An N-(3-phen 10 boronic acid)-L-aspartate intermediate and a process for preparing the same

Abstract

The present application relates to the field of boron neutron capture therapy (BNCT), and particularly relates to an intermediate of N-(3-phenyl 10 boronic acid)-L-aspartic acid and a preparation method thereof. The intermediate has a structure of formula I, R1 and R2 are as defined herein. The preparation method of the compound of formula I comprises the following steps: reacting a compound of formula II with a boronizing agent in an organic solvent under the action of a palladium catalyst and a base in an inert gas atmosphere to obtain the compound of formula I. The yield of the compound of formula I obtained by the preparation method is as high as 94.74%, the Grignard low-temperature reaction is avoided, the process difficulty is reduced, and the industrial production of N-(3-phenyl 10 boronic acid)-L-aspartic acid can be realized.

Description

Technical Field

[0001] This invention relates to the field of boron neutron capture therapy (BNCT), specifically to an N-(3-benzene) 10 Boric acid)-L-aspartic acid intermediate and its preparation method. 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 Boric acid-L-aspartic acid intermediate and its preparation method.

[0005] Summary of the Invention

[0006] The first aspect of the present invention provides an N-(3-benzene) 10 Boric acid)-L-aspartic acid intermediate, said intermediate having the structure of formula I:

[0007]

[0008] in:

[0009] R1 is selected from hydrogen or a carboxyl protecting group, wherein the carboxyl protecting group is selected from one of C1-C6 alkyl, Bzl or Trt, and preferably the carboxyl protecting group is selected from C1-C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, primary butyl and tert-butyl; more preferably tert-butyl.

[0010] R2 is selected from hydrogen or an amino protecting group, wherein the amino protecting group is selected from one of Cbz, Boc, tBu, Ac, MOB, PMB, DMB, Teoc, Moc, Eoc or Trt, preferably Boc or Cbz.

[0011] for R3, R4, R5, R6, R7, R8, R9, R 10 R 11 and R 12 Each is independently selected from hydrogen or C1-C4 alkyl; the C1-C4 alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl or isobutyl.

[0012] In some implementations, the for R3, R4, R5, and R6 are each independently selected from hydrogen or methyl, with R3, R4, R5, and R6 preferably being methyl.

[0013] In some embodiments, the compound of formula I preferably has the following structure:

[0014]

[0015]

[0016] The definitions of R1 and R2 are the same as those described above.

[0017] In some embodiments, the compound of formula I is specifically selected from the following structures:

[0018]

[0019]

[0020] The second aspect of the present invention provides a method for preparing the above-mentioned intermediate: in an inert gas atmosphere, under the action of a palladium catalyst and a base, the compound shown in Formula II reacts with a boriding agent in an organic solvent to obtain the compound shown in Formula I;

[0021]

[0022] Where: Hal is I or Br, R1, R2, and The definition is the same as the one described above;

[0023] The boriding agent mentioned in the above preparation method is The definition is the same as the one mentioned above, R 13 It is a C1-C5 alkyl group, such as methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, isobutyl, preferably isopropyl or isobutyl.

[0024] The alkali used in the above preparation method 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.

[0025] In some embodiments, the molar ratio of the strong base to the compound of formula II is (2-5):1, preferably 3:1.

[0026] The palladium catalyst used in the above preparation method 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.

[0027] 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.

[0028] The organic solvent used in the above preparation method 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.

[0029] The reaction temperature described in the above preparation method is 90-120℃, and the reaction time is 5-10h; in some embodiments, the reaction temperature is preferably 100℃ and the reaction time is 8h.

[0030] In some embodiments, the boriding agent has the following structure:

[0031]

[0032]

[0033] The following structure is preferred:

[0034]

[0035] The compound of formula I described in this invention can be prepared into compound of formula III by deprotection reaction under suitable conditions.

[0036]

[0037] Definitions and Explanations:

[0038] In this specification, Teoc, Cbz, and Boc refer to structures having the following formula:

[0039]

[0040] 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. Attached Figure Description

[0041] Figure 1 Compound III prepared in Example 34 1 H NMR spectrum.

