A method and ligand for the efficient preparation of peptide boric acid inhibitors

Abstract

This invention provides a highly efficient method and ligand for preparing peptide borate inhibitors. A key intermediate such as stereospecific 2-pinacol boronic acid ester pyrrolidine is constructed by asymmetric catalytic carborohydride boration of a synthesized chiral P / Si ligand with [Ir(cod)OMe]2. Further, the 2-pinacol boronic acid ester pyrrolidine is acidified to prepare the compound shown in formula (3'). The compound shown in formula (3') reacts with the amino acid shown in formula (III) to obtain the compound shown in formula (I). The compound shown in formula (I) is further reacted to obtain the peptide borate inhibitor shown in formula (II). The entire method is short, efficient, and simple to operate.

Description

Technical Field

[0001] This invention relates to the field of organic chemistry, and provides a method and ligand for the efficient preparation of peptide boric acid inhibitors. Background Technology

[0002]

[0003] Peptide boric acid inhibitors are an important intermediate for anticancer drugs. Existing synthetic routes require the use of chiral auxiliaries and resolution with L-(-)-dibenzoyl tartaric acid. The entire process requires five steps to obtain the key intermediate. The steps are complex, and there are significant losses during the reaction process and post-processing, resulting in a very low yield of the final target product.

[0004] Stereospecific 2-pinacolborate pyrrolidine is a valuable building block in the organic synthesis of peptide borate inhibitors, and how to effectively control stereospecificity is a technical problem that urgently needs to be solved.

[0005] Therefore, it is necessary to provide an efficient method for preparing peptide boric acid inhibitors and ligands. Summary of the Invention

[0006] To address the problems mentioned in the background art, this invention provides an efficient method and ligand for preparing peptide borate inhibitors. A method is employed to construct a stereospecific key intermediate such as 2-pinacol boronic acid ester pyrrolidine by asymmetric catalytic carborohydride boration of a synthesized chiral P / Si ligand with [Ir(cod)OMe]2, followed by further preparation of the peptide borate inhibitor. This method is short, efficient, and simple to operate.

[0007] In a first aspect, a ligand is provided having a structure as shown in formula (L1): .

[0008] Secondly, a method for preparing a ligand is provided, including... ; Step (1): The compound shown in formula (S1) and the compound shown in formula (S2) are reacted in the presence of sodium hydride to obtain the compound shown in formula (S3); Step (2): The compound shown in formula (S3) is reacted in the presence of n-butyllithium and Ph2SiHCl, and further reacted with THF·BH3 to obtain the compound shown in formula (S4); Step (3): The compound shown in formula (S4) was reacted with DABCO (triethylenediamine or 1,4-diazabicyclo[2.2.2]octane) to prepare the compound shown in formula (L1).

[0009] In some embodiments, the molar ratio of the compound shown in formula (S1) to the compound shown in formula (S2) is 1:(0.5~5), preferably 1:0.5, 1:1, 1:1.5, 1:2, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:5, and any two of the above values ​​constitute any one of the ranges.

[0010] In some embodiments, the molar ratio of the compound shown in formula (S1) to sodium hydride is 1:(0.5~5), preferably 1:0.5, 1:1, 1:1.5, 1:2, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:5, and any two of the above values ​​constitute any one of the ranges.

[0011] In some embodiments, step (1) involves reacting at room temperature for 20-28 hours, preferably 24 hours. In this invention, room temperature is preferably any one of the ranges of 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, or any two of the above values, for example, 20-30°C.

[0012] In some embodiments, the molar ratio of the compound shown in formula (S3) to n-butyllithium is 1:(0.5~5), preferably 1:0.5, 1:1, 1:1.2, 1:1.5, 1:2, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:5, and any two of the above values ​​constitute any one of the ranges.

[0013] In some embodiments, the molar ratio of the compound shown in formula (S3) to Ph2SiHCl is 1:(0.5~5), preferably 1:0.5, 1:1, 1:1.2, 1:1.5, 1:2, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:5, and any two of the above values ​​constitute any one of the ranges.

[0014] In some embodiments, the compound shown in formula (S3) is reacted at -78°C for 1-2 h in the presence of n-butyllithium, followed by the addition of Ph2SiHCl and the reaction being brought to room temperature overnight, and then the temperature is raised to 60-65°C for 2-5 h.

[0015] In some embodiments, the molar ratio of the compound shown in formula (S3) to THF·BH3 is 1:(0.5~5), preferably 1:0.5, 1:1, 1:1.2, 1:1.5, 1:2, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:5, and any two of the above values ​​constitute any one of the ranges.

[0016] In some embodiments, in step (2), THF·BH3 solution is added under an argon atmosphere and reacted at room temperature for 10-15 h, preferably 12 h.

[0017] In some embodiments, the molar ratio of the compound shown in formula (S4) to DABCO is 1:(0.5~5), preferably 1:0.5, 1:1, 1:1.2, 1:1.5, 1:2, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:5, and any two of the above values ​​constitute any one of the ranges.

[0018] In some embodiments, step (3) involves reacting at 45~55℃ for 10~15h, preferably any one of any two values ​​from 45℃, 50℃, 55℃, and above. Preferably, the reaction time is 10h, 11h, 12h, 13h, 14h, 15h, and any one of any two values ​​from above.

[0019] Thirdly, a method for preparing 2-pinacolborate pyrrolidine is provided, comprising: ; The compound shown in formula (1') was reacted with B2pin2 in the presence of the ligand shown in formula (L1), [Ir(cod)OMe]2 and anhydrous cyclohexane to prepare the compound shown in formula (2'); R a R b R c R d R e and R f Each is independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, arylalkyl, hydroxyalkyl, cycloalkylalkyl, fluorinated arylalkyl, alkyl-OC(=O)-alkyl, HOC(=O)-alkyl, alkyl-C(=O)-, alkyl-OC(=O)-, aryl-C(=O)-, heteroaryl-C(=O)-, aryl-OC(=O)-, aryl, heterocyclic, alkyl-OC(=O)-heterocyclic or alkyl; or R d and R e Together with the attached carbon atom, it forms cycloalkyl or aryl groups.

[0020] In some embodiments, R a R b R c R d R e and R f Each is independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C 6-12 Aryl C 1-12 Alkyl, hydroxyl C 1-12 Alkyl, C3-12 cycloalkyl C 1-12 Alkyl, fluorinated C 6-12 Aryl C 1-12 Alkyl, C 1-12 Alkyl-OC(=O)-C 1-12 Alkyl, HOC(=O)-C 1-12 Alkyl, C 1-12 Alkyl-C(=O)-, C 1-12 Alkyl-OC(=O)-, C 6-12 Aryl-C(=O)-, C 1-12 heteroaryl-C(=O)-, C 6-12 Aryl-OC(=O)-, C 6-12 Aryl, C 2-12 Heterocyclic group, C 1-12 Alkyl-OC(=O)-C 2-12 Heterocyclic group or C 1-12 Alkyl; or R d and R e Together with the attached carbon atom, they form C 3-12 cycloalkyl or C 6-12 Aryl.

[0021] In some embodiments, R a R b R c R d R e and R f Each is independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C 6-12 Aryl C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-12 cycloalkyl C 1-6 Alkyl, fluorinated C 6-12 Aryl C 1-6 Alkyl, C 1-6 Alkyl-OC(=O)-C 1-6 Alkyl, HOC(=O)-C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-OC(=O)-, C 6-12 Aryl-C(=O)-, C 1-12 heteroaryl-C(=O)-, C 6-12 Aryl-OC(=O)-, C 6-12 Aryl, C 2-12 Heterocyclic group, C 1-6 Alkyl-OC(=O)-C 2-12 Heterocyclic group or C 1-6 Alkyl; or R d and Re Together with the attached carbon atom, they form C 3-12 cycloalkyl or C 6-12 Aryl.

[0022] In some embodiments, R a R b R c R d R e and R f Each is independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, diphenylmethane, 1-naphthylethyl, hydroxymethane, cyclopropylethyl, 4-fluorosubstituted phenylethyl, ethyl-OC(=O)-methyl, HOC(=O)-propyl, methyl or ethyl; or R d and R e Together with the attached carbon atom, it forms a cyclopropyl or phenyl group.

[0023] In some embodiments, the preparation method involves reacting at 0-80°C for 10-50 hours, preferably at 55-65°C for 40-50 hours. The preferred temperature range is 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, or any two of the above values. The preferred reaction time range is 10 hours, 15 hours, 20 hours, 25 hours, 30 hours, 35 hours, 40 hours, 45 hours, 50 hours, or any two of the above values.

