Boron-10 isotope labeled borate compound and synthesis method thereof

Abstract

The invention relates to the technical field of organic synthesis, in particular to boron-10 isotope labeled borate compounds and a synthesis method thereof. According to the method, boron trifluoride-10 and aryl iodide or aryl bromide are used as raw materials for the first time, and boron-10-labeled boric acid ester and derivatives thereof are efficiently synthesized in the presence of a transition metal nickel catalyst and a reducing agent zinc. Boron trifluoride-10 is used as a specific boron-10 source and is an ideal precursor for synthesizing a target isotope compound. The method is novel in route, mild in reaction condition and high in atom economy. Compared with the prior art, the method has the characteristics of high raw material pertinence, simplicity and convenience in operation, mild conditions, suitability for green synthesis of isotope labeled compounds and the like, and a new way is provided for preparation of boron-10 labeled functional molecules.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a boron-10 isotope-labeled borate ester compound and its synthesis method. Background Technology

[0002] Boron neutron capture therapy (BNCT) is a promising targeted cancer treatment technology. Its core principle is the use of boron-10 (… 10 B) Isotopes undergo nuclear fission after capturing thermal neutrons, producing high-energy amine alpha particles and lithium-7. These particles can precisely destroy tumor cells within the micrometer range, thereby effectively protecting surrounding healthy tissues. 10 B-type neutrons are an ideal vector for BNCT due to their extremely high thermal neutron capture cross-section (3835 barns), but the key to successful treatment lies in achieving a sufficiently high concentration of neutrons within tumor cells. 10 B concentration.

[0003] However, the development of BNCT faces serious challenges. Currently, only two drugs (L-BPA and BSH) are used clinically, with L-BPA being the only one approved by the FDA. A fundamental bottleneck lies in the availability of BNCTs in nature. 10 Boron trifluoride (BF3) has a low abundance (19.8%), necessitating isotopic enrichment. Currently, the main industrial method for producing enriched BF3 is chemical exchange distillation using boron trifluoride (BF3) as a raw material. 10 BF3. Despite 10 BF3 is the most important in business. 10 The source is B, but how to directly utilize it to construct the crucial carbon-boron (C-) group in organic molecules is a question. 10 The B) bond remains an unsolved problem. This significantly limits its potential applications in BNCT drug development. 10 B. Compound diversity (Expert Rev. Mol. Med. 2022, 24, e14; Clin. Cancer Res. 2005, 11, 3987-4002; Med. Res. Rev. 2023, 43, 1809-1830; J. Radioanal. Nucl. Chem. 2019, 320, 785-791; Chem. Rev. 2016, 116, 9091-9161; Chem. Rev. 2021, 121, 13238-13341; Chem. Rev. 2021, 121, 3561-3597).

[0004] In terms of synthetic methods, traditional strategies (such as reacting organolithium reagents with borate esters) suffer from problems such as cumbersome steps and poor functional group tolerance. Although recent studies have successfully synthesized [these methods]... 10 BF3 was synthesized 10B-labeled boron reagents are C- 10 The construction of B bonds offers a new approach, but this method still requires multiple separation operations and is not direct or efficient enough. Therefore, it is necessary to develop a method that can be directly and commercially available. 10 Using BF3 as a raw material, C- can be constructed efficiently and easily. 10 New methods for B-bonding have become an urgent need in this field. Summary of the Invention

[0005] To address the aforementioned problems, this invention provides a boron-10 isotope-labeled borate ester compound and its synthesis method. The synthesis method provided by this invention is the first to use boron-10 trifluoride (… 10 Boron-10 labeled boron esters and their derivatives can be efficiently synthesized from aryl iodine or aryl bromide using BF3 as a starting material in the presence of a transition metal nickel catalyst and a reducing agent zinc. Boron-10 trifluoride, as a specific source of boron-10, is an ideal precursor for the synthesis of target isotope compounds. This method is novel, with mild reaction conditions and high atom economy. Compared with existing technologies, this invention features strong raw material targeting, simple operation, mild conditions, and applicability to the green synthesis of isotope-labeled compounds, providing a new route for the preparation of boron-10 labeled functional molecules. The core highlight of this invention lies in the pioneering development of a nickel-catalyzed reduction coupling strategy, which successfully achieves direct synthesis of commercially available boron-10 labeled compounds through a boron ion activation mechanism. 10 BF3 was used as a boron source to construct C- 10 The B bond has broken through a key synthetic bottleneck for the development of BNCT drugs (Tetrahedron Lett. 2008, 49, 4977-4980; Chem 2023, 9, 3212-3223; Chem 2023, 9, 3015-3017).

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] This invention provides a boron-10 isotope-labeled borate ester compound, the structural formula of which is shown in Formula I:

[0008]

[0009] In Formula I, R1 represents a substituent on the double bond, which can be monosubstituted or polysubstituted. The double bond can be an aromatic ring, and each R1 is independently selected from: hydrogen, substituted or unsubstituted C1-C. 20 Alkyl, substituted or unsubstituted C1-C 20 The five- or eight-membered ring is formed between two adjacent carbons on an alkoxy group, a thiomethyl group, an ester group, a substituted or unsubstituted aryl group, or a five- or eight-membered ring, wherein the five- or eight-membered ring is connected to another aryl fused ring, and the five- or eight-membered ring may be a five- or eight-membered heterocycle.