[0042] Figure 2 The HPLC spectrum of compound III prepared in Example 34 is shown. Detailed Implementation

[0043] 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.

[0044] All boron in the boron-containing compounds involved in this invention are... 10 boron.

[0045] Unless otherwise specified, other reagents and solvents used in this invention can be prepared by conventional methods or purchased commercially.

[0046] Boring agent It can be prepared by using BF3·OEt2 as a raw material through a series of reactions shown in the figure below:

[0047]

[0048] in, The definition is the same as the one described above.

[0049] Boring agent It can be obtained by esterification and transesterification of boric acid, as shown in the figure below:

[0050]

[0051] in, The definition is the same as the one described above.

[0052] The compound of formula II described in the above preparation method can be obtained by condensation of compound IV and compound V under the action of onium salt condensing agents (such as HBTU, TBTU, HATU, etc.) and organic bases (triethylamine, diisopropylethylamine, N-methylmorpholine, etc.):

[0053]

[0054] Where Hal is I or Br, R1, R2 and The definition is the same as the one described above.

[0055] Example 1:

[0056] Preparation of compound II-1

[0057]

[0058] 5.0 g of 3-iodoaniline, 7.26 g of N-tert-butyloxycarbonyl-L-aspartic acid-1-tert-butyl ester, 9.54 g of HATU, 3.0 mL of triethylamine, and 30 mL of acetonitrile were added to a reaction flask, and the mixture was reacted at 50 °C for 5 h. After the reaction was completed, 50 mL of water was added, and the mixture was combined with ethyl acetate (50 mL × 2). The organic phases were dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The solution was then purified by preparative chromatography to obtain 4.99 g of compound II-1 (ESI-MS: [M+H)). + =491.10).

[0059] Example 2

[0060] Preparation of compound II-2

[0061]

[0062] 5.0 g of 3-bromoaniline, 10.38 g of N-benzyloxycarbonyl-L-aspartic acid-1-tert-butyl ester, 9.54 g of HATU, 3.0 mL of triethylamine, and 30 mL of acetonitrile were added to a reaction flask, and the mixture was reacted at 50 °C for 5 h. After the reaction was completed, 50 mL of water was added, and the mixture was combined with ethyl acetate (50 mL × 2). The organic phases were dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The solution was then purified by preparative chromatography to obtain 6.64 g of compound II-2 (ESI-MS: [M+H)). + =477.09).

[0063] Example 3

[0064] Preparation of compound II-3

[0065]

[0066] 5.0 g of 3-bromoaniline, 10.36 g of N-tert-butyloxycarbonyl-L-aspartic acid-1-benzyl ester, 9.54 g of HATU, 3.0 mL of triethylamine, and 30 mL of acetonitrile were added to a reaction flask, and the mixture was reacted at 50 °C for 5 h. After the reaction was completed, 50 mL of water was added, and the mixture was combined with ethyl acetate (50 mL × 2). The organic phases were dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The solution was then purified by preparative chromatography to obtain 7.11 g of compound II-3 (ESI-MS: [M+H)). + =477.09).

[0067] Example 4

[0068] Preparation of compound II-4

[0069]

[0070] 3.93 g of 3-bromoaniline, 7.25 g of N-tert-butyloxycarbonyl-L-aspartic acid-1-tert-butyl ester, 9.54 g of HATU, 3.0 mL of triethylamine, and 30 mL of acetonitrile were added to a reaction flask, and the mixture was reacted at 50 °C for 5 h. After the reaction was completed, 50 mL of water was added, and the mixture was combined with ethyl acetate (50 mL × 2). The organic phases were dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The solution was then purified by preparative chromatography to obtain 5.11 g of compound II-4 (ESI-MS: [M+H)). + =443.11).