[0024] In some embodiments, the amount of ligand shown in formula (L1) is 1 to 15 mol% of the amount of compound shown in formula (1'), preferably 1 to 5 mol%, preferably 1 mol%, 2 mol%, 3 mol%, 4 mol%, 5 mol%, 6 mol%, 7 mol%, 8 mol%, 9 mol%, 10 mol%, 11 mol%, 12 mol%, 13 mol%, 14 mol%, 15 mol%, and any two of the above values ​​constitute any one of the ranges.

[0025] In some embodiments, the amount of [Ir(cod)OMe]2 added is 1-15 mol% of the amount of the compound shown in formula (1'), preferably 1-5 mol%, preferably 1 mol%, 2 mol%, 3 mol%, 4 mol%, 5 mol%, 6 mol%, 7 mol%, 8 mol%, 9 mol%, 10 mol%, 11 mol%, 12 mol%, 13 mol%, 14 mol%, 15 mol%, and any two of the above values ​​forming a range. In some embodiments, the solvent is an ester or ether solvent, selected from at least one of ethyl acetate, methyl acetate, dimethyl ether (DME), diethyl ether, etc.

[0026] In some embodiments, the molar ratio of the compound shown in formula (1') to B2pin2 is 1:(0.1~1), preferably 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, and any two of the above values ​​constitute any one of the ranges.

[0027] Fourthly, a method for efficiently preparing peptide boric acid inhibitors is provided, including... ; Wherein, "*" indicates R configuration, S configuration, or racemic configuration; Step A: Acidify the compound shown in formula (2') to prepare the compound shown in formula (3'); Step B: The compound shown in formula (3') reacts with the amino acid shown in formula (III) to obtain the compound shown in formula (I); Step C: The compound shown in formula (I) is further reacted to obtain the peptide boric acid inhibitor shown in formula (II); R a R b R c R d R e and R f It has the definition as described in this invention; R 1 R 1a R 2a and R 2 Each is independently selected from hydrogen, alkyl-C(=O)-, alkyl-OC(=O)-, aryl-C(=O)-, heteroaryl-C(=O)-, aryl-OC(=O)-, aryl, heterocyclic, alkyl-OC(=O)-heterocyclic or alkyl; R 3 It can be hydrogen, cycloalkyl, heterocyclic, aryl, alkylaryl, heteroaryl, or alkyl.

[0028] In some embodiments, the compound represented by formula (3') is selected from one of the following structures: , , , , , , , , , , and .

[0029] Fifthly, a method for efficiently preparing peptide boric acid inhibitors is provided, including... ; Wherein, "*" indicates R configuration, S configuration, or racemic configuration; Step A: Acidify the compound shown in formula (2a) to prepare the compound shown in formula (3a); Step B: The compound shown in formula (3a) reacts with the amino acid shown in formula (III) to obtain the compound shown in formula (I'); Step C: The compound shown in formula (I') is further reacted to prepare the peptide boric acid inhibitor shown in formula (II'); R 1 R 1a R 2a and R 2 Each is independently selected from hydrogen, alkyl-C(=O)-, alkyl-OC(=O)-, aryl-C(=O)-, heteroaryl-C(=O)-, aryl-OC(=O)-, aryl, heterocyclic, alkyl-OC(=O)-heterocyclic or alkyl; R 3 It can be hydrogen, cycloalkyl, heterocyclic, aryl, alkylaryl, heteroaryl, or alkyl.

[0030] In some embodiments, R 1 R 1a R 2a and R 2 Each is independently selected from hydrogen and C. 1-12 Alkyl-C(=O)-, C 1-12 Alkyl-OC(=O)-, C 6-12 Aryl-C(=O)-, C 1-12 heteroaryl-C(=O)-, C 6-12 Aryl-OC(=O)-, C 6-12 Aryl, C 2-12 Heterocyclic group, C 1-12 Alkyl-OC(=O)-C 2-12 Heterocyclic group or C 1-12 alkyl.

[0031] In some embodiments, R 3 For hydrogen, C 3-12 cycloalkyl, C 2-12 Heterocyclic group, C 6-12 Aryl, C 1-12 Alkyl C 6-12 Aryl, C 1-12 heteroaryl or C 1-12 alkyl.

[0032] In some embodiments, R 1 R 1a R 2a and R 2 Each is independently selected from hydrogen, methyl-C(=O)-, ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, n-butyl-C(=O)-, tert-butyl-C(=O)-, n-pentyl-C(=O)-, n-hexyl-C(=O)-, methyl-OC(=O)-, ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)- n-Butyl-OC(=O)-, tert-Butyl-OC(=O)-, n-pentyl-OC(=O)-, n-hexyl-OC(=O)-, phenyl-C(=O)-, 3-pyridyl-C(=O)-, 4-pyridyl-C(=O)-, 3-pyrrolidinyl, tert-Butyl-OC(=O)-3-pyrrolidinyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl or n-hexyl.

[0033] In some embodiments, R 3 It can be hydrogen, 3-pyrrolidinyl, 2-pyrrolidinyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, or n-hexyl.

[0034] In some embodiments, the compound represented by formula (I) or the compound represented by formula (I') is selected from one of the following structures: , , .

[0035] In some embodiments, the amino acid represented by formula (III) is selected from one of the following structures: , , .

[0036] In some embodiments, in step A, the acid used for acidification is selected from at least one of hydrochloric acid, sulfuric acid, and nitric acid.

[0037] In some embodiments, the molar ratio of the compound shown in formula (3a) or the compound shown in formula (3') to the amino acid shown in formula (III) is 1:(0.5~5), preferably 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:2, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:5, and any two of the above values ​​constitute any one of the ranges.

[0038] In some embodiments, in step B, at -5 to 5°C, the amino acid represented by formula (III) is in HOBT (1-hydroxybenzotriazole), EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) and N The compound shown in formula (I) or the compound shown in formula (I') is prepared by reacting the compound shown in formula (3a) or the compound shown in formula (3') with the compound shown in formula (3') in the presence of -methylmorpholine.

[0039] In some embodiments, the molar ratio of the amino acid and HOBT shown in formula (III) is 1:(0.5~5), preferably 1:0.5, 1:1, 1:1.5, 1:2, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:5, and any two of the above values ​​constitute any one of the ranges.

[0040] In some embodiments, the molar ratio of the amino acid and EDC shown in formula (III) is 1:(0.5~5), preferably 1:0.5, 1:1, 1:1.5, 1:2, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:5, and any two of the above values ​​constitute any one of the ranges.

[0041] In some embodiments, the amino acids represented by formula (III) and N The molar ratio of methylmorpholine is 1:(0.5~5), preferably 1:0.5, 1:1, 1:1.5, 1:2, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:5, or any two of the above values ​​forming any one of the ranges.

[0042] In some embodiments, in step C, after the compound shown in formula (I) or the compound shown in formula (I') reacts with hydrochloric acid, it is further reacted with an acid compound in an acetone-hydrochloric acid mixture to obtain the peptide boric acid inhibitor shown in formula (II) or the peptide boric acid inhibitor shown in formula (II'). Preferably, the acid compound is methylboric acid. Preferably, the molar ratio of the compound shown in formula (I) or the compound shown in formula (I') to the acid compound is 1:(0.5~5), preferably 1:0.5, 1:1, 1:1.5, 1:1.52, 1:1.55, 1:1.59, 1:1.6, 1:1.7, 1:2, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:5, and any two of the above values ​​forming any one of the ranges. Preferably, the volume ratio of acetone to hydrochloric acid in the acetone-hydrochloric acid mixture is 1:(0.5~5), preferably 1:0.5, 1:1, 1:1.5, 1:1.52, 1:1.55, 1:1.59, 1:1.6, 1:1.7, 1:2, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:5, or any two of the above values ​​forming a range. Preferably, the reaction is carried out at 15~35℃ for 8~12 hours.