[0010] Replacement C1-C 20 Alkyl, substituted C1-C 20 The substituents in alkoxy and substituted aryl groups are halogens, C1-C 20 Alkyl, C1-C 20 Alkoxy or halogen-substituted C1-C 20 Any one of alkyl, thiomethyl, ester, and aryl groups;

[0011] Y is selected from either an oxygen atom or a nitrogen atom;

[0012] R2 indicates Where n is 0 or 1, when n is 1, there is a substituent on the methylene group, selected from: C1-C6 alkyl, substituted or unsubstituted aryl;

[0013] R3, R4, R5, and R6 are each independently selected from hydrogen, C1-C6 alkyl, substituted or unsubstituted aryl groups, and R3 and R4 cannot be substituted or unsubstituted aryl groups at the same time, and R5 and R6 cannot be substituted or unsubstituted aryl groups at the same time.

[0014] R2 indicates a substituted or unsubstituted naphthyl group.

[0015] In substituted aryl and substituted naphthyl groups, the substituents are halogenated and C1-C. 20 Alkyl, C1-C 20 Alkoxy or halogen-substituted C1-C 20 Any one of alkyl, ester, or aryl groups.

[0016] Preferably, the structural formula of the borate ester compound is shown in any one of formulas I-1 to I-24:

[0017]

[0018]

[0019] This invention also provides a method for synthesizing boron-10 isotope-labeled borate ester compounds, comprising the following steps:

[0020] 1) Under a nitrogen atmosphere, the compound shown in Formula III is mixed with boron trifluoride, anisole, nickel catalyst, reducing agent, organic base and Lewis acid shown in Formula IV, and then subjected to a reduction coupling reaction to obtain the reactant, the structural formula of which is shown in Formula V.

[0021]

[0022] In Equation III, R1 is defined the same as R1 in Equation I, and X represents I or Br;

[0023] In equation V, R1 is defined the same as R1 in equation I;

[0024] 2) React the reactants described in step 1) with the compound shown in formula VI to obtain formula V, then add triethylamine and react to obtain formula I;

[0025]

[0026] In Equation VI, the definitions of n, Y, R3, R4, R5, and R6 are the same as those in Equation I;

[0027] 3) Concentrate the reaction solution described in step 2), and then perform silica gel chromatography to separate the borate ester compounds.

[0028] Preferably, the molar ratio of the compound shown in Formula III to the volume molar ratio of boron trifluoride shown in Formula IV in step 1) is 0.2 mol: 0.4 mmol.

[0029] The nickel catalyst comprises (dmphen)NiBr2, and the molar ratio of the nickel catalyst to the compound shown in Formula III is 1:10.

[0030] Preferably, the reducing agent in step 1) comprises zinc, wherein the molar ratio of zinc to the compound shown in Formula III is 3:1;

[0031] The organic base includes N,N-diisopropylethylamine, and the molar ratio of the organic base to the compound shown in Formula III is 2:1.

[0032] Preferably, the Lewis acid in step 1) comprises aluminum chloride, and the molar ratio of the Lewis acid to the compound shown in Formula III is 0.22:0.2.

[0033] Preferably, the conditions for the reductive coupling reaction in step 1) include: a temperature of 80–90°C and a time of 12 h.

[0034] Preferably, in step 2), the molar ratio of the compound represented by Formula III, triethylamine, and the compound represented by Formula VI is 1:2:2.

[0035] Preferably, the reaction conditions in step 2) include: a temperature of 20–30°C and a time of 1 hour.

[0036] Preferably, in step 3), the stationary phase for silica gel chromatography is 200-mesh silica gel, and the mobile phase is petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate is 50:1.

[0037] The beneficial effects of this invention are:

[0038] The method of this invention uses boron trifluoride-10 for the first time ( 10Boron-10 labeled boron esters and their derivatives can be efficiently synthesized from boron trifluoride (BF3) using iodobenzene or bromobenzene as raw materials in the presence of a transition metal nickel catalyst and a reducing agent zinc. Boron-10 trifluoride, as a specific source of boron-10, is an ideal precursor for the synthesis of target isotope compounds. This method is novel, with mild reaction conditions and high atom economy. Compared with existing technologies, this invention features strong raw material targeting, simple operation, mild conditions, and applicability to the green synthesis of isotope-labeled compounds, providing a new route for the preparation of boron-10 labeled functional molecules. Attached Figure Description

[0039] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the accompanying drawings used in the embodiments will be briefly described below.

[0040] Figure 1 The mass spectrometry comparison data of the compound shown in Formula I-1 is shown in the figure.

[0041] Figure 2 The mass spectrometry comparison data of the compound shown in Formula I-2 is shown in the figure.

[0042] Figure 3 Mass spectrometry comparison data of the compounds shown in Formula I-3;

[0043] Figure 4 Mass spectrometry comparison data of the compounds shown in Formula I-4;

[0044] Figure 5 Mass spectrometry comparison data of the compounds shown in Formula I-5;

[0045] Figure 6 Mass spectrometry comparison data of the compounds shown in Formula I-6;

[0046] Figure 7 Mass spectrometry comparison data of the compounds shown in Formula I-7;

[0047] Figure 8 Mass spectrometry comparison data of the compounds shown in Formula I-8;

[0048] Figure 9 Mass spectrometry comparison data of the compounds shown in Formula I-9;

[0049] Figure 10 The mass spectrometry comparison data of the compound shown in Formula I-10 is shown in the figure.

[0050] Figure 11 The mass spectrometry comparison data of the compound shown in Formula I-1 is shown in the figure.