[0071] Example 5: Preparation of Compound 5

[0072]

[0073] 5.40 g of compound II-4, 8.1 g of cesium carbonate, 3.58 g of pinacol diborate, 0.26 g of Pd(dppf)Cl2, 55 mL of toluene, and 0.11 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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 mixture was then purified by preparative chromatography (column: WelFlash C18-I (20-40 μm); gradient elution with methanol and water) to give 5.15 g of compound 5 (ESI-MS: [M+H)). + =490.29), yield 86.36%.

[0074] Example 6

[0075] 5.40 g of compound II-4, 8.1 g of cesium carbonate, 3.58 g of pinacol diborate, 0.26 g of Pd(dppf)Cl2, 55 mL of toluene, and 0.28 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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 mixture was purified by preparative chromatography to obtain 5.45 g of compound 5, with a yield of 91.39%.

[0076] Example 7

[0077] 5.40 g of compound II-4, 8.1 g of cesium carbonate, 3.58 g of pinacol diborate, 0.26 g of Pd(dppf)Cl2, 55 mL of toluene, and 0.55 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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 mixture was purified by preparative chromatography to obtain 5.22 g of compound 5, with a yield of 87.53%.

[0078] Example 8

[0079] 5.40 g of compound II-4, 8.1 g of cesium carbonate, 3.58 g of pinacol diborate, 0.26 g of Pd(dppf)Cl2, 55 mL of toluene, and 0.18 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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. Preparative chromatography was used to purify the mixture to obtain 5.26 g of solid compound 5, with a yield of 88.20%.

[0080] Example 9

[0081] 5.40 g of compound II-4, 8.1 g of cesium carbonate, 3.58 g of pinacol diborate, 0.9 g of Pd(dppf)Cl2, 55 mL of toluene, and 0.28 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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 mixture was purified by preparative chromatography to obtain 5.41 g of compound 5, with a yield of 90.72%.

[0082] Example 10

[0083] 5.40 g of compound II-4, 8.1 g of cesium carbonate, 3.58 g of pinacol diborate, 0.1 g of Pd(dppf)Cl2, 55 mL of toluene, and 0.28 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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 mixture was purified by preparative chromatography to obtain 5.36 g of compound 5, with a yield of 89.88%.

[0084] Example 11

[0085] 5.40 g of compound II-4, 19.85 g of cesium carbonate, 3.58 g of pinacol diborate, 0.26 g of Pd(dppf)Cl2, 55 mL of toluene, and 0.28 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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 mixture was purified by preparative chromatography to obtain 5.18 g of compound 5, with a yield of 86.86%.

[0086] Example 12

[0087] 5.40 g of compound II-4, 11.82 g of cesium carbonate, 3.58 g of pinacol diborate, 0.26 g of Pd(dppf)Cl2, 55 mL of toluene, and 0.28 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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 mixture was purified by preparative chromatography to obtain 5.66 g of compound 5, with a yield of 94.74%.

[0088] Example 13

[0089] 5.40 g of compound II-4, 11.82 g of cesium carbonate, 3.58 g of pinacol diborate, 0.26 g of Pd(dppf)Cl2, and 55 mL of toluene were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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 mixture was purified by preparative chromatography to obtain 4.70 g of compound 5, with a yield of 78.88%.

[0090] Example 14

[0091] 5.40 g of compound II-4, 3.60 g of potassium acetate, 3.58 g of pinacol diborate, 0.26 g of Pd(dppf)Cl2, and 55 mL of toluene were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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 mixture was purified by preparative chromatography to obtain 4.90 g of compound 5, with a yield of 82.17%.

[0092] Example 15

[0093] 5.40 g of compound II-4, 3.60 g of potassium acetate, 3.58 g of pinacol diborate, 0.26 g of Pd(dppf)Cl2, 55 mL of toluene, and 0.28 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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 mixture was purified by preparative chromatography to obtain 5.48 g of compound 5, with a yield of 91.89%.

[0094] Example 16

[0095] 5.40 g of compound II-4, 7.0 g of cesium acetate, 3.58 g of pinacol diborate, 0.26 g of Pd(dppf)Cl2, 55 mL of toluene, and 0.28 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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 mixture was purified by preparative chromatography to obtain 5.27 g of compound 5, with a yield of 88.37%.