[0043] In some embodiments, in step C, after the compound shown in formula (I) or the compound shown in formula (I') reacts with hydrochloric acid, it is further reacted with an acid compound in the presence of PyBOP (benzotriazol-1-yl-oxytripyrrolylphosphine hexafluorophosphate) and DIPEA (N,N-diisopropylethylamine) to prepare the peptide borate inhibitor shown in formula (II) or the peptide borate inhibitor shown in formula (II'). Preferably, the acid compound is nicotinic acid. Preferably, the molar ratio of the compound shown in formula (I) or the compound shown in formula (I') to the acid compound is 1:(0.5~5), preferably 1:0.5, 1:1, 1:2, 1:1.5, 1:1.52, 1:1.55, 1:2, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:5, and any two of the above values ​​forming any one of the ranges. Preferably, the molar ratio of the compound shown in formula (I) to PyBOP is 1:(0.5~5), preferably any one of the following ranges: 1:0.5, 1:1, 1:1.2, 1:1.5, 1:1.52, 1:1.55, 1:2, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:5, or any two of the above values. Preferably, the molar ratio of the compound shown in formula (I) or formula (I') to DIPEA is 1:(0.5~5), preferably any one of the following ranges: 1:0.5, 1:1, 1:1.2, 1:1.5, 1:1.52, 1:1.55, 1:2, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:5, or any two of the above values. Preferably, the reaction is carried out at 15~35°C for 8~12 hours.

[0044] In some embodiments, in step C, after the compound shown in formula (I) or the compound shown in formula (I') reacts with hydrochloric acid, it is further reacted with an acid compound in the presence of HATU (2-(7-azabenzotriazole)-tetramethylurea hexafluorophosphate) and 2,4,6-trimethylpyridine to prepare the peptide borate inhibitor shown in formula (II) or the peptide borate inhibitor shown in formula (II'). Preferably, the acid compound is isonicotinic acid. Preferably, the molar ratio of the compound shown in formula (I) or the compound shown in formula (I') to the acid compound is 1:(0.5~5), preferably 1:0.5, 1:1, 1:1.5, 1:1.52, 1:1.55, 1:2, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:5, and any two of the above values ​​forming any one of the ranges. Preferably, the molar ratio of the compound shown in formula (I) or formula (I') to HATU is 1:(0.5~5), preferably any one of the following ranges: 1:0.5, 1:1, 1:1.2, 1:1.5, 1:1.52, 1:1.55, 1:2, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:5, or any two of the above values. Preferably, the molar ratio of the compound shown in formula (I) or formula (I') to 2,4,6-trimethylpyridine is 1:(0.5~5), preferably any one of the following ranges: 1:0.5, 1:1, 1:1.2, 1:1.5, 1:1.52, 1:1.55, 1:2, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:5, or any two of the above values. Preferably, the reaction is carried out at 15~35°C for 8~12 hours.

[0045] In some embodiments, the peptide borate inhibitor shown in formula (II) or formula (II') is selected from one of the following structures: , , , .

[0046] Compared with the prior art, the present invention has the following beneficial effects: 1. This invention provides a method for asymmetric catalytic carbohydride boronization of chiral P / Si ligands with [Ir(cod)OMe]2 to construct a stereospecific pyrrolidine intermediate of 2-pinacol boronic acid ester, which can be further reacted to efficiently prepare peptide boric acid inhibitors. The method is short, efficient, and simple to operate.

[0047] 2. This invention creatively uses a stereospecific 2-pinacol boronic acid pyrrolidine intermediate to react with an amino acid compound, and then prepares a peptide boronic acid inhibitor through a deprotection reaction, which effectively improves the yield of the reaction product and has high enantioselectivity; at the same time, the substrate has broad applicability.

[0048] In summary, the technical solution of this invention has the advantages of high originality, simple operation, low cost, environmental friendliness, and good prospects for industrial scale-up.

[0049] Terminology Explanation Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0050] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0051] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0052] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0053] In the following content, all numbers disclosed herein, whether or not they use words such as "approximately" or "about," are approximate values. The value of each number may vary by 1%, 2%, 5%, 7%, 8%, 10%, 15%, or 20%. Whenever a number with a value of N is disclosed, any numbers with values ​​of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, N+ / -10%, N+ / -15%, or N+ / -20% will be explicitly disclosed, where "+ / -" indicates addition or subtraction. Detailed Implementation

[0054] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. The specific embodiments described herein are for illustrative purposes only and are not intended to limit the invention in any way. Furthermore, descriptions of well-known structures and techniques are omitted in the following description to avoid unnecessarily obscuring the concepts of this disclosure. Such structures and techniques have also been described in many publications.

[0055] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0056] In this invention, min represents minutes; h represents hours; g represents grams; mL represents milliliters; and mg represents milligrams.

[0057] In this invention, 1 H NMR represents the hydrogen nuclear magnetic resonance spectrum. 13 C NMR represents carbon nuclear magnetic resonance spectrum.

[0058] Preparation of intermediates (1) Preparation of 1d

[0059] Towards( R A cold (0 °C) solution of 2-(diphenylmethyl)pyrrolidine hydrochloride S5 (2.74 g, 10.0 mmol) in 30 mL of dichloromethane (DCM) was mixed with di-tert-butyl dicarbonate ((Boc)₂O) (2.18 g, 10.0 mmol) and triethylamine (Et₃N) (2.23 g, 22.0 mmol). The mixture was stirred at 0 °C for 10 minutes, and then stirred at room temperature for 12 hours. After the reaction was complete, the mixture was washed with 30 mL of water (3 x 10 mL). The organic layer was concentrated to obtain the residue, which was purified by silica gel rapid column chromatography to obtain the desired product as a white solid 1d (2.73 g, 8.1 mmol, 81%).

[0060] Characterization of compound 1d: 1 H NMR (400 MHz, CDCl3): d 7.45 – 6.98 (m, 10H), 4.81 – 4.11 (m, 2H), 3.61 – 3.00 (m, 2H), 2.07 – 1.78 (m, 2H), 1.77 – 1.69 (m, 1H), 1.46 – 1.18(m, 10H) ppm. 13 C NMR (101 MHz, CDCl3): d 154.60, 142.42, 141.76, 129.59, 129.34,129.00, 128.36, 128.11, 126.54, 126.18, 79.21, 60.72, 59.94, 54.03, 52.93,46.33, 45.76, 29.51, 28.46, 28.25, 23.34, 22.48 ppm. (2) Preparation in 1 hour

[0061] In a flame-dried 100 mL flask containing phosphonium bromide S7A (10.0 mmol) and THF (30 mL) under a N2 atmosphere at 0 °C, the phosphonium bromide was introduced into the flask. t BuOK (1.35 g, 12.0 mmol). After stirring at room temperature for 0.5 hours, S6 (1.99 g, 10 mmol) was slowly added to the reaction mixture. The resulting mixture was stirred at room temperature for another 7.5 hours. The reaction mixture was then evaporated and diluted with H2O (50 mL). The mixture was then extracted three times (50 mL × 3) with EtOAc. The combined organic layers were dried over anhydrous Na2SO4. After solvent removal, the residue was filtered through a silica gel pad using PE / EtOAc (EtOAc = 40:1) to obtain crude S7 for the next step.

[0062] FeCl3 (0.32 g, 2.0 mmol, 0.2 equivalents) and N2H4·H2O (5.01 g, 100 mmol, 10.0 equivalents) were added sequentially to an ethanol (20 mL) solution of S7 at room temperature. The resulting mixture was stirred in air at room temperature for 36 hours. The reaction mixture was then evaporated under vacuum, diluted with H2O (20 mL), and extracted with EtOAc (10 mL x 3). The combined organic phases were then dried over anhydrous Na2SO4 and evaporated under vacuum to give the target compound 1 h (2.15 g, 90%).

[0063] Characterization of compound 1h: 1 H NMR (400 MHz, CDCl3): d 3.76 (s, 1H), 3.45 – 3.23 (m, 2H), 1.99 –1.71 (m, 4H), 1.62 (s, 1H), 1.55 – 1.30 (m, 10H), 1.27 – 1.08 (m, 2H), 0.76 –0.60 (m, 1H), 0.40 (d, J = 7.3 Hz, 2H), 0.00 (s, 2H) ppm. 13 C NMR (101 MHz, CDCl3): d 154.53, 78.68, 56.99, 46.35, 45.95, 34.51,33.95, 31.49, 30.59, 29.84, 28.48, 23.71, 23.04, 10.73, 4.64, 4.33 ppm. (3) Preparation of 1j

[0064] In a N2 atmosphere at 0 °C, phosphonium bromide S8A (10 mmol) and THF (30 mL) were introduced into a flame-dried 100 mL flask. tBuOK (1.35 g, 12 mmol). After stirring at room temperature for 0.5 hours, S6 (1.99 g, 10 mmol) was slowly added to the reaction mixture. The resulting mixture was stirred at room temperature for another 7.5 hours. The reaction mixture was then evaporated and diluted with H2O (50 mL). The mixture was then extracted three times (50 mL x 3) with EtOAc. The combined organic layers were dried over anhydrous Na2SO4. After removing the solvent, the residue was filtered through a silica gel pad using PE / EtOAc (EtOAc = 40:1) to obtain crude S8 for the next step.