[0051] Figure 12 The mass spectrometry comparison data of the compound shown in Formula I-12 is shown in the figure.

[0052] Figure 13 The mass spectrometry comparison data of the compound shown in Formula I-13 is shown in the figure.

[0053] Figure 14 The mass spectrometry comparison data of the compound shown in Formula I-14 is shown in the figure.

[0054] Figure 15 The mass spectrometry comparison data of the compound shown in Formula I-15 is shown in the figure.

[0055] Figure 16 The mass spectrometry comparison data of the compound shown in Formula I-16 is shown in the figure.

[0056] Figure 17 The mass spectrometry comparison data of the compound shown in Formula I-17 is shown in the figure.

[0057] Figure 18 The mass spectrometry comparison data of the compound shown in Formula I-18 is shown in the figure.

[0058] Figure 19 The mass spectrometry comparison data of the compound shown in Formula I-19 is shown in the figure.

[0059] Figure 20 The mass spectrometry comparison data of the compound shown in Formula I-20 is shown in the figure.

[0060] Figure 21 The mass spectrometry comparison data of the compound shown in Formula I-21 is shown in the figure.

[0061] Figure 22 Mass spectrometry comparison data of the compound shown in Formula I-22;

[0062] Figure 23 The mass spectrometry comparison data of the compound shown in Formula I-23 is shown in the figure.

[0063] Figure 24 This is a comparison of mass spectrometry data for the compound shown in Formula I-24. Detailed Implementation

[0064] This invention provides a boron-10 isotope-labeled borate ester compound, the structural formula of which is shown in Formula I:

[0065]

[0066] In Formula I, R1 represents a substituent on the double bond, which can be monosubstituted or polysubstituted. The double bond can be an aromatic ring, and each R1 is independently selected from: hydrogen, substituted or unsubstituted C1-C. 20 Alkyl, substituted or unsubstituted C1-C 20The five- or eight-membered ring is formed between two adjacent carbons on an alkoxy group, a thiomethyl group, an ester group, a substituted or unsubstituted aryl group, or a five- or eight-membered ring, wherein the five- or eight-membered ring is connected to another aryl fused ring, and the five- or eight-membered ring may be a five- or eight-membered heterocycle.

[0067] Replacement C1-C 20 Alkyl, substituted C1-C 20 The substituents in alkoxy and substituted aryl groups are halogens, C1-C 20 Alkyl, C1-C 20 Alkoxy or halogen-substituted C1-C 20 Any one of alkyl, ester, or aryl groups;

[0068] Y is selected from either an oxygen atom or a nitrogen atom;

[0069] R2 indicates Where n is 0 or 1, when n is 1, there is a substituent on the methylene group, selected from: C1-C6 alkyl, substituted or unsubstituted aryl;

[0070] R3, R4, R5, and R6 are each independently selected from hydrogen, C1-C6 alkyl, substituted or unsubstituted aryl groups, and R3 and R4 cannot be substituted or unsubstituted aryl groups at the same time, and R5 and R6 cannot be substituted or unsubstituted aryl groups at the same time.

[0071] R2 indicates a substituted or unsubstituted naphthyl group.

[0072] In substituted aryl and substituted naphthyl groups, the substituents are halogenated and C1-C. 20 Alkyl, C1-C 20 Alkoxy or halogen-substituted C1-C 20 Any one of alkyl, ester, or aryl groups.

[0073] In this invention, the preferred structural formula of the borate ester compound is as shown in any one of formulas I-1 to I-24:

[0074]

[0075]

[0076] This invention also provides a method for synthesizing boron-10 isotope-labeled borate ester compounds, comprising the following steps:

[0077] 1) Under a nitrogen atmosphere, the compound shown in Formula III is mixed with boron trifluoride, anisole, nickel catalyst, reducing agent, organic base and Lewis acid shown in Formula IV, and then subjected to a reduction coupling reaction to obtain the reactant, the structural formula of which is shown in Formula V.

[0078]

[0079] In Equation III, R1 is defined the same as R1 in Equation I, and X represents I or Br;

[0080] In equation V, R1 is defined the same as R1 in equation I;

[0081] 2) React the reactants described in step 1) with the compound shown in formula VI to obtain formula V, then add triethylamine and react to obtain formula I;

[0082]

[0083] In Equation VI, the definitions of n, Y, R3, R4, R5, and R6 are the same as those in Equation I;

[0084] 3) Concentrate the reaction solution described in step 2), and then perform silica gel chromatography to separate the borate ester compounds.

[0085] In this invention, under a nitrogen atmosphere, a reductive coupling reaction is carried out by mixing the compound shown in Formula III with boron trifluoride, anisole, a nickel catalyst, a reducing agent, an organic base, and a Lewis acid, as shown in Formula IV, to obtain a reactant. The structural formula of the reactant is shown in Formula V. In this invention, the molar ratio of the compound shown in Formula III to the volume of boron trifluoride and the molar ratio of anisole shown in Formula IV is preferably 0.2 mmol:48 μL:0.2 mol. In this invention, the nickel catalyst preferably comprises (dmphen)NiBr2, and the molar ratio of the nickel catalyst to the compound shown in Formula III is preferably 1:10. In this invention, the reducing agent preferably comprises zinc, and the molar ratio of zinc to the compound shown in Formula III is preferably 3:1. In this invention, the organic base preferably comprises N,N-diisopropylethylamine (DIPEA), and the molar ratio of the organic base to the compound shown in Formula III is preferably 1:1. In this invention, the Lewis acid preferably comprises aluminum chloride, and the molar ratio of the Lewis acid to the compound shown in Formula III is preferably 0.23:0.2. In this invention, the preferred conditions for the reductive coupling reaction are: a temperature of 80–90°C and a time of 12 h.

