CN112876503B - Borate compound for cancer boron neutron capture therapeutic drug and preparation thereof - Google Patents

Abstract

The invention relates to a borate compound for a boron neutron capture therapeutic drug for cancer, which has the following structural general formula:

(ii) a In the formula R¹Is aryl, R²,R³,R⁴Are one of H, alkyl, aryl, silicon base and boron base. The invention also discloses a preparation method of the borate compound. The invention has better stability and acid resistance, and has stronger selectivity to head and neck cancer cells (CAL 27).

Description

Borate compound for cancer boron neutron capture therapeutic drug and preparation thereof

technical field

The present invention relates to the field of medicinal chemistry and radiation medicine, in particular to borate compounds used for cancer boron neutron capture therapeutic drugs and their preparation.

Background technique

Head and neck cancer is a kind of cancer with high incidence, difficult to treat and high mortality. Its eradication is a huge challenge for human medicine. In recent years, with the continuous advancement of domestic and foreign drug research and development, people have made great progress in the development of anticancer drugs, but there is still an urgent need for new and more effective cancer treatment methods.

Boron neutron capture therapy (BNCT) is a novel radiotherapy technique targeting tumor cells. BNCT is a binary approach based on nuclear capture and fission reactions with significantly lower side effects compared to conventional radiotherapy and chemotherapy. , high selectivity and high efficiency. When non-radioactive ¹⁰ B atoms are irradiated with low-energy thermal/epithermal neutrons, highly linear energy transfer (LET) alpha particles and ⁷ Li recoil nuclei are produced. These high-LET particles have a length of 5–9 μm, which is similar to the diameter of a cell, and thus selectively generate strong thermal effects only with tumor cells containing ¹⁰ B molecules, killing cancer cells without causing excessive damage to surrounding normal cells.

At present, mercaptododecaborane disodium salt (BSH) and (L)-4-dihydroxyboryl phenylalanine (BPA) have been clinically used as boron drugs for BNCT treatment of tumors [Patent Publication No. CN 111971563 A and CN 111204736 A]; among them, BPA was approved for marketing in Japan in March 2020, becoming the world's first BNCT boron drug approved for marketing. However, both BSH and BPA were found to have insufficient tumor targeting in BNCT clinical studies. The chemical structure modification of boronic acid and borane is the main research strategy at present, but the efficiency still needs to be further improved. Patent application No. 201980041340.X proposes an aggregated boron 10 agent that can be used in boron neutron capture therapy, and can selectively or locally target tumor tissue in a short time, with small side effects, low invasiveness and can It has the advantage of exerting local killing effect on tumor tissue. Chinese patent 202011268512.8 discloses carborane celecoxib and its preparation and application in boron neutron capture therapy for head and neck cancer. The compound not only has high boron loading, strong tumor selectivity, but also exerts the curative effect of radiotherapy at the same time It can exert anti-inflammatory effect and reduce the side effects of treatment. Chinese patent 202010020070.9 discloses the preparation of boron-containing carbon quantum dots and its application in tumor diagnosis and boron neutron capture therapy. The boron-containing carbon quantum dots have good biocompatibility and excellent in vivo fluorescence imaging. Effect.

The tumor cell microenvironment is weakly acidic (pH = 6.5 ~ 6.8), while the tumor cell lysosome is more acidic (pH around 5.0). If the basicity of boron-containing molecules is increased, it is expected to further improve the selectivity of boron drugs in cancer cells. Tetracoordinated boronic acids have certain weak basicity, and are common intermediates in the chemical reactions of organic boronic acids. Due to their high instability, the research on these compounds is extremely limited. In 2020, Li Yuehui et al. reported that arylboronic acid compounds could be effectively stabilized in the presence of silane, and arylboronic acid sodium salts were used as catalysts in heterogeneous catalytic reactions [ Green Chem. , 2020, 22, 5317-5324]. Therefore, on the basis of improving the stability of borates, the modification of boronic acid-based boron drug molecules should be able to obtain more efficient drugs for boron neutron capture therapy of cancer.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is to provide a borate compound with better stability and acid resistance, which is used as a boron neutron capture therapy drug for cancer.