[0065] At room temperature, FeCl3 (0.32 g, 4.0 mmol, 0.2 equivalents) and N2H4·H2O (5.01 g, 100 mmol, 10.0 equivalents) were added sequentially to an ethanol (20 mL) solution of S2. The resulting mixture was stirred in air at room temperature for 36 hours. The reaction mixture was then evaporated under vacuum, diluted with H2O (20 mL), and extracted with EtOAc (10 mL x 3). The combined organic phases were then dried over anhydrous Na2SO4 and evaporated under vacuum to give the target compound 1j (2.96 g, 91%).

[0066] Characterization of compound 1j: 1 H NMR (400 MHz, CDCl3): d 8.03 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 7.9Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.48 (p, J = 6.8 Hz, 2H), 7.42 – 7.27 (m,2H), 3.90 (s, 1H), 3.56 – 3.26 (m, 2H), 3.07 (dd, J = 10.2, 5.5 Hz, 2H), 2.28– 1.97 (m, 2H), 1.97 – 1.70 (m, 4H), 1.41 (s, 9H) ppm. 13 C NMR (101 MHz, CDCl3): d154.74, 133.92, 131.82, 128.80, 126.60,125.82, 125.80, 125.59, 125.45, 123.71, 79.05, 57.31, 46.33, 35.68, 30.85,29.91, 28.53, 22.65 ppm. Example 1

[0067] Compound S1 was synthesized according to the literature "J. Am. Chem. Soc. 2026, 148, 17, 18468–18481".

[0068] Compound S1 (2.0 g, 4.0 mmol, 1.0 equiv) and NaH (0.32 g, 12.8 mmol, 3.2 equiv) were mixed with THF (60 mL). A 20 mL solution of THF containing compound S2 (0.76 g, 4.0 mmol, 1.0 equiv) was slowly added dropwise to the mixture in a water bath at room temperature. The mixture was stirred at room temperature for 24 h. PE (petroleum ether) was added to the mixture, and the precipitated solid was removed by filtration with diatomaceous earth. The reaction mixture was concentrated and purified by silica gel column chromatography (PE / DCM (V:V) = 100:0 to 10:1) to give compound S3 (white solid, 1.46 g, 70% yield).

[0069] Characterization of compound S3: 1 H NMR (400 MHz, CDCl3): d 7.83 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 8.1Hz, 1H), 7.61 (ddd, J = 7.8, 3.2, 1.4 Hz, 1H), 7.42 – 7.34 (m, 2H), 7.28 (s,1H), 7.20 (m, 2H), 7.09 (m, 4H), 6.95 (s, 1H), 6.79 (dt, J = 7.6, 1.8 Hz,1H), 4.05 (s, 3H), 3.91 (dd, J = 14.1, 4.1 Hz, 1H), 3.45 (dd, J= 15.5, 11.0Hz, 1H), 3.30 (s, 3H), 2.38 (d, J = 11.1 Hz, 1H), 2.23 (t, J = 14.4 Hz, 1H)ppm. 13 C NMR (101 MHz, CDCl3): d 155.34 (d, J = 2.3 Hz), 154.86, 138.12 (d, J = 24.9 Hz), 135.68 (d, J = 4.7 Hz), 134.41, 133.76 (d, J = 1.5 Hz), 133.16, 132.49 (d, J = 1.8 Hz), 131.26, 129.75 (d, J = 28.7 Hz), 129.50, 127.53 (d, J = 2.0 Hz), 127.11, 127.05, 127.02, 126.92, 126.79, 126.68, 126.61, 126.00,125.77, 125.41, 123.64, 123.53, 105.49 (d, J = 0.7 Hz), 104.92, 55.74, 54.79,22.34 (d, J = 23.4 Hz), 21.68 (d, J = 17.8 Hz) ppm. 31 P NMR (162 MHz, CDCl3): d 1.18 ppm.

[0070] Compound S3 (0.42 g, 0.8 mmol, 1.0 equiv) was mixed with THF (20 mL). The reaction mixture was cooled to -78 °C and added dropwise under an argon atmosphere. n-BuLi (0.38 mL, 2.5 M in n-hexane, 0.96 mmol, 1.2 equiv) was added, and the mixture was stirred at -78 °C for 1 hour. Then, Ph₂SiHCl (0.26 mL, 1.2 mmol, 1.5 equiv) was added dropwise, and the solution was gradually heated to room temperature with stirring overnight. The temperature was then raised to 60 °C and stirred for 3 hours. The temperature was then slowly lowered to 0 °C, and THF·BH₃ solution (5.0 mL, 1.0 M in THF, 5.0 equiv) was added under an argon atmosphere, followed by stirring at room temperature for 12 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (PE / DCM (V:V) = 100:0 to 10:1) to give compound S4 (white solid, 0.38 g, 74% yield).

[0071] Compound S4 (0.28 g, 0.5 mmol, 1.0 equiv) and DABCO (0.33 g, 2.5 mmol, 5.0 equiv) were mixed with Toluene (10 mL). The reaction was heated to 50 °C and stirred for 12 hours. The system was then slowly restored to room temperature. The reaction mixture was concentrated and purified by neutral alumina column chromatography (PE / EA(V:V) = 100:0 to 8:2) to give compound L1 (white solid, 0.23 g, 72% yield).

[0072] Characterization of compound L1: 1 H NMR (400 MHz, CDCl3): d 7.80 (dd, J = 13.0, 8.2 Hz, 2H), 7.69 –7.61 (m, 2H), 7.58 – 7.53 (m, 2H), 7.43 – 7.33 (m, 9H), 7.23 (d, J = 7.8 Hz,2H), 7.20 – 6.98 (m, 6H), 6.76 (dd, J = 7.8, 2.7 Hz, 1H), 5.99 (d, J = 8.3Hz, 1H), 3.98 (s, 3H), 3.42 (s, 3H), 3.34 (dd, J = 17.6, 6.0 Hz, 1H), 3.03(dd, J = 14.1, 4.8 Hz, 1H), 2.59 (dd, J= 11.7, 2.0 Hz, 1H), 2.02 (dd, J =14.2, 11.2 Hz, 1H) ppm. 13 C NMR (101 MHz, CDCl3): d 155.41, 155.29, 144.36 (d, J = 21.9 Hz),140.71 (d, J = 45.7 Hz), 137.16 (d, J = 13.8 Hz), 136.24, 136.03, 135.34 (d, J = 4.6 Hz), 134.76, 134.72, 134.68, 134.35, 133.57, 133.20, 130.51, 129.46(d, J = 12.1 Hz), 128.91, 128.39, 127.91, 127.54, 125.46 (d, J = 19.5 Hz),126.92, 126.67 (d, J = 9.3 Hz), 126.65, 125.55, 125.36, 123.49, 123.48,105.46, 104.80, 55.67, 54.75, 23.51 (d, J = 24.1 Hz), 22.08 (d, J = 18.4 Hz)ppm. 31 P NMR (162 MHz, CDCl3): d -3.58 ppm. Example 2

[0073] (1) In an argon-filled glove box, a dried 250 mL Schleck tube was filled with [Ir(cod)OMe]2 (66.3 mg, 2.0 mol%), ligand L1 (126.2 mg, 4.0 mol%), and anhydrous cyclohexane (25 mL). After stirring at room temperature for 15 minutes, tert-butylpyrrolidine-1-carboxylic acid ester 1a (856.2 mg, 5.0 mmol, 1.0 equivalent) and B2pin2 (1.27 g, 5.0 mmol, 1.0 equivalent) were added. The Schleck tube was sealed and removed from the glove box. The resulting mixture was then stirred at 60 °C for 48 hours. After the reaction was complete, the reaction mixture was evaporated under reduced pressure to remove the solvent, and then purified by silica gel chromatography to give the target product 2a (1.40 g, 94% yield, 99% ee) as a white solid.