[0086] In this invention, the reactants are reacted with the compound shown in Formula VI to obtain Formula V, and then triethylamine is added and reacted again to obtain Formula I. In this invention, the molar ratio of the compound shown in Formula III, triethylamine, and the compound shown in Formula VI is 1:2:2. The compound shown in Formula VI is designated as (RYH)2. In this invention, the preferred reaction conditions include a temperature of 20–30°C and a reaction time of 1 hour.

[0087] In this invention, the reaction solution is concentrated and then separated by silica gel chromatography to obtain borate ester compounds. In this invention, the stationary phase for silica gel chromatography is preferably 200-mesh silica gel, and the mobile phase is preferably petroleum ether and ethyl acetate, with a preferred volume ratio of 50:1.

[0088] To further illustrate the present invention, the following detailed description is provided in conjunction with embodiments, but these should not be construed as limiting the scope of protection of the present invention.

[0089] Examples 1-18

[0090] Synthesize compounds shown in formulas I-1 to I-18

[0091] The compound shown in Formula I-1 was synthesized according to the synthetic route diagram shown, and the specific steps are as follows:

[0092] The pre-dried reaction tube was lowered to room temperature under vacuum. In a nitrogen-filled glove box, DIPEA (0.2 mmol, 2.0 equiv) and anisole (1.0 ml, 0.2 M) were sequentially introduced into a dry tube equipped with a magnetic stir bar. The mixture was cooled to -35°C, and then... 10 BF3OEt2 (48 μl, 0.4 mmol), AlCl3 (29 mg, 0.23 mmol), (dmphenNiBr2) (0.02 mmol, 10% mol), zinc powder (0.6 mmol, 3.0 equiv), and aryl iodine or aryl bromide of formula III-1 (0.2 mmol, 1.0 equiv) were added. The mixture was stirred at 80-90 °C for 12 h. After the reaction was complete, Et3N (0.4 mmol, 2.0 equiv) and pinacol (a type of formula VI) (0.4 mmol, 2.0 equiv) were added, and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated and subjected to column chromatography (stationary phase: 200 mesh silica gel; mobile phase: petroleum ether and ethyl acetate in a volume ratio of 100-50:1) to obtain compounds of formulas I-1 to I-18 after separation and purification.

[0093] R represents a substituent on the double bond, which can be monosubstituted or polysubstituted. The double bond can be an aromatic ring, and each R is independently selected from: hydrogen, substituted or unsubstituted C1-C. 20 Alkyl, substituted or unsubstituted C1-C 20 The five- or eight-membered ring is formed between two adjacent carbons on an alkoxy group, a thiomethyl group, an ester group, a substituted or unsubstituted aryl group, or a five- or eight-membered ring, wherein the five- or eight-membered ring is connected to another aryl fused ring, and the five- or eight-membered ring may be a five- or eight-membered heterocycle.

[0094] Replacement C1-C 20 Alkyl, substituted C1-C 20The substituents in alkoxy and substituted aryl groups are halogens, C1-C 20 Alkyl, C1-C 20 Alkoxy or halogen-substituted C1-C 20 Any one of alkyl, thiomethyl, ester, and aryl groups

[0095]

[0096] Its structural formula is:

[0097]

[0098] The compound shown in Formula I-1 was derived from aryl iodine compounds in 56% (22.8 mg) yield and from aryl bromide compounds in 50% (20.3 mg) yield. The structural confirmation data are as follows:

[0099] 1 H NMR (400MHz, CDCl3) δ7.84-7.78(m,2H),7.49-7.41(m,1H),7.40-7.33(m,2H),1.34(s,12H). 13 C NMR (101MHz, CDCl3) δ134.9,131.4,127.8,83.9,25.0.

[0100] Mass spectrometry comparison data of ordinary boron and 10B are as follows: Figure 1 As shown.

[0101]

[0102] The compound shown in Formula I-2 was derived from aryl iodides in 61% (26.5 mg) yield and from aryl bromides in 51% (22.1 mg) yield. The structural confirmation data are as follows:

[0103] 1 H NMR (400MHz, CDCl3) δ7.70 (d, J = 7.7Hz, 2H), 7.18 (d, J = 7.7Hz, 2H), 2.36 (s, 3H), 1.33 (s, 12H). 13 C NMR (101MHz, CDCl3) δ141.5,134.9,128.7,83.7,25.0,21.8.

[0104] Mass spectrometry comparison data of ordinary boron and 10B are as follows: Figure 2 As shown.

[0105]

[0106] The compound shown in Formula I-3 was derived from aryl iodides in 65% (33.6 mg) yield and from aryl bromides in 65% (33.7 mg) yield. The structural confirmation data are as follows:

[0107] 1 H NMR (400MHz, CDCl3) δ7.78-7.74(m,2H),7.43-7.39(m,2H),1.34(s,12H),1.32(s,9H) 13 C NMR (151MHz, CDCl3) δ154.7,134.8,124.9,83.8,35.0,31.3,25.0.

[0108] Mass spectrometry comparison data of ordinary boron and 10B are as follows: Figure 3 As shown.