Another technical problem to be solved by the present invention is to provide the preparation of the borate compound for the treatment of cancer boron neutron capture.

In order to solve the above-mentioned problems, the borate compound for the treatment of cancer boron neutron capture therapy according to the present invention is characterized in that: the general structural formula of the borate compound is as follows:

；式中R¹为芳基，R² , R³ , R⁴ 均为H、烷基、芳基、硅基、硼基中的一种。

In the formula, R ¹ is an aryl group, and R ² , R ³ , and R ⁴ are all one of H, an alkyl group, an aryl group, a silicon group, and a boron group.

The above-mentioned preparation method of borate compound for cancer boron neutron capture therapeutic drug is characterized in that: adding boric acid compound, strong base and reaction solvent in reaction vessel, and reacting at 25～180 ℃ for 30 s～48 h after cooling to room temperature to obtain reaction solution A; the reaction solution A is filtered to obtain solid A, which is recrystallized and separated to obtain borate compound A; the molar ratio of the boric acid compound and the strong base The ratio is 1:0.5~1:10.

Its chemical reaction formula is as follows (Formula I):

The above-mentioned preparation method of borate compound for cancer boron neutron capture therapeutic drug is characterized in that: adding boric acid compound, strong base and reaction solvent in reaction vessel, and reacting at 25～180 ℃ for 30 s～48 After h, a stabilizing reagent was added, and the reaction was cooled to room temperature to obtain a reaction solution B; the reaction solution B was filtered to obtain a solid B, and the solid B was recrystallized and separated to obtain the borate compound B; the boric acid compound The molar ratio to the strong base is 1:0.5~1:10; the molar ratio of the boric acid compound to the stabilizing reagent is 1:0.5~5.

Its chemical reaction formula is as follows (Formula II):

The boronic acid compound refers to aryl boronic acid or aliphatic boronic acid.

；式中R¹是指苯基、对甲苯基、甲基、三氟甲基、链状或环状的烷基、包括稠环或杂环的芳基、硅氧基、卤素中各种官能团单取代或者多取代。Described boronic acid compound refers to the phenylalanine compound that is connected with B(OH) ₂ group on benzene ring, and its structural formula is

In the formula, R ¹ refers to various functional groups in phenyl, p-tolyl, methyl, trifluoromethyl, chain or cyclic alkyl groups, aryl groups including fused or heterocyclic rings, siloxy groups, and halogens single or multiple substitutions.

The structural formula of the boronic acid compound is one of the following:

。

.

The strong base refers to metal hydroxides or alkoxylates.

The strong base refers to one of NaOH, KOH, LiOH, sodium methoxide, sodium ethoxide, disodium ethylene glycol, sodium glycerol, and sodium salt of sugar.

The stabilizing reagent refers to any reagent with an electron withdrawing group.

The stabilizing reagents refer to sodium pentafluorophenyl, phenylsilane, diphenylsilane, triphenylsilane, 2-(trimethylsilyl)phenyltrifluoromethanesulfonic acid, hexamethyldisilane, One of the reagents of phenyldisilane, tert-butyldimethylsilyl chloride, diethylsilane, triethylsilane, trimethylsilanol and triethylsilanol.

The reaction solvent refers to organic solvents, including but not limited to dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, acetonitrile, methanol, dioxane, N-methylpyrrolidone, toluene, xylene, One or more of mesitylene.

The reaction temperature is preferably 60 to 100 °C; the reaction time is preferably 1 h to 6 h.

Compared with the prior art, the present invention has the following advantages:

1. Compared with the previous research objects limited to boric acid compounds, the present invention discloses a preparation method of a four-coordination borate based on a stabilization strategy, and the obtained borate has better stability and acid resistance, It breaks people's conventional understanding that borates are unstable and easy to decompose.

2. The present invention effectively improves the stability of the borate by dispersing the charge of the borate anion by using groups such as metals, Si groups, and B groups with certain Lewis acidity.

3. The present invention is a brand-new improvement to the category of known BNCT boron drugs, successfully enriches and expands the scope of boron drugs, fills up the defects of the existing borate preparation technology, and realizes the high-efficiency, high-efficiency, and high-efficiency of borate with different structures. low cost production.