[0074] Characterization of compound 2a: 1 H NMR (400 MHz, CDCl3): d 3.51 – 3.25 (m, 2H), 3.23 – 3.09 (m, 1×0.35H), 3.00 (dd, J = 9.9, 6.8 Hz, 1×0.65H), 2.09 – 1.66 (m, 4H), 1.56 –1.39 (m, 9H), 1.34 – 1.14 (m, 12H) ppm. 13 C NMR (101 MHz, CDCl3): d 154.94, 154.49, 83.43, 83.33, 78.89,46.45, 45.86, 28.77, 28.55, 28.47, 27.73, 27.17, 25.45, 25.02, 24.64, 24.36ppm. 11 B NMR (128 MHz, CDCl3): d 32.49 ppm.

[0075] (2) Under ice-water bath conditions, a solution of 1,4-dioxane in 4 N hydrochloric acid (15 mL) was added to 2a (891.6 mg, 3.0 mmol). The reaction mixture was heated to room temperature and stirred for 12 hours. After removing the solvent under vacuum, a white powder compound 3a (686.6 mg, 98%) was obtained.

[0076] Characterization of compound 3a: 1 H NMR (400 MHz, CDCl3): d 10.03 (s, 1H), 8.76 (s, 1H), 3.42 (s, 2H), 3.17 (s, 1H), 2.27 – 2.14 (m, 1H), 2.08 – 1.86 (m, 3H), 1.31 (s, 12H) ppm. 13 C NMR (101 MHz, CDCl3): d 85.46, 45.97, 27.15, 24.98, 24.95, 24.56ppm. 11 B NMR (128 MHz, CDCl3): d 32.08 ppm. Example 3 Referring to the steps of Example 2, in the presence of ligand L1, [Ir(cod)OMe]2 and anhydrous cyclohexane, the compound shown in formula (1') was reacted with B2pin2 and further acidified to prepare the compound shown in formula (3').

[0077]

[0078]

[0079] General Step A: In an argon-filled glove box, a dried 10 mL microwave tube was filled with [Ir(cod)OMe]2 (4.0 mg, 2.0 mol%) and ligand. ent -L1 (7.6 mg, 4.0 mol%) and anhydrous cyclohexane (1.5 mL). After stirring at room temperature for 15 minutes, any one of tert-butylpyrrolidine-1-carboxylic acid ester 1b-1l (0.3 mmol, 1.0 equivalent) and B2pin2 (76.2 mg, 0.3 mmol, 1.0 equivalent) were added. The microwave tube was capped and removed from the glove box. The resulting mixture was then stirred at 60 °C for 24 hours. After the reaction was complete, the solvent was removed by evaporation under reduced pressure, and the product was purified by silica gel chromatography. Then, a solution of 1,4-dioxane in 4 N hydrochloric acid (1.5 mL) was added to the above product under ice-water bath conditions, and the reaction mixture was heated to room temperature and stirred for 12 hours. After removing the solvent under vacuum, a white solid compound 3b-3l was given.

[0080] Compound 3b: (Yield 81%, 98% ee).

[0081] 1 H NMR (400 MHz, CDCl3): d 10.51 (s, 1H), 9.74 (s, 1H), 3.95 – 3.72 (m, 2H), 3.51 (s, 1H), 2.69 – 2.48 (m, 2H), 1.32 (s, 12H) ppm. 13 C NMR (101 MHz, CDCl3): d 127.50, 86.11, 51.53 (t, J = 36.4 Hz), 36.38 (t, J = 25.1 Hz), 24.82, 24.76 ppm. 19 F NMR (377 MHz, CDCl3): d -96.03 (d, J = 236.2 Hz), -98.49 (d, J =236.5 Hz) ppm. 11 B NMR (128 MHz, CDCl3): d 31.19 ppm. Compound 3c: (Yield 95%, 96% ee).

[0082] 1 H NMR (400 MHz, CDCl3): d 10.91 (s, 1H), 9.06 (s, 1H), 7.32 – 7.22 (m, 4H), 4.90 – 4.56 (m, 4H), 1.27 (s, 12H) ppm. 13 C NMR (101 MHz, CDCl3): d 135.88, 133.51, 128.63, 128.07, 122.93,122.50, 85.80, 51.03, 24.90, 24.54 ppm. Compound 3d: (Yield 88%, >20:1 dr).

[0083] 1 H NMR (400 MHz, CDCl3): d 10.66 (s, 1H), 7.57 – 7.20 (m, 10H), 6.61(s, 1H), 4.73 (s, 1H), 4.28 (s, 1H), 3.53 (s, 1H), 2.36 (s, 1H), 2.03 – 1.74(m, 3H), 1.30 (s, 12H) ppm. 13 C NMR (101 MHz, CDCl3): d 140.89, 140.29, 129.63, 129.01, 128.14,127.96, 127.77, 127.34, 85.67, 65.27, 52.78, 30.12, 26.07, 25.11, 25.01 ppm. 11 B NMR (128 MHz, CDCl3): d 31.26 ppm. Compound 3e: (Yield 83%, >20:1 dr).

[0084] 1 H NMR (400 MHz, CDCl3): d 9.18 (s, 1H), 8.91 (s, 1H), 4.10 – 3.79 (m,3H), 3.70 – 3.50 (m, 1H), 3.26 (s, 1H), 2.25 (s, 1H), 2.06 – 1.79 (m, 1H),1.31 (s, 12H)ppm. 13 C NMR (101 MHz, CDCl3): d 85.42, 62.61, 61.01, 28.48, 27.35, 24.94,24.88 ppm. 11 B NMR (128 MHz, CDCl3): d 32.52 ppm. Compound 3f: (Yield 75%, >20:1 dr).

[0085] 1 H NMR (400 MHz, CDCl3): d9.71 (s, 1H), 8.99 (s, 1H), 3.80 (s, 1H), 3.37 (s, 1H), 2.21 (d, J = 40.7 Hz, 2H), 1.81 (d, J = 61.5 Hz, 2H), 1.61 (s,3H), 1.30 (s, 12H)ppm. 13 C NMR (101 MHz, CDCl3): d 85.19, 56.67, 32.41, 26.32, 24.90, 24.81,17.72 ppm. 11 B NMR (128 MHz, CDCl3): d 31.94 ppm. Compound 3g: (Yield 81%, >20:1 dr).

[0086] 1 H NMR (400 MHz, CDCl3): d 9.68 (s, 1H), 8.92 (s, 1H), 3.58 (s, 1H), 3.39 (s, 1H), 2.26 (s, 1H), 2.14 (s, 2H), 1.90 – 1.72 (m, 3H), 1.41 – 1.36(m, 4H), 1.30 (s, 12H), 0.91 (t, J = 6.4 Hz, 3H) ppm. 13 C NMR (101 MHz, CDCl3): d 85.12, 77.42, 77.11, 76.80, 60.91, 31.75,30.36, 29.16, 26.07, 24.89, 24.75, 22.44, 14.00 ppm. 11 B NMR (128 MHz, CDCl3): d 33.01 ppm. Compound 3h: (Yield 93%, >20:1 dr).

[0087] 1 H NMR (400 MHz, CDCl3): d9.76 (s, 1H), 8.84 (s, 1H), 3.65 (s, 1H), 3.42 (s, 1H), 2.36 – 2.05 (m, 3H), 2.01 – 1.69 (m, 3H), 1.44 – 1.17 (m, 14H), 0.72 (s, 1H), 0.43 (d, J = 6.2 Hz, 2H), 0.08 (s, 2H) ppm. 13 C NMR (101 MHz, CDCl3): d 85.14, 60.65, 32.14, 32.07, 30.53, 26.03, 24.92, 24.78, 10.55, 4.71, 4.64 ppm. 11 B NMR (128 MHz, CDCl3): d 32.86 ppm. Compound 3i: (Yield 78%, >20:1 dr).

[0088] 1 H NMR (400 MHz, CDCl3): d 9.86 (s, 1H), 9.06 (s, 1H), 7.19 (d, J = 6.3 Hz, 2H), 6.90 (t, J = 7.8 Hz, 2H), 3.58 (s, 1H), 3.41 (s, 1H), 2.75 (s, 2H), 2.45 (s, 1H), 2.27 (s, 1H), 2.10 – 1.96 (m, 2H), 1.85 – 1.67 (m, 2H), 1.29 – 1.25 (m, 12H) ppm. 13 C NMR (101 MHz, CDCl3): d 161.40 (d, J = 243.6 Hz), 136.14, 130.08 (d, J = 7.8 Hz), 115.15 (d, J = 21.1 Hz), 85.20, 60.18, 33.95, 32.35, 30.62, 26.02, 24.89, 24.74 ppm. 11 B NMR (128 MHz, CDCl3): d33.24 ppm. Compound 3j (Yield 90%, >20:1 dr).