[0109]

[0110] The compound shown in Formula I-4 has a yield of 63% (29.4 mg) derived from aryl iodides and 60% (28.0 mg) derived from aryl bromides. The structural confirmation data are as follows:

[0111] 1 H NMR (400MHz, CDCl3) δ7.75 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 3.83 (s, 3H), 1.33 (s, 12H). 13 C NMR (101MHz, CDCl3) δ162.3,136.7,113.4,83.7,55.2,25.0.

[0112] Mass spectrometry comparison data of ordinary boron and 10B are as follows: Figure 4 As shown.

[0113]

[0114] The compound shown in Formula I-5 was derived from aryl iodides in 58% (32.4 mg) yield and from aryl bromides in 51% (28.5 mg) yield. The structural confirmation data are as follows:

[0115] 1 H NMR (400MHz, CDCl3) δ7.9 (d, J = 7.8Hz, 2H), 7.66-7.57 (m, 4H), 7.48-7.40 (m, 2H), 7.39-7.31 (m, 1H), 1.36 (s, 12H). 13C NMR (101MHz, CDCl3) δ144.0,141.2,135.4,128.9,127.7,127.4,126.6,84.0,25.0.

[0116] Mass spectrometry comparison data of ordinary boron and 10B are as follows: Figure 5 As shown.

[0117]

[0118] The compound shown in Formula I-6 was derived from aryl iodides in 67% (33.4 mg) yield and from aryl bromides in 55% (27.4 mg) yield. The structural confirmation data are as follows:

[0119] 1 H NMR (400MHz, CDCl3) δ7.70 (d, J = 8.1Hz, 2H), 7.22 (d, J = 8.2Hz, 2H), 2.49 (s, 3H), 1.34 (s, 12H). 13 C NMR (101MHz, CDCl3) δ142.7,135.2,125.1,83.9,25.0,15.2.

[0120] Mass spectrometry comparison data of ordinary boron and 10B are as follows: Figure 6 As shown.

[0121]

[0122] The compound shown in Formula I-7 was derived from aryl iodides in 56% (41.5 mg) yield and from aryl bromides in 59% (43.7 mg) yield. The structural confirmation data are as follows:

[0123] 1 H NMR (400MHz, CDCl3) δ7.66 (d, J = 8.4Hz, 2H), 7.27-7.20 (m, 4H), 7.14-7.07 (m, 4H), 7.07-6.99 (m, 4H), 1.33 (s, 12H). 13 C NMR (101MHz, CDCl3) δ150.7,147.5,136.0,129.4,125.1,123.5,121.9,83.7,25.0.

[0124] Mass spectrometry comparison data of ordinary boron and 10B are as follows: Figure 7 As shown.

[0125]

[0126] The compound shown in Formula I-8 has a yield of 65% (33.6 mg) from aryl iodides and 65% (33.7 mg) from aryl bromides. The structural confirmation data are as follows:

[0127] 1 H NMR (400MHz, CDCl3) δ8.13(d,J=7.8Hz,2H),8.04(d,J=8.2Hz,2H),7.58(d,J=8.2Hz,2H),7.47-7.35(m,4H),7.32-7.26(m,2H),1.39(s,12H). 13 C NMR (101MHz, CDCl3) δ140.7,140.5,136.5,126.2,126.1,123.7,120.4,120.2,110.0,84.2,25.1.

[0128] Mass spectrometry comparison data of ordinary boron and 10B are as follows: Figure 8 As shown.

[0129]

[0130] The compound shown in Formula I-9 has a yield of 65% (33.6 mg) from aryl iodides and 65% (33.7 mg) from aryl bromides. The structural confirmation data are as follows:

[0131] 1 H NMR (400MHz, CDCl3) δ8.05 (s, 1H), 7.80 (d, J = 7.3Hz, 1H), 7.73-7.66 (m, 1H), 7.66-7.56 (m, 2H), 7.48-7.39 (m, 3H), 7.36-7.30 (m, 1H), 1.36 (s, 12H). 13 C NMR (101MHz, CDCl3) δ141.3,140.7,133.8,133.7,130.2,128.8,128.3,127.4,127.3,84.0,25.0.

[0132] Mass spectrometry comparison data of ordinary boron and 10B are as follows: Figure 9 As shown.

[0133]

[0134] The compound shown in Formula I-10 was derived from aryl iodides in 51% (33.4 mg) yield and from aryl bromides in 49% (33.0 mg) yield. The structural confirmation data are as follows:

[0135] 1H NMR (400MHz, CDCl3) δ8.05(d,J=1.6Hz,1H),7.99(dd,J=7.7,1.6Hz,1H),7.76(d,J=7.8Hz,1H),7.44-7.36(m,5H),3.92(s,3H),1.21(s,12H). 13 C NMR (101MHz, CDCl3) δ167.2,147.7,142.4,134.5,131.5,129.8,129.2,128.1,127.4,127.2,84.3,52.3,24.7.

[0136] Mass spectrometry comparison data of ordinary boron and 10B are as follows: Figure 10 As shown.

[0137]

[0138] The compound shown in Formula I-11 was derived from aryl iodides in 29% (17.6 mg) yield and from aryl bromides in 45% (27.4 mg) yield. The structural confirmation data are as follows:

[0139] 1 H NMR (400MHz, CDCl3) δ7.81-7.74(m,1H),7.66-7.52(m,2H),7.47-7.31(m,5H),1.20(s,12H). 13 C NMR (101MHz, CDCl3) δ148.4,141.1,135.0,132.1,129.6,129.0,128.3,128.0,119.0,113.7,84.6,24.7.