[0096] Example 17

[0097] 5.40 g of compound II-4, 7.0 g of cesium acetate, 3.58 g of pinacol diborate, 0.26 g of Pd(dppf)Cl2, and 55 mL of toluene were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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 mixture was purified by preparative chromatography to obtain 4.1 g of compound 5, with a yield of 68.75%.

[0098] Example 18

[0099] 5.40 g of compound II-4, 11.82 g of cesium carbonate, 3.58 g of pinacol diborate, 0.26 g of Pd(dppf)Cl2, 30 mL of toluene, and 0.15 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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 mixture was purified by preparative chromatography to obtain 5.28 g of compound 5, with a yield of 88.54%.

[0100] Example 19

[0101] 5.40 g of compound II-4, 11.82 g of cesium carbonate, 3.58 g of pinacol diborate, 0.26 g of Pd(dppf)Cl2, 100 mL of toluene, and 0.5 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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 mixture was purified by preparative chromatography to obtain 5.46 g of compound 5, with a yield of 91.56%.

[0102] Example 20

[0103] 5.40 g of compound II-4, 11.82 g of cesium carbonate, 3.58 g of pinacol diborate, 0.26 g of Pd(dppf)Cl2, 55 mL of toluene, and 0.28 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 120 °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 5.23 g of compound 5, with a yield of 87.70%.

[0104] Example 21

[0105] 5.40 g of compound II-4, 11.82 g of cesium carbonate, 3.58 g of pinacol diborate, 0.26 g of Pd(dppf)Cl2, 55 mL of toluene, and 0.28 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 90 °C for 10 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 5.17 g of compound 5, with a yield of 86.70%.

[0106] Example 22

[0107] 5.40 g of compound II-4, 11.82 g of cesium carbonate, 3.58 g of pinacol diborate, 0.26 g of Pd(dppf)Cl2, 55 mL of toluene, and 0.28 mL of DMF were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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 mixture was purified by preparative chromatography to obtain 5.44 g of compound 5, with a yield of 91.22%.

[0108] Example 23

[0109] 5.40 g of compound II-4, 11.82 g of cesium carbonate, 3.58 g of pinacol diborate, 0.26 g of Pd(dppf)Cl2, 55 mL of toluene, and 0.28 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 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 mixture was purified by preparative chromatography to obtain 5.38 g of compound 5, with a yield of 90.22%.

[0110] Example 24

[0111] 5.96 g of compound II-1, 11.82 g of cesium carbonate, 3.58 g of pinacol diborate, 0.26 g of Pd(dppf)Cl2, 55 mL of toluene, and 0.28 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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 mixture was purified by preparative chromatography to obtain 5.46 g of compound 5, with a yield of 91.75%.

[0112] Example 25: Preparation of Compound 2

[0113]

[0114] 5.40 g of compound II-4, 11.82 g of cesium carbonate, 3.16 g of neopentyl glycol diboronate, 0.26 g of Pd(dppf)Cl2, 55 mL of toluene, and 0.28 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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 mixture was then purified by preparative chromatography (column: WelFlash C18-I (20-40 μm); gradient elution with methanol and water) to give 5.34 g of compound 2 (ESI-MS: [M+H)). + =476.27), yield 92.19%.

[0115] Example 26: Compound 9

[0116]

[0117] 5.40 g of compound II-4, 11.82 g of cesium carbonate, 2.04 g of 1,3-propanediol isopropylboronic acid, 0.26 g of Pd(dppf)Cl2, 55 mL of toluene, and 0.28 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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 mixture was then purified by preparative chromatography (column: WelFlash C18-I (20-40 μm); gradient elution with methanol and water) to give 4.98 g of compound 9 (ESI-MS: [M+H)). + =448.24), yield 91.36%.

