0096] Example 26: Preparation of Compound 4

[0097]

[0098] 4.80 g m-bromoaniline, 27.5 g cesium carbonate, 8.75 g bis(2,4-dimethyl-2,4-pentanediol)borate, 0.60 g Pd(dppf)Cl2, 50 mL toluene, and 0.25 mL DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was then purified by preparative chromatography (column: WelFlash C18-I (20-40 μm); methanol and water gradient elution) to give 5.94 g of compound 4 (ESI-MS: [M+H)). + =233.16), yield 91.63%.

[0099] Example 27: Preparation of Compound 8

[0100]

[0101] 4.80 g of m-bromoaniline, 27.5 g of cesium carbonate, 6.21 g of 4,6-dimethyl-2-(1-methylbutoxy)-1,3,2-dioxoboronide, 0.60 g of Pd(dppf)Cl2, 50 mL of toluene, and 0.25 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated NaCl (40 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was then purified by preparative chromatography (column: WelFlash C18-I (20-40 μm); gradient elution with methanol and water) to obtain 4.21 g of compound 8 (ESI-MS: [M+H)). + =205.13), yield 91.41%.

Claims

1. A method for preparing a compound of formula I, characterized in that, The process includes the following steps: in an inert gas atmosphere, under the action of a palladium catalyst and a base, the compound of formula II reacts with a borizing agent in an organic solvent to obtain the compound of formula I; Where Hal is I or Br; The boriding agent is for R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 Each is independently selected from hydrogen or C1-C4 alkyl, R 11 It is a C1-C5 alkyl group; The palladium catalyst is Pd(dppf)Cl2.

2. The preparation method according to claim 1, characterized in that, The for R1, R2, R3, and R4 are each independently selected from hydrogen or methyl.

3. The preparation method according to claim 2, characterized in that, R1, R2, R3, and R4 are all methyl groups.

4. The preparation method according to claim 1, characterized in that, The boriding agent is selected from the following structures:

5. The preparation method according to claim 1, characterized in that, The alkali is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium acetate, sodium methoxide, sodium acetate, cesium acetate, cesium carbonate, or potassium carbonate.

6. The preparation method according to claim 5, characterized in that, The alkali is cesium carbonate.

7. The preparation method according to claim 1, characterized in that, The volume-to-mass ratio of the organic solvent to the compound of formula II is 5-20 mL / g, and the organic solvent is a mixed solvent; the mixed solvent is selected from toluene-dimethyl sulfoxide, toluene-dioxane, and toluene-N,N-dimethylformamide, and the volume ratio of the two solvents in the mixed solvent is (500-100):

1.

8. The preparation method according to claim 7, characterized in that, The volume ratio of the two solvents in the mixed solvent is (100-300):

1.

9. The preparation method according to claim 8, characterized in that, The volume ratio of the two solvents in the mixed solvent is 200:

1.

10. The preparation method according to claim 1, characterized in that, The reaction temperature is 90-120℃, and the reaction time is 3-8h.

11. The preparation method according to claim 1, characterized in that, The molar ratio of the compound of formula II to the borizing agent is 1:(1-1.2).

12. The preparation method according to claim 1, characterized in that, The molar ratio of the palladium catalyst to the compound of formula II is (0.01-0.1):

1.

13. The preparation method according to claim 12, characterized in that, The molar ratio of the palladium catalyst to the compound of formula II is 0.03:

1.

14. The preparation method according to claim 1, characterized in that, The molar ratio of the base to the compound of formula II is (2-5):

1.

15. The preparation method according to claim 14, characterized in that, The molar ratio of the base to the compound of formula II is 3:1.

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