4. The biological activity assay results of the borate provided by the present invention show that the BPA-derived borate has strong selectivity for head and neck cancer cells (CAL27), and has obvious effects on head and neck cancer cells in boron neutron capture therapy. Inducing apoptosis, it shows better efficiency than BPA, which is expected to reduce the dosage of boron drugs, and shows better application prospects than traditional boric acid boron drugs.

5. The process of the invention is simple and the synthesis efficiency is high.

Detailed ways

The borate compound used for the treatment of cancer boron neutron capture, the general structural formula of the borate compound is as follows:

；式中R¹为芳基，R² , R³ , R⁴ 均为H、烷基、芳基、硅基、硼基中的一种。

In the formula, R ¹ is an aryl group, and R ² , R ³ , and R ⁴ are all one of H, an alkyl group, an aryl group, a silicon group, and a boron group.

The materials used in the following examples can be obtained from commercial sources unless otherwise specified.

【One-step method】

Preparation method of borate compound for cancer boron neutron capture therapeutic drug:

Add boric acid compound, strong base and reaction solvent to the reaction vessel, react at 25-180 °C for 30 s-48 h, and then cool to room temperature to obtain reaction solution A; Reaction solution A is filtered to obtain solid A, which is recrystallized , and the borate compound A is obtained by separation.

【Two-step method】

Preparation method of borate compound for cancer boron neutron capture therapeutic drug:

Add boric acid compound, strong base and reaction solvent to the reaction vessel, react at 25-180 ℃ for 30 s-48 h, add stabilizing reagent, and cool down to room temperature after the reaction to obtain reaction solution B; reaction solution B is filtered to obtain solid B , the solid B is recrystallized and separated to obtain borate compound B.

Wherein: the boronic acid compound refers to aryl boronic acid or aliphatic boronic acid. Such as: 4-dihydroxyboronyl phenylalanine (BPA), phenylboronic acid, 1-naphthalene boronic acid, 2-anthracene boronic acid, methyl boronic acid, 3-acetylphenyl boronic acid, 3-biphenyl boronic acid, 4-biphenyl Boric acid, 4-n-butylbenzeneboronic acid, 4-acetophenylboronic acid, etc.

；式中R¹是指苯基、对甲苯基、甲基、三氟甲基、链状或环状的烷基、包括稠环或杂环的芳基、硅氧基、卤素中各种官能团单取代或者多取代。Boronic acid compounds refer to phenylalanine compounds with B(OH) ₂ groups connected to the benzene ring, and its structural formula is

In the formula, R ¹ refers to various functional groups in phenyl, p-tolyl, methyl, trifluoromethyl, chain or cyclic alkyl groups, aryl groups including fused or heterocyclic rings, siloxy groups, and halogens single or multiple substitutions.

The structural formula of the boronic acid compound is one of the following:

。

.

Strong bases refer to hydroxides or alkoxylates of metals.

Strong base refers to one of NaOH, KOH, LiOH, sodium methoxide, sodium ethoxide, disodium ethylene glycol, sodium glycerol, and sodium salt of sugar.

Stabilizing reagent refers to any reagent with electron withdrawing groups.

Stabilizing reagents refer to sodium pentafluorophenyl, phenylsilane, diphenylsilane, triphenylsilane, 2-(trimethylsilyl)phenyltrifluoromethanesulfonic acid, hexamethyldisilane, hexaphenylsilane One of the reagents of disilane, tert-butyldimethylsilyl chloride, diethylsilane, triethylsilane, trimethylsilanol and triethylsilanol.

Reaction solvent refers to organic solvents, including but not limited to dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, acetonitrile, methanol, dioxane, N-methylpyrrolidone, toluene, xylene, mesitylene One or more of toluene.

The reaction temperature is preferably 60 to 100 °C; the reaction time is preferably 1 h to 6 h.

Strong bases are pre-prepared pure products or purchased directly from commercial channels; boronic acid compounds can be prepared in advance and used after separation and purification, or they can be prepared in situ during the reaction process without any treatment and used directly.

The borate compound A and the borate compound B are tetracoordinate borates, and their chemical structural formulas are shown in formulas I and II, and the preferred structures are:

Example 1: Preparation of borate compound (1) (two-step process).