[0140] Mass spectrometry comparison data of ordinary boron and 10B are as follows: Figure 11 As shown.

[0141]

[0142] The compound shown in Formula I-12 was derived from aryl iodides in 88% (53.3 mg) yield and from aryl bromides in 71% (43.0 mg) yield. The structural confirmation data are as follows:

[0143] 1 H NMR (400MHz, CDCl3) δ8.50-8.43(m,3H),8.03-7.96(m,2H),7.56-7.41(m,4H),1.58(s,12H). 13C NMR (101MHz, CDCl3) δ136.0,131.3,129.6,128.9,128.4,125.9,125.0,84.5,25.3.

[0144] Mass spectrometry comparison data of ordinary boron and 10B are as follows: Figure 12 As shown.

[0145]

[0146] The compound shown in Formula I-13 was derived from aryl iodides in 79% (38.7 mg) yield and from aryl bromides in 70% (34.3 mg) yield. The structural confirmation data are as follows:

[0147] 1 H NMR (400MHz, CDCl3) δ7.66 (s, 1H), 7.64-7.57 (m, 1H), 6.79 (d, J = 8.0Hz, 1H), 4.57 (dd, J = 9.2, 8.3Hz, 2H), 3.19 (t, J = 8.7Hz, 2H), 1.33 (s, 12H). 13 C NMR (151MHz, CDCl3) δ163.0,135.7,131.6,126.6,109.1,83.6,71.5,29.3,25.0.

[0148] Mass spectrometry comparison data of ordinary boron and 10B are as follows: Figure 13 As shown.

[0149]

[0150] The compound shown in Formula I-14 was derived from aryl iodides in 48% (24.9 mg) yield and from aryl bromides in 50% (25.9 mg) yield. The structural confirmation data are as follows:

[0151] 1 H NMR (400MHz, CDCl3) δ8.41-8.34(m,1H),8.08(s,1H),7.92-7.85(m,1H),7.44-7.38(m,1H),7.36-7.31(m,1H),1.38(s,12H). 13 C NMR (151MHz, CDCl3) δ142.9,140.9,139.2,125.6,124.4,124.3,122.3,83.7,25.1.

[0152] Mass spectrometry comparison data of ordinary boron and 10B are as follows: Figure 14 As shown.

[0153]

[0154] The compound shown in Formula I-15 was derived from aryl iodides in 67% (34.3 mg) yield and from aryl bromides in 64% (32.7 mg) yield. The structural confirmation data are as follows:

[0155] 1 H NMR (400MHz, CDCl3) δ8.16 (s, 1H), 7.67 (dd, J = 8.3, 1.2Hz, 1H), 7.35-7.29 ( m,1H),7.03(d,J=3.1Hz,1H),6.54-6.45(m,1H),3.77(s,3H),1.36(s,12H). 13 C NMR (101MHz, CDCl3) δ138.8,129.0,129.0,128.3,127.7,108.7,101.8,83.5,32.9,25.0.

[0156] Mass spectrometry comparison data of ordinary boron and 10B are as follows: Figure 15 As shown.

[0157]

[0158] The compound shown in Formula I-16 was derived from aryl iodides in 53% (26.1 mg) yield and from aryl bromides in 45% (22.2 mg) yield. The structural confirmation data are as follows:

[0159] 1 H NMR (400MHz, CDCl3) δ7.36(d,J=6.9Hz,1H),7.24(d,J=1.1Hz,1H),6.83(d,J=7.7Hz,1H),5.95(s,2H),1.33(s,12H). 13 C NMR (101MHz, CDCl3) δ150.3,147.3,129.9,114.1,108.4,100.9,83.9,25.0.

[0160] Mass spectrometry comparison data of ordinary boron and 10B are as follows: Figure 16 As shown.

[0161]

[0162] The compound shown in Formula I-17, with a yield of 73% (55.7 mg), is derived from an alkenyl bromide. The structural confirmation data are as follows:

[0163] 1H NMR (400MHz, CDCl3) δ7.36-7.32(m,2H),7.31-7.27(m,3H),7.14-7.10(m,2H),7.09-7.0 7(m,2H),7.06(s,1H),7.06-7.04(m,2H),7.03(s,1H),6.97-6.93(m,2H),1.12(s,12H). 13 C NMR (101MHz, CDCl3) δ151.5,144.8,142.0,141.8,131.1,129.8,129.5,128.1,128.1,127.7,127.6,126.9,126.0,83.8,24.7.

[0164] Mass spectrometry comparison data of ordinary boron and 10B are as follows: Figure 17 As shown.

[0165]

[0166] The compound shown in Formula I-18 yielded 44% (20.2 mg) of alkenyl bromide, and the structural confirmation data are as follows:

[0167] 1 H NMR (400MHz, CDCl3) δ7.52-7.46(m,2H),7.40(d,J=18.5Hz,1H),7.37-7.28(m,3H),6.17(d,J=18.4Hz,1H),1.32(s,12H). 13 C NMR (101MHz, CDCl3) δ149.7,137.6,129.1,128.7,127.2,83.5,25.0.

[0168] Mass spectrometry comparison data of ordinary boron and 10B are as follows: Figure 18 As shown.