[0118] Example 27: Preparation of Compound 6

[0119]

[0120] 5.40 g of compound II-4, 11.82 g of cesium carbonate, 1.83 g of 2-isopropoxy-1,3,2-dioxaborane, 0.26 g of Pd(dppf)Cl2, 55 mL of toluene, and 0.28 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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 mixture was then purified by preparative chromatography (column: WelFlash C18-I (20-40 μm); gradient elution with methanol and water) to give 4.78 g of compound 6 (ESI-MS: [M+H)). + =434.22), yield 90.53%.

[0121] Example 28: Preparation of Compound 1

[0122]

[0123] 5.40 g of compound II-4, 11.82 g of cesium carbonate, 2.80 g of 4,4',5,5'-tetramethyl-2,2'-bi-1,3,2-dioxoboronyl pentane, 0.26 g of Pd(dppf)Cl2, 55 mL of toluene, and 0.28 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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 mixture was then purified by preparative chromatography (column: WelFlash C18-I (20-40 μm); gradient elution with methanol and water) to obtain 5.25 g of compound 1 (ESI-MS: [M+H)). + =462.25), yield 93.39%.

[0124] Example 29: Preparation of Compound 3

[0125]

[0126] 5.40 g of compound II-4, 11.82 g of cesium carbonate, 3.58 g of bis(2-methyl-2,4-pentanediol)borate, 0.26 g of Pd(dppf)Cl2, 55 mL of toluene, and 0.28 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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 mixture was then purified by preparative chromatography (column: WelFlash C18-I (20-40 μm); gradient elution with methanol and water) to give 5.32 g of compound 3 (ESI-MS: [M+H)). + =490.29), yield 89.21%.

[0127] Example 30: Preparation of Compound 4

[0128]

[0129] 5.40 g of compound II-4, 11.82 g of cesium carbonate, 3.98 g of bis(2,4-dimethyl-2,4-pentanediol)borate, 0.26 g of Pd(dppf)Cl2, 55 mL of toluene, and 0.28 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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 mixture was then purified by preparative chromatography (column: WelFlash C18-I (20-40 μm); methanol and water gradient elution) to obtain 5.56 g of compound 4 (ESI-MS: [M+H)). + =504.30), yield 90.64%.

[0130] Example 31: Preparation of Compound 10

[0131]

[0132] 5.40 g of compound II-4, 11.82 g of cesium carbonate, 2.82 g of 4,6-dimethyl-2-(1-methylbutoxy)-1,3,2-dioxoboronide, 0.26 g of Pd(dppf)Cl2, 55 mL of toluene, and 0.28 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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 mixture was then purified by preparative chromatography (column: WelFlash C18-I (20-40 μm); gradient elution with methanol and water) to obtain 5.26 g of compound 10 (ESI-MS: [M+H)). + =476.27), yield 90.80%.

[0133] Example 32: Preparation of Compound 7

[0134]

[0135] 6.38 g of compound II-2, 11.82 g of cesium carbonate, 3.58 g of 4,6-dimethyl-2-(1-methylbutoxy)-1,3,2-dioxoboronide, 0.26 g of Pd(dppf)Cl2, 55 mL of toluene, and 0.28 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °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 mixture was then purified by preparative chromatography (column: WelFlash C18-I (20-40 μm); methanol and water gradient elution) to obtain 5.98 g of compound 7 (ESI-MS: [M+H)). + =524.27), yield 93.86%.

[0136] Example 33: Preparation of Compound 8

[0137]

[0138] 6.40 g of compound II-3, 11.82 g of cesium carbonate, 3.58 g of 4,6-% methyl-2-(1-methylbutoxy)-1,3,2-dioxoboronide, 0.26 g of Pd(dppf)Cl2, 55 mL of toluene, and 0.28 mL of DMSO were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 8 h. After the reaction was complete, the solvent was removed under reduced pressure. 50 mL of water was added to the residue, 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 give 5.97 g of compound 8 (ESI-MS: [M+H)). + =524.27), yield 93.41%.