[0089] 1 H NMR (400 MHz, CDCl3): d 9.98 (s, 1H), 8.97 (s, 1H), 8.10 – 7.91 (m,3H), 7.79 (d, J = 6.8 Hz, 1H), 7.65 (s, 1H), 7.53 – 7.39 (m, 3H), 7.28 (s,1H), 3.95 – 3.46 (m, 2H), 3.36 – 3.11 (m, 2H), 2.65 (s, 1H), 2.36 – 2.10 (m,3H), 1.82 (d, J = 5.1 Hz, 2H), 1.34 – 1.21 (m, 12H) ppm. 13 C NMR (101 MHz, CDCl3): d 136.42, 133.83, 131.66, 128.74, 126.97,126.92, 126.16, 125.67, 125.47, 124.04, 85.21, 60.62, 33.15, 31.00, 30.49,28.45, 26.39, 25.15, 25.02, 24.63 ppm. 11 B NMR (128 MHz, CDCl3): d 32.91 ppm. Compound 3k: (Yield 67%, >20:1 dr).

[0090] 1 H NMR (400 MHz, CDCl3): d 10.44 (s, 1H), 8.18 (s, 1H), 4.16 (q, J =7.0 Hz, 2H), 3.85 (s, 1H), 3.52 – 3.37 (m, 2H), 2.91 (dd, J = 17.4, 5.9 Hz,1H), 2.26 (s, 2H), 1.96 – 1.79 (m, 2H), 1.30 – 1.22 (m, 15H) ppm. 13 C NMR (101 MHz, CDCl3): d 170.76, 85.44, 61.24, 57.17, 35.74, 30.49,25.95, 24.79, 24.72, 14.11 ppm. 11 B NMR (128 MHz, CDCl3): d 31.37 ppm. Compound 3l: (Yield 61%, >20:1 dr).

[0091] 1 H NMR (400 MHz, CDCl3): d 10.00 (s, 1H), 7.66 (s, 1H), 4.63 (s, 1H), 3.67 – 3.30 (m, 4H), 2.25 (d, J = 47.0 Hz, 2H), 1.30 (s, 12H) ppm. 13 C NMR (101 MHz, CDCl3): d 85.74, 69.87, 54.48, 36.01, 24.97, 24.67ppm. 11 B NMR (128 MHz, CDCl3): d 30.79 ppm. Example 4

[0092] Under ice-water bath conditions, to N -Boc-L-valine 4 (108.6 mg, 0.5 mmol) was added to a solution of hydroxybenzotriazole (HOBT, 67.6 mg, 0.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, 100.9 mg, 0.65 mmol) in CH2Cl2 (2.0 mL). After 30 minutes, 3a (116.8 mg, 0.5 mmol) and N1-Methylmorpholine (NMM, 151.7 mg, 1.5 mmol) was used, and the solution was slowly heated to room temperature. After stirring overnight, the mixture was washed successively with water, 0.1 M KHSO4 aqueous solution, and NaHCO3 aqueous solution. The organic layer was filtered through a silica gel stopper and eluted with EtOAc. The filtrate was evaporated to give compound 5 (187.1 mg, 94%, >20:1 dr).

[0093] Characterization of compound 5: 1 H NMR (500 MHz, CDCl3): d 5.30 (d, J = 9.3 Hz, 1H), 4.23 (dd, J =9.3, 6.3 Hz, 1H), 3.79 – 3.71 (m, 1H), 3.46 (td, J = 9.8, 6.6 Hz, 1H), 3.08(dd, J = 11.1, 6.7 Hz, 1H), 2.09 – 1.90 (m, 4H), 1.70 (qd, J = 11.0, 6.2 Hz,1H), 1.41 (s, 9H), 1.26 (s, 6H), 1.22 (s, 6H), 1.00 (d, J = 6.8 Hz, 3H), 0.94(d, J = 6.8 Hz, 3H) ppm. 13 C NMR (126 MHz, CDCl3): d 170.18, 155.90, 83.38, 79.21, 56.48,46.60, 31.34, 28.41, 27.60, 26.93, 24.91, 24.76, 19.32, 17.43 ppm. 11 B NMR (128 MHz, CDCl3): d 31.70 ppm. Example 5

[0094] Under ice-water bath conditions, a solution (2.5 mL) of 1,4-dioxane in 4 N hydrochloric acid was added to 5 (187.1 mg, 0.47 mmol). The reaction mixture was heated to room temperature and stirred for 12 hours. After removing the solvent under vacuum, the residue was ready for use in the next step without further purification.

[0095] The above residue and methylboric acid (44.7 mg, 0.75 mmol) were added to a small round-bottom flask and dissolved in acetone / 0.2 N HCl (1:1, 2 mL / 2 mL). The mixture was stirred overnight at room temperature. All solvent was then removed under vacuum, and the residue was diluted with water (10 mL) and extracted with DCM (3 × 10 mL). The aqueous layer was concentrated under reduced pressure to give the product Talabostat hydrochloride 6 (98 mg, 83%).

[0096] Characterization of compound 6: 1 H NMR (600 MHz, D2O): d 4.07 (d, J = 5.3 Hz, 1H), 3.67 (t, J = 8.3,1H), 3.41 (td, J = 10.4, 6.5 Hz, 1H), 2.99 (dd, J = 11.5, 7.0 Hz, 1H), 2.27 –2.20 (m, 1H), 2.07 – 2.00 (m, 2H), 1.91 – 1.82 (m, 1H), 1.68 – 1.58 (m, 1H),1.01 (d, J = 7.0 Hz, 3H), 0.91 (d, J = 6.9 Hz, 3H) ppm. 13 C NMR (101 MHz, D2O): d 166.93, 56.90, 47.60, 28.63, 26.79, 26.63,18.06, 15.72 ppm. 11 B NMR (128 MHz, D2O): d 30.77 ppm. Example 7

[0097] Under ice-water bath conditions, a solution (2.5 mL) of 1,4-dioxane in 4 N hydrochloric acid was added to 5 (190.9 mg, 0.48 mmol). The reaction mixture was heated to room temperature and stirred for 12 hours. After most of the solvent was removed under vacuum, the residue could be used in the next step without further purification.

[0098] Nicotinic acid (59.1 mg, 0.48 mmol) was dissolved in DCM (2 mL). PyBOP (301.8 mg, 0.58 mmol) was added under ice-cooling, followed by the residue from the previous step and DIPEA (186.1 mg, 1.44 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was quenched with H₂O, and the product was extracted with EtOAc. The combined organic layers were washed with saturated NH₄Cl and brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by rapid silica gel column chromatography to give product 7 (165.7 mg, 86%).

[0099] Characterization of compound 7: 1 H NMR (500 MHz, CDCl3): d 9.01 (s, 1H), 8.70 (s, 1H), 8.10 – 8.03 (m,1H), 7.39 (d, J = 8.2 Hz, 1H), 7.36 – 7.31 (m, 1H), 4.80 – 4.71 (m, 1H), 3.97– 3.88 (m, 1H), 3.55 (q, J = 9.5 Hz, 1H), 3.14 (dd, J = 10.7, 7.1 Hz, 1H), 2.22 (h, J = 6.9 Hz, 1H), 2.14 – 1.92 (m, 3H), 1.81 – 1.68 (m, 1H), 1.27 (s, 6H), 1.23 (s, 6H), 1.09 (d, J = 6.3 Hz, 3H), 1.04 (d, J = 6.7 Hz, 3H) ppm. 13 C NMR (126 MHz, CDCl3): d169.67, 165.48, 152.21, 148.58, 135.03,129.81, 123.27, 83.60, 56.13, 47.13, 31.54, 27.46, 27.03, 24.99, 24.62,19.27, 18.30 ppm. 11 B NMR (128 MHz, CDCl3): d 31.06 ppm. Example 8

[0100] Add 7 (165.7 mg, 0.41 mmol) and methylboric acid (31.9 mg, 0.53 mmol) to a small round-bottom flask and dissolve in acetone / 0.2 N HCl (1:1, 2 mL / 2 mL). Stir overnight at room temperature. Then remove all solvent under vacuum, dilute the residue with water (10 mL), and extract with DCM (3 × 10 mL). Concentrate the aqueous layer under reduced pressure to give product 8 (121.7 mg, 92%).