Under air atmosphere, (L)-4-dihydroxyboryl phenylalanine (0.05 mmol, 10.45 mg), sodium hydroxide (0.15 mmol, 6 mg), toluene (4 mL) and a magnetic stirrer were added to 35 mL glass pressure-resistant tube. Then triphenylsilane (0.15 mmol, 39 mg) was added, and the reaction tube was reacted at 90° C. for 6 hours. After the reaction is completed, the reaction system is cooled to room temperature, the reaction vessel is opened at room temperature, and filtered; the obtained solid is recrystallized and separated to obtain the reaction product. The pure product yield of the target product was 78%.

¹ H NMR (300 MHz, DMSO) δ 12.89 (s, 1H), 8.71 (d, 2H), 7.75 (d, 2H), 7.46 (m, 18H), 7.39-7.35 (m, 27H), 7.2(d , 2H), 4.18(s, 1H), 3.42(d, 2H).

¹³ C NMR (100 MHz, DMSO) δ 174.7, 138.3, 136.6, 135.7, 133.3, 132.5, 130.0, 129.5, 127.7, 56.7, 37.3.

Example 2: Preparation of borate compound (2) (one-step method)

Under air atmosphere, phenylboronic acid (0.05 mmol, 6.1 mg), sodium triphenylsiliconate (0.025 mmol, 7.46 mg), and a magnetic stirring bar were added to a 35 mL glass pressure-resistant tube. Then, toluene (4 mL) was added, and the reaction tube was reacted at 90°C for 6 hours. After the reaction is completed, the reaction system is cooled to room temperature, the reaction vessel is opened at room temperature, and filtered; the obtained solid is recrystallized and separated to obtain the reaction product. The pure product yield of the target product was 75%.

¹ H NMR (300 MHz, DMSO) δ 7.75(d, 2H), 7.48 - 7.44 (m, 6H), 7.37-7.39(m, 10m) 7.36(s, 1H), 7.35(s, 1H), 4.2 ( d, 2H).

¹³ C NMR (101 MHz, DMSO) δ 138.5, 138.3, 133.4, 132.5, 130.0, 129.5, 128.7.

Example 3: Preparation of borate compound (3) (two-step method)

Under air atmosphere, phenylboronic acid (0.05 mmol, 6.1 mg), sodium hydroxide (0.5 mmol, 20 mg), toluene (4 mL) and a magnetic stir bar were added to a 35 mL glass pressure-resistant tube. Then triphenylsilane (0.15 mmol, 39 mg) was added, and the reaction tube was reacted at 90° C. for 12 hours. After the reaction is completed, the reaction system is cooled to room temperature, the reaction vessel is opened at room temperature, and filtered; the obtained solid is recrystallized and separated to obtain the reaction product. The pure product yield of the target product was 75%.

¹ H NMR (300 MHz, DMSO) δ 7.75 (d, 2H), 7.48-7.44 (m, 18H), 7.34-7.38 (m, 30H).

¹³ C NMR (101 MHz, DMSO) δ 138.3, 133.4, 132.5, 130.0, 129.5, 128.7.

Example 4: Preparation of borate compound (4) (one-step method)

Under air atmosphere, F-BPA (0.05 mmol, 11.35 mg), sodium triphenylsiliconate (0.2 mmol, 59.68 mg), and a magnetic stirrer were added to a 35 mL glass pressure-resistant tube. The reaction tube was reacted at 90°C for 6 hours. After the reaction is completed, the reaction system is cooled to room temperature, the reaction vessel is opened at room temperature, and filtered; the obtained solid is recrystallized and separated to obtain the reaction product. The pure product yield of the target product was 85%.

¹ H NMR (300 MHz, DMSO) δ 12.89 (s, 1H), 8.71 (d, 2H), 7.52 (s, 1H), 7.46 (m, 6H), 7.35-7.39 (m, 9H), 7.18 (s , 1H), 7.04 (s, 1H), 4.2(d, 2H), 4.18(m, 1H), 3.42 (d, 2H).

¹³ C NMR (101 MHz, DMSO) δ 174.7, 160.2, 138.3, 137.3, 132.5, 130.0, 129.5, 128.1, 115.6, 56.7, 32.4.