[0169] Examples 19-24

[0170] Synthesize the compounds shown in formulas I-19 to I-24

[0171] The compound shown in Formula I-1 was synthesized according to the synthetic route diagram shown, and the specific steps are as follows:

[0172] The pre-dried reaction tube was lowered to room temperature under vacuum. In a nitrogen-filled glove box, DIPEA (0.2 mmol, 2.0 equiv) and anisole (1.0 ml, 0.2 M) were sequentially introduced into a dry tube equipped with a magnetic stir bar. The mixture was cooled to -35°C, and then... 10BF3OEt2 (48 μL, 0.4 mmol), AlCl3 (29 mg, 0.23 mmol), (dmphenNiBr2) (0.02 mmol, 10% mol), zinc powder (0.6 mmol, 3.0 equiv), and aryl iodine (0.2 mmol, 1.0 equiv) as shown in Formula III-1 were added. The mixture was stirred at 80-90 °C for 12 h. After the reaction was complete, Et3N (0.4 mmol, 2.0 equiv) and (RYH)2 (0.4 mmol, 2.0 equiv) were added, and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated and subjected to column chromatography (stationary phase: 200-mesh silica gel; mobile phase: petroleum ether and ethyl acetate in a volume ratio of 100-50:1). After purification, compounds of Formulas I-19 to I-24 were obtained. In (RYH)2, Y is selected from oxygen or nitrogen atoms.

[0173] R2 indicates Where n is 0 or 1, when n is 1, there is a substituent on the methylene group, selected from: C1-C6 alkyl, substituted or unsubstituted aryl;

[0174] R3, R4, R5, and R6 are each independently selected from hydrogen, C1-C6 alkyl, substituted or unsubstituted aryl groups, and R3 and R4 cannot be substituted or unsubstituted aryl groups at the same time, and R5 and R6 cannot be substituted or unsubstituted aryl groups at the same time.

[0175] R2 indicates a substituted or unsubstituted naphthyl group.

[0176] In substituted aryl and substituted naphthyl groups, the substituents are halogenated and C1-C. 20 Alkyl, C1-C 20 Alkoxy or halogen-substituted C1-C 20 Any one of alkyl, ester, or aryl groups.

[0177]

[0178] Its structural formula is:

[0179]

[0180] The compound shown in Formula I-19, with a yield of 42% (26.8 mg), is derived from an aryl iodine compound, and its structural confirmation data are as follows:

[0181] 1 H NMR (400MHz, CDCl3) δ7.67-7.60(m,1H),7.51-7.30(m,8H),7.06-6.93(m,4H),6.07(d,J=6.8Hz,2H),5.43(s,2H). 13C NMR (101MHz, CDCl3) δ146.5,142.8,141.2,136.3,132.9,129.8,129.5,129.2,128.5,127.7,127.6,127.0,119.6,117.6,105.9.

[0182] Mass spectrometry comparison data of ordinary boron and 10B are as follows: Figure 19 As shown.

[0183]

[0184] The compound shown in Formula I-20, with a yield of 42% (26.8 mg), is derived from an aryl iodine compound, and its structural confirmation data are as follows:

[0185] 1 H NMR (400MHz, CDCl3) δ7.79-7.75(m,1H),7.49-7.44(m,1H),7.42(dd,J=7.2,1.5Hz,1H),7.39(s,5H),7.38-7.33(m,1H),6.15(s,2H). 13 C NMR (151MHz, CDCl3) δ147.6,143.6,136.1,134.6,129.6,129.5,129.4,128.3,127.5,126.9,119.2,111.1.

[0186] Mass spectrometry comparison data of ordinary boron and 10B are as follows: Figure 20 As shown.

[0187]

[0188] The compound shown in Formula I-21, with a yield of 40% (27.6 mg), is derived from an aryl iodine compound, and its structural confirmation data are as follows:

[0189] 1 H NMR (400MHz, CDCl3) δ7.52 (d, J = 7.3Hz, 1H), 7.43-7.36 (m, 1H), 7.32-7.25 (m, 2H), 7.19-7.09 (m ,6H),7.07-7.02(m,3H),7.01-6.94(m,2H),6.92-6.87(m,1H),6.82-6.78(m,2H),6.43(s,1H). 13C NMR (101MHz, CDCl3) δ147.1,143.2,140.2,137.4,136.0,135.1,129.2,129.1, 128.9,128.8,128.2,126.6,126.6,126.5,125.3,119.9,119.3,111.3,110.1.

[0190] Mass spectrometry comparison data of ordinary boron and 10B are as follows: Figure 21 As shown.

[0191]

[0192] The compound shown in Formula I-19, with a yield of 62% (40.9 mg), is derived from an aryl iodine compound, and its structural confirmation data are as follows:

[0193] 1 H NMR (400MHz, CDCl3) δ7.79-7.73(m,1H),7.49-7.30(m,8H),4.27(dd,J=8.8,2.1Hz,1H),2.30-2.16(m,2H),2.03(t, J=5.5Hz,1H),1.93-1.84(m,1H),1.78-1.68(m,1H),1.34(s,3H),1.27(s,3H),1.23(d,J=10.8Hz,1H),0.81(s,3H). 13 C NMR (101MHz, CDCl3) δ147.8,143.5,134.7,130.2,129.2,129.2,127.9,127.0,126.5,86.1,78.4,51.4,39.6,38.3,35.4,28.6,27.2,26.7,24.1.

[0194] Mass spectrometry comparison data of ordinary boron and 10B are as follows: Figure 22 As shown.