[0101] Characterization of compound 8: 1 H NMR (600 MHz, D2O): d 9.32 – 8.77 (m, 2H), 8.70 (d, J = 8.1 Hz,1H), 8.02 (s, 1H), 4.59 (d, J = 8.4 Hz, 1H), 3.95 (t, J = 9.1 Hz, 1H), 3.58(q, J = 10.2 Hz, 1H), 2.98 (dd, J = 11.4, 7.0 Hz, 1H), 2.24 – 2.16 (m, 1H), 2.16 – 2.10 (m, 1H), 2.10 – 2.03 (m, 1H), 1.98 – 1.90 (m, 1H), 1.69 (qd, J =11.6, 6.4 Hz, 1H), 1.01 (d, J = 6.7 Hz, 6H) ppm. 13 C NMR (151 MHz, D2O): d170.32, 165.55, 145.93, 142.88, 142.64,132.21, 126.72, 57.82, 47.55, 29.65, 26.99, 26.64, 18.22, 17.75 ppm. 11 B NMR (193 MHz, D2O): d 30.80 ppm. Example 9

[0102] Towards N -Boc-D-alanine 9 (94.6 mg, 0.5 mmol) was added to an ice-cold solution in CH2Cl2 (2.0 mL) containing hydroxybenzotriazole (HOBT, 67.6 mg, 0.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, 100.9 mg, 0.65 mmol). After stirring for 30 min, 3a (116.8 mg, 0.5 mmol) and N-methylmorpholine (NMM, 151.7 mg, 1.5 mmol) were added, and the solution was slowly heated to room temperature. After stirring overnight, the mixture was washed successively with water, 0.1 M KHSO4 aqueous solution, and NaHCO3 aqueous solution. The organic layer was filtered through a silica gel stopper and eluted with EtOAc. The solution was concentrated under vacuum to give compound 10 (176.9 mg, 96%, >20:1dr).

[0103] Characterization of compound 10: 1 H NMR (500 MHz, CDCl3): d 5.46 (d, J = 7.9 Hz, 1H), 4.40 (p, J = 7.1Hz, 1H), 3.59 (q, J = 8.4 Hz, 1H), 3.48 – 3.41 (m, 1H), 2.98 (dd, J = 10.4,6.5 Hz, 1H), 2.19 – 2.08 (m, 1H), 2.03 – 1.93 (m, 2H), 1.78 – 1.68 (m, 1H),1.44 (s, 9H), 1.29 (d, J = 6.9 Hz, 3H), 1.26 (d, J = 16.1 Hz, 12H) ppm. 13 C NMR (126 MHz, CDCl3): d 170.89, 154.87, 82.97, 79.14, 46.94,45.86, 28.29, 27.54, 26.49, 24.69, 24.59, 18.61 ppm. 11 B NMR (128 MHz, CDCl3): d 29.15 ppm. Example 10

[0104] Under ice-water bath conditions, a solution (2.5 mL) of 1,4-dioxane in 4 N hydrochloric acid was added to 10 (176.9 mg, 0.48 mmol). The reaction mixture was heated to room temperature and stirred for 12 hours. The solvent was removed under vacuum, and the residue was ready for use in the next step without further purification.

[0105] Isonicotinic acid (59.1 mg, 0.48 mmol) was dissolved in CH₂Cl₂ / DMF (1.8 mL / 0.2 mL). HATU (220.5 mg, 0.58 mmol) was added under ice-water bath conditions, followed by 2,4,6-trimethylpyridine (174.5 mg, 1.44 mmol). After stirring for 30 minutes, the residue from the previous step was added. The reaction mixture was stirred overnight at room temperature. The reaction was quenched with H₂O, and the product was extracted with EtOAc. The combined organic layers were washed with saturated NH₄Cl and brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was used for the next step without further purification (153.0 mg, 85% yield).

[0106] The residue and methylboric acid (36.8 mg, 0.615 mmol) were added to a small round-bottom flask and dissolved in acetone / 0.2 N HCl (1:1, 2 mL / 2 mL). After stirring overnight at room temperature, all solvent was removed under vacuum, and the residue was diluted with water (10 mL) and extracted with DCM (3 × 10 mL). The aqueous layer was concentrated under reduced pressure to give product 11 (116.0 mg, 98%, >20:1 dr).

[0107] Characterization of compound 11: 1 H NMR (600 MHz, D2O): d 8.96 (s, 2H), 8.35 (d, J= 6.0 Hz, 2H), 4.83(q, J = 7.2 Hz, 1H), 3.68 (dd, J = 8.8, 5.1 Hz, 2H), 3.01 (dd, J = 10.6, 7.3Hz, 1H), 2.17 – 2.11 (m, 1H), 2.11 – 2.04 (m, 1H), 2.03 – 1.96 (m, 1H), 1.70(qd, J = 10.7, 6.3 Hz, 1H), 1.46 (d, J = 7.0 Hz, 3H) ppm. 13 C NMR (151 MHz, D2O): d 171.18, 164.96, 149.33, 142.67, 125.50,48.19, 46.90, 26.95, 26.48, , 15.31 ppm. 11 B NMR (128 MHz, D2O): d 32.88 ppm. Example 11

[0108] Under ice-water bath conditions, to N -Boc amino acid 12 (241.1 mg, 0.7 mmol) was added to a solution of hydroxybenzotriazole (HOBT, 94.6 mg, 0.7 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, 141.3 mg, 0.91 mmol) in CH2Cl2 (4.0 mL). After stirring for 30 minutes, 3 (163.5 mg, 0.7 mmol) and N 1-Methylmorpholine (NMM, 212.4 mg, 2.1 mmol) was used, and the solution was slowly heated to room temperature. After stirring overnight, the mixture was washed successively with water, 0.1 M KHSO4, and NaHCO3 solution. The organic layer was filtered through a silica gel stopper and eluted with EtOAc. The filtrate was evaporated to give compound 13 (358.0 mg, 98%).

[0109] Example 12

[0110] Under ice-water bath conditions, a solution (2.5 mL) of 1,4-dioxane in 4 N hydrochloric acid was added to 13 (358.0 mg, 0.69 mmol). The reaction mixture was heated to room temperature and stirred for 12 hours. After removing the solvent under vacuum, the residue was ready for use in the next step without further purification.

[0111] The residue and methylboric acid (62.6 mg, 1.05 mmol) were added to a small round-bottom flask and dissolved in acetone / 0.2N HCl (1:1, 4 mL / 4 mL). After stirring overnight at room temperature, all volatiles were removed under vacuum. The residue was diluted with water (10 mL) and extracted with DCM (3 × 10 mL). The aqueous layer was concentrated under reduced pressure to give product 14 (184.0 mg, 97%, >20:1 dr).

[0112] Characterization of compound 14: 1 H NMR (400 MHz, D2O): d 4.13 – 3.83 (m, 3H), 3.70 – 3.61 (m, 1H), 3.46 – 3.35 (m, 2H), 3.33 – 3.14 (m, 3H), 3.09 – 2.82 (m, 1H), 2.46 – 2.34(m, 1H), 2.14 – 2.03 (m, 1H), 1.92 – 1.61 (m, 3H), 1.57 – 1.37 (m, 1H) ppm. 13 C NMR (101 MHz, D2O): d 162.59, 55.68, 47.24, 46.46, 46.43, 44.52,27.16, 26.73, 26.35 ppm. 11 B NMR (128 MHz, D2O): d 32.78 ppm. The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A ligand, characterized in that, It has the structure shown in equation (L1): 。 2. A method for preparing the ligand according to claim 1, characterized in that, include ； Step (1): The compound shown in formula (S1) and the compound shown in formula (S2) are reacted in the presence of sodium hydride to obtain the compound shown in formula (S3); Step (2): The compound shown in formula (S3) is reacted in the presence of n-butyllithium and Ph2SiHCl, and further reacted with THF·BH3 to obtain the compound shown in formula (S4); Step (3): The compound shown in formula (S4) is reacted with DABCO to prepare the compound shown in formula (L1).