Example 5: Preparation of borate compound (5) (two-step method)

Under air atmosphere, BPA-Tyr (0.05 mmol, 18.61 mg), potassium hydroxide (0.2 mmol, 11.2 mg), toluene (4 mL) and a magnetic stirrer were added to a 35 mL glass pressure-resistant tube. Then triphenylsilane (0.25 mmol, 65.10 mg) was added, and the reaction tube was reacted at 100° C. for 10 hours. After the reaction is completed, the reaction system is cooled to room temperature, the reaction vessel is opened at room temperature, and filtered; the obtained solid is recrystallized and separated to obtain the reaction product. The pure product yield of the target product was 70%.

¹ H NMR (300 MHz, DMSO) δ 12.8 9 (m, 1H), 9.06 (m, 1H), 8.86 (m, 2H), 8.32 (m, 1H), 7.75 (d, 2H), 7.48-7.44 ( m, 24H), 7.38-7.34 (m, 20), 7.2 (m, 2H), 6.96 (m, 2H), 6.68 (m, 2H), 4.72 (m, 1H), 3.95 (d, 1H), 3.44 (m, 2H), 3.12 (m, 2H).

¹³ C NMR (101 MHz, DMSO) δ 174.7, 171.7, 155.7, 138.3, 136.6, 135.7, 132.5, 130.2, 130.0, 129.5, 129.2, 127.7, 115.8, 59.2, 56.0, 38.7, 3

Example 6: Preparation of borate compound (6) (one-step method)

Under air atmosphere, BPA-Tyr (0.05 mmol, 18.61 mg), sodium triphenylsiliconate (0.05 mmol, 14.92 mg), and a magnetic stirring bar were added to a 35 mL glass pressure-resistant tube. Then, toluene (10 mL) was added, and the reaction tube was reacted at 90° C. for 6 hours. After the reaction is completed, the reaction system is cooled to room temperature, the reaction vessel is opened at room temperature, and filtered; the obtained solid is recrystallized and separated to obtain the reaction product. The pure product yield of the target product was 85%.

¹ H NMR (300 MHz, DMSO) δ 12.89 (s, 1H), 9.06 (s, 1H), 8.86 (m, 2H), 8.32 (s, 1H), 7.75 (m, 2H) 7.46 (m, 6H) , 7.38-7.34 (m, 9H), 7.20 (m, 2H), 6.96(m, 2H), 6.68 (m, 2H), 4.72 (m, 1H), 4.20 (m, 2H), 3.95 (m, 1H) ), 3.44 (m, 2H), 3.21 (m, 2H).

¹³ C NMR (101 MHz, DMSO) δ 174.7, 171.7, 155.7, 138.3, 136.6, 135.7, 133.3, 132.5, 130.2, 130.0, 129.5, 129.2, 127.7, 115.8, 59.2, 5.56.0,

Example 7: Preparation of borate compound (7) (two-step method)

Under air atmosphere, (L)-4-dihydroxyboryl phenylalanine (0.05 mmol, 10.45 mg), potassium hydroxide (0.2 mmol, 11.2 mg), toluene (4 mL) and a magnetic stir bar were added to 35 mL glass pressure-resistant tube. Triphenylsilane (0.025 mmol, 6.51 mg) was then added, and the reaction tube was reacted at 100° C. for 10 hours. After the reaction is completed, the reaction system is cooled to room temperature, the reaction vessel is opened at room temperature, and filtered; the obtained solid is recrystallized and separated to obtain the reaction product. The pure product yield of the target product was 75%.

¹ H NMR (500 MHz, Chloroform-d) δ 7.64–7.57 (m, 7H), 7.61–7.53 (m, 1H), 7.39–7.29 (m, 9H), 7.12 (dt, J = 9.5, 1.1 Hz, 1H), 3.05–2.91 (m, 1H).

¹³ C NMR (125 MHz, Chloroform-d) δ 174.88, 139.48, 135.07, 134.68, 133.60, 133.39, 132.18, 129.80, 127.46, 56.92, 37.79.