[0195]

[0196] The compound shown in Formula I-23, with a yield of 80% (46.9 mg), is derived from an aryl iodine compound. The structural confirmation data are as follows:

[0197] 1 H NMR (400MHz, CDCl3) δ7.64 (d, J = 8.1Hz, 1H), 7.43-7.28 (m, 8H), 1.77 (s, 2H), 1.20 (s, 12H). 13C NMR (101MHz, CDCl3) δ146.6,144.5,133.3,129.1,129.0,129.0,127.9,126.5,126.4,71.1,48.8,31.5.

[0198] Mass spectrometry comparison data of ordinary boron and 10B are as follows: Figure 23 As shown.

[0199]

[0200] The compound shown in Formula I-24, with a yield of 86% (57.7 mg), is derived from an aryl iodine compound, and its structural confirmation data are as follows:

[0201] 1 H NMR (400MHz, CDCl3) δ7.76 (dd, J = 7.7, 1.5Hz, 1H), 7.46-7.27 (m, 8H), 1.70-1.54 (m, 8H), 0.78 (t, J = 7.5Hz, 12H). 13 C NMR (101MHz, CDCl3) δ148.0,143.7,134.9,130.1,129.3,129.2,127.8,126.8,126.4,88.9,26.1,8.8.

[0202] Mass spectrometry comparison data of ordinary boron and 10B are as follows: Figure 24 As shown.

[0203] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A boron-10 isotope-labeled boronate compound, characterized by, The structural formula of the borate compound is shown as formula I: In formula I, R1 represents a substituent on a double bond, which is mono- or poly- substituted, the double bond can be an aromatic ring, each R1 is independently selected from: hydrogen, substituted or unsubstituted C1-C 20 alkyl, substituted or unsubstituted C1-C 20 alkoxy, thiomethyl, ester, substituted or unsubstituted aryl, any one of five- to eight-membered rings formed between two adjacent carbons on a benzene ring, wherein the five- to eight-membered ring is connected with another aryl fused ring, and the five- to eight-membered ring can be a five- to eight-membered heterocyclic ring; substituted C1-C 20 alkyl, substituted C1-C 20 alkyl, substituted C1-C 20 alkyl, C1-C 20 alkyl, C1-C 20 alkyl, C1-C Y is selected from an oxygen atom or a nitrogen atom; R2represents wherein n is 0 or 1 and when n is 1, the methylene group is substituted with a substituent selected from the group consisting of C1-C6alkyl, substituted or unsubstituted aryl; R3, R4, R5, R6 are each independently selected from hydrogen, C1-C6 alkyl, substituted or unsubstituted aryl, and R3, R4 cannot be substituted or unsubstituted aryl at the same time, R5, R6 cannot be substituted or unsubstituted aryl at the same time; or R2represents substituted or unsubstituted naphthyl substituted aryl, substituted naphthyl, the substituents being halogen, C1-C 20 alkyl, C1-C 20 alkoxy, halogen-substituted C1-C 20 alkyl, ester, aryl.

2. The borate ester compound according to claim 1, characterized by, The structural formula of the borate compound is shown as any one of formula I-1 to formula I-24:

3. A method for synthesizing boron-10 isotope-labeled boronate ester compounds, characterized by, Comprising the following steps: 1) mixing the compound shown as formula III with boron trifluoride, anisole, a nickel catalyst, a reducing agent, an organic base, a Lewis acid shown as formula IV under a nitrogen atmosphere, and then performing a reductive coupling reaction to obtain a reactant, and the structural formula of the reactant is shown as formula V; In formula III, R1 is defined as R1 in formula I, and X represents I or Br; In formula V, R1 is defined as R1 in formula I; 2) reacting the reactant in step 1) with a compound shown as formula VI to obtain formula V, and then adding triethylamine to react to obtain formula I; In formula VI, n, Y, R3, R4, R5, R6 are defined as n, Y, R3, R4, R5, R6 in formula I; 3) concentrating the reaction solution in step 2), and then performing silica gel chromatography to obtain the borate compound.

4. The method of synthesis of claim 3, wherein, The molar ratio of the compound shown as formula III to the volume molar ratio of boron trifluoride shown as formula IV in step 1) is 0.2 mol:0.4 mmol. The nickel catalyst includes (dmphen)NiBr2, and the molar ratio of the nickel catalyst to the compound shown as formula III is 1:

10.

5. The method of synthesis of claim 3, wherein, The reducing agent in step 1) includes zinc, and the molar ratio of the zinc to the compound shown as formula III is 3:1; The organic base includes N,N-diisopropyl ethylamine, and the molar ratio of the organic base to the compound shown as formula III is 2:

1.

6. The method of synthesis of claim 3, wherein, The Lewis acid in step 1) includes aluminum chloride, and the molar ratio of the Lewis acid to the compound shown as formula III is 0.22:0.

2.

7. The method of synthesis of claim 3, wherein, The conditions of the reductive coupling reaction in step 1) include a temperature of 80-90°C and a time of 12h.

8. The method of synthesis of claim 3, wherein, The molar ratio of the compound shown as formula III, triethylamine, and the compound shown as formula VI in step 2) is:1:2:

2.

9. The method of synthesis of claim 3, wherein, The conditions of the reaction in step 2) include a temperature of 20-30°C and a time of 1h.

10. The method of synthesis of claim 3, wherein, The stationary phase of the silica gel chromatography in step 3) is 200 mesh silica gel, and the mobile phase is petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether and ethyl acetate is 100-50:1.

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