[0139] Example 34

[0140]

[0141] Compound 5 prepared in Example 12 was dissolved in 20 mL of ethyl acetate, and 10 mL of 4 mol / L hydrochloric acid-ethyl acetate solution was added dropwise. The mixture was stirred at room temperature for 4 h. After the reaction was complete, a sample was taken to confirm the reaction was complete. The mixture was then concentrated to dryness by vacuum distillation at room temperature to obtain a white solid. The obtained white solid was dissolved in 20 mL of water, adsorbed using an anion exchange resin, eluted with water, and lyophilized to obtain 2.65 g of compound III, with a yield of 91.24% and a purity of 99.78% (see [link to example]). Figure 2 The corresponding data is shown in the table below.

[0142] RT Area %Area Height 1 0.870 3738.79 0.083 3347 2 0.938 2921.10 0.065 1722 3 1.076 4473161.21 99.784 2608595 4 4.435 3037.57 0.068 299

Claims

1. An N-(3-benzene) 10 Boric acid)-L-aspartic acid intermediate, characterized in that, It has the structure of Formula I: Wherein, R1 is selected from hydrogen or carboxyl protecting groups; R2 is selected from hydrogen or amino protecting groups; for R3, R4, R5, R6, R7, R8, R9, R 10 R 11 and R 12 Each is independently selected from hydrogen or C1-C4 alkyl groups.

2. The intermediate according to claim 1, characterized in that, The carboxyl protecting group is selected from C1-C6 alkyl, Bzl, or Trt; the amino protecting group is selected from Cbz, Boc, tBu, Ac, MOB, PMB, DMB, Teoc, Moc, Eoc, or Trt.

3. The intermediate according to claim 2, characterized in that, The carboxyl protecting group is selected from C1-C6 alkyl groups.

4. The intermediate according to claim 3, characterized in that, The carboxyl protecting group is tert-butyl.

5. The intermediate according to claim 2, characterized in that, The amino protecting group is selected from Boc or Cbz.

6. The intermediate according to claim 1, characterized in that, The for R3, R4, R5, and R6 are each independently selected from hydrogen or methyl.

7. The intermediate according to claim 6, characterized in that, R3, R4, R5, and R6 are all methyl groups.

8. The intermediate according to claim 1, characterized in that, Compounds of Formula I are selected from the following structures: Wherein R1 and R2 are as defined in claim 1.

9. The intermediate according to claim 1, characterized in that, Compounds of Formula I are selected from the following structures:

10. 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 shown in Formula II reacts with a borizing agent in an organic solvent to obtain the compound shown in Formula I; in: Hal is either I or Br; R1, R2 and The definition is the same as that in claim 1; The boriding agent is The definition is the same as that in claim 1, R 13 It is a C1-C5 alkyl group.

11. The preparation method according to claim 10, 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.

12. The preparation method according to claim 11, characterized in that, The alkali is cesium carbonate.

13. The preparation method according to claim 10, characterized in that, The palladium catalyst is selected from any one of Pd2(dba)3, Pd(PPh3)4, PdCl2(PPh3)2, PdCl2, Pd(OAc)2, and Pd(dppf)Cl2.

14. The preparation method according to claim 13, characterized in that, The palladium catalyst is Pd(dppf)Cl2.

15. The preparation method according to claim 10, 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.

16. The preparation method according to claim 15, characterized in that, The volume ratio of the two solvents in the mixed solvent is (100-300):

1.

17. The preparation method according to claim 16, characterized in that, The volume ratio of the two solvents in the mixed solvent is 200:

1.

18. The preparation method according to claim 10, characterized in that, The reaction temperature is 90-120℃, and the reaction time is 5-10h.

19. The preparation method according to claim 10, characterized in that, The molar ratio of the compound of formula II to the borizing agent is 1:(1-1.2); the molar ratio of the palladium catalyst to the compound of formula II is (0.01-0.1):1; and the molar ratio of the base to the compound of formula II is (2-5):

1.

20. The preparation method according to claim 19, characterized in that, The molar ratio of the palladium catalyst to the compound of formula II is 0.03:

1.

21. The preparation method according to claim 19, characterized in that, The molar ratio of the base to the compound of formula II is 3:1.

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