3. The preparation method according to claim 2, characterized in that, The molar ratio of the compound shown in formula (S1) to the compound shown in formula (S2) is 1:(0.5~5); Alternatively, the molar ratio of the compound shown in formula (S1) to sodium hydride is 1:(0.5~5). Alternatively, step (1) can be carried out at room temperature for 20-28 hours; Alternatively, the molar ratio of the compound shown in formula (S3) to n-butyllithium is 1:(0.5~5). Alternatively, the molar ratio of the compound shown in formula (S3) to Ph2SiHCl is 1:(0.5~5); Alternatively, the compound shown in formula (S3) is reacted at -78°C for 1-2 h in the presence of n-butyllithium, followed by the addition of Ph2SiHCl and the reaction being brought to room temperature overnight, and then the temperature is raised to 60-65°C for 2-5 h. Alternatively, the molar ratio of the compound shown in formula (S3) to THF·BH3 is 1:(0.5~5). Alternatively, in step (2), THF·BH3 solution is added under an argon atmosphere and reacted at room temperature for 10-15 hours; Alternatively, the molar ratio of the compound shown in formula (S4) to DABCO is 1:(0.5~5). Alternatively, step (3) can be carried out at 45-55℃ for 10-15 hours.

4. A method for preparing 2-pinacolborate pyrrolidine, characterized in that, include: ； The compound shown in formula (1') was reacted with B2pin2 in the presence of the ligand shown in formula (L1), [Ir(cod)OMe]2 and anhydrous cyclohexane to prepare the compound shown in formula (2'); R a R b R c R d R e and R f Each is independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, arylalkyl, hydroxyalkyl, cycloalkylalkyl, fluorinated arylalkyl, alkyl-OC(=O)-alkyl, HOC(=O)-alkyl, alkyl-C(=O)-, alkyl-OC(=O)-, aryl-C(=O)-, heteroaryl-C(=O)-, aryl-OC(=O)-, aryl, heterocyclic, alkyl-OC(=O)-heterocyclic or alkyl; or R d and R e Together with the attached carbon atom, it forms cycloalkyl or aryl groups.

5. The preparation method according to claim 4, characterized in that, The preparation method involves reacting at 0~80℃ for 10~50 hours; Alternatively, the amount of ligand used in formula (L1) is 1-15 mol% of the amount of compound used in formula (1'). Alternatively, the amount of [Ir(cod)OMe]2 added is 1~15 mol% of the amount of the compound shown in formula (1'). Alternatively, the molar ratio of the compound shown in formula (1') to B2pin2 is 1:(0.1~1). Or, R a R b R c R d R e and R f Each is independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C 6-12 Aryl C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-12 cycloalkyl C 1-6 Alkyl, fluorinated C 6-12 Aryl C 1-6 Alkyl, C 1-6 Alkyl-OC(=O)-C 1-6 Alkyl, HOC(=O)-C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-OC(=O)-, C 6-12 Aryl-C(=O)-, C 1-12 heteroaryl-C(=O)-, C 6-12 Aryl-OC(=O)-, C 6-12 Aryl, C 2-12 Heterocyclic group, C 1-6 Alkyl-OC(=O)-C 2-12 Heterocyclic group or C 1-6 Alkyl; or R d and R e Together with the attached carbon atom, they form C 3-12 cycloalkyl or C 6-12 Aryl.

6. A method for efficiently preparing peptide boric acid inhibitors, characterized in that, include ； Wherein, "*" indicates R configuration, S configuration, or racemic configuration; Step A: Acidify the compound shown in formula (2') to prepare the compound shown in formula (3'); Step B: The compound shown in formula (3') reacts with the amino acid shown in formula (III) to obtain the compound shown in formula (I); Step C: The compound shown in formula (I) is further reacted to obtain the peptide boric acid inhibitor shown in formula (II); R a R b R c R d R e and R f It has the definition as described in claim 4; R 1 R 1a R 2a and R 2 Each is independently selected from hydrogen, alkyl-C(=O)-, alkyl-OC(=O)-, aryl-C(=O)-, heteroaryl-C(=O)-, aryl-OC(=O)-, aryl, heterocyclic, alkyl-OC(=O)-heterocyclic or alkyl; R 3 It can be hydrogen, cycloalkyl, heterocyclic, aryl, alkylaryl, heteroaryl, or alkyl.

7. The preparation method according to claim 6, characterized in that, R 1 R 1a R 2a and R 2 Each is independently selected from hydrogen and C. 1-12 Alkyl-C(=O)-, C 1-12 Alkyl-OC(=O)-, C 6-12 Aryl-C(=O)-, C 1-12 heteroaryl-C(=O)-, C 6-12 Aryl-OC(=O)-, C 6-12 Aryl, C 2-12 Heterocyclic group, C 1-12 Alkyl-OC(=O)-C 2-12 Heterocyclic group or C 1-12 alkyl; Or, R 3 For hydrogen, C 3-12 cycloalkyl, C 2-12 Heterocyclic group, C 6-12 Aryl, C 1-12 Alkyl C 6-12 Aryl, C 1-12 heteroaryl or C 1-12 alkyl; Or, R 1 R 1a R 2a and R 2 Each is independently selected from hydrogen, methyl-C(=O)-, ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, n-butyl-C(=O)-, tert-butyl-C(=O)-, n-pentyl-C(=O)-, n-hexyl-C(=O)-, methyl-OC(=O)-, ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)- n-Butyl-OC(=O)-, tert-Butyl-OC(=O)-, n-Pentyl-OC(=O)-, n-Hexyl-OC(=O)-, phenyl-C(=O)-, 3-pyridyl-C(=O)-, 4-pyridyl-C(=O)-, 3-pyrrolidinyl, tert-Butyl-OC(=O)-3-pyrrolidinyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl or n-hexyl; Or, R 3 It can be hydrogen, 3-pyrrolidinyl, 2-pyrrolidinyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, or n-hexyl.

8. The preparation method according to claim 6, characterized in that, The compound represented by formula (I) is selected from one of the following structures: 、 、 ； Alternatively, the amino acid represented by formula (III) is selected from one of the following structures: 、 、 ； Alternatively, the peptide borate inhibitor shown in formula (II) is selected from one of the following structures: 、 、 、 。 9. The preparation method according to claim 6, characterized in that, Step A, the acid used for acidification is selected from at least one of hydrochloric acid, sulfuric acid, and nitric acid; Alternatively, the molar ratio of the compound shown in formula (3') to the amino acid shown in formula (III) is 1:(0.5~5); Alternatively, in step B, at -5 to 5°C, the amino acids shown in formula (III) are reacted in HOBT, EDC, and... N The compound shown in formula (I) was prepared by reacting the compound shown in formula (3') with the compound shown in formula (I) in the presence of methylmorpholine; Alternatively, the molar ratio of the amino acid and HOBT shown in formula (III) is 1:(0.5~5). Alternatively, the molar ratio of the amino acid and EDC shown in formula (III) is 1:(0.5~5). Or, the amino acids shown in formula (III) and N The molar ratio of methylmorpholine is 1:(0.5~5).

10. The preparation method according to claim 6, characterized in that, Step C: After the compound shown in formula (I) reacts with hydrochloric acid, it is further reacted with an acid compound in an acetone-hydrochloric acid mixture to obtain the peptide boric acid inhibitor shown in formula (II); or, the acid compound is methylboric acid; or, the molar ratio of the compound shown in formula (I) to the acid compound is 1:(0.5~5); or, the volume ratio of acetone to hydrochloric acid in the acetone-hydrochloric acid mixture is 1:(0.5~5); or, the reaction is carried out at 15~35℃ for 8~12h. Alternatively, in step C, after the compound shown in formula (I) reacts with hydrochloric acid, it is further reacted with an acid compound in the presence of PyBOP and DIPEA to obtain the peptide boric acid inhibitor shown in formula (II); or, the acid compound is nicotinic acid; or, the molar ratio of the compound shown in formula (I) to the acid compound is 1:(0.5~5); or, the molar ratio of the compound shown in formula (I) to PyBOP is 1:(0.5~5); or, the molar ratio of the compound shown in formula (I) to DIPEA is 1:(0.5~5); or, the reaction is carried out at 15~35℃ for 8~12h. Alternatively, in step C, after the compound shown in formula (I) reacts with hydrochloric acid, it is further reacted with an acid compound in the presence of HATU and 2,4,6-trimethylpyridine to prepare the peptide boric acid inhibitor shown in formula (II); or, the acid compound is isonicotinic acid; or, the molar ratio of the compound shown in formula (I) to the acid compound is 1:(0.5~5); or, the molar ratio of the compound shown in formula (I) to HATU is 1:(0.5~5); or, the molar ratio of the compound shown in formula (I) to 2,4,6-trimethylpyridine is 1:(0.5~5); or, the reaction is carried out at 15~35°C for 8~12 h.

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