Example 8: Preparation of borate compound (8) (one-step method)

Under air atmosphere, BPA-Tyr (0.05 mmol, 18.61 mg), sodium triphenylsiliconate (0.2 mmol, 59.68 mg), and a magnetic stirrer were added to a 35 mL glass pressure-resistant tube. Then, toluene (4 mL) was added, and the reaction tube was reacted at 80°C for 48 hours. After the reaction is completed, the reaction system is cooled to room temperature, the reaction vessel is opened at room temperature, and filtered; the obtained solid is recrystallized and separated to obtain the reaction product. The pure product yield of the target product was 78%.

¹ H NMR (500 MHz, Chloroform-d) δ 7.90 (d, J = 9.0 Hz, 1H), 7.64-7.57(m, 7H), 7.59-7.52 (m, 2H), 7.39-7.29 (m, 10H) , 7.14 (dt, J = 9.1, 1.1 Hz, 2H), 6.95 (dt, J = 8.6, 1.1 Hz, 2H), 6.75-6.69 (m, 2H), 6.14 (s, 1H), 5.92(s, 2H) ), 4.54 (dt, J = 9.0, 6.8 Hz, 1H), 3.88 (p, J = 5.9 Hz, 1H), 3.02 (m, J= 15.4, 5.7, 1.0 Hz, 1H), 2.95 (m, J = 6.8, 2.7, 1.0 Hz, 2H), 2.88 (m, J = 15.2, 5.7, 1.0 Hz, 1H), 2.58 (dd, J = 8.0, 6.0 Hz, 1H), 2.42 (dd, J = 8.0, 5.9 Hz , 1H).

¹³ C NMR (125 MHz, Chloroform-d) δ 176.68, 173.61, 156.46, 136.89,135.07, 134.96, 134.52, 132.75, 130.65, 129.99, 129.80, 128.56, 127.46,115.72, 54.89, 54.55, 38.40, 37.66.

Example 9: Preparation of borate compound (9) (two-step method)

Under air atmosphere, Tyr-BPA (0.05 mmol, 18.61 mg), sodium hydroxide (0.2 mmol, 8 mg), toluene (4 mL) and a magnetic stirrer were added to a 35 mL glass pressure-resistant tube. Then triphenylsilane (0.15 mmol, 39 mg) was added, and the reaction tube was reacted at 90° C. for 12 hours. After the reaction is completed, the reaction system is cooled to room temperature, the reaction vessel is opened at room temperature, and filtered; the obtained solid is recrystallized and separated to obtain the reaction product. The pure product yield of the target product was 90%.

¹ H NMR (500 MHz, Chloroform-d) δ 7.64-7.57 (m, 7H), 7.61-7.53 (m, 1H), 7.39-7.29 (m, 11H), 7.07 (m, J = 19.2, 8.6, 1.1 Hz, 2H), 6.75-6.69 (m, 1H), 4.54 (dt, J = 9.0, 6.8 Hz, 0H), 3.06-2.96 (m, 1H).

¹³ C NMR (125 MHz, Chloroform-D) Δ 176.69, 173.61, 156.84, 139.48,135.16, 135.07, 133.60, 132.17, 130.70, 127.46, 127.25,115.38, 54.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.

Example 10: Preparation of borate compound (10) (one-step method)

Under air atmosphere, (L)-4-dihydroxyboryl phenylalanine (0.05 mmol, 10.45 mg), sodium triphenylsiliconate (0.05 mmol, 14.92 mg) and a magnetic stirrer were added to 35 mL of in glass pressure-resistant tubes. Then DCE (4 mL) was added, and the reaction tube was reacted at 80°C for 24 hours. After the reaction is completed, the reaction system is cooled to room temperature, the reaction vessel is opened at room temperature, and filtered; the obtained solid is recrystallized and separated to obtain the reaction product. The pure product yield of the target product was 89%.

¹ H NMR (500 MHz, Chloroform-d) δ 7.64-7.57 (m, 3H), 7.61-7.52 (m, 1H), 7.39-7.29 (m, 4H), 7.13 (dt, J = 9.0, 1.0 Hz, 1H), 5.92 (s, 1H), 3.87(tt, J = 6.6, 5.1 Hz, 0H), 3.05-2.91 (m, 1H).

¹³ C NMR (125 MHz, Chloroform-d) δ 174.88, 136.89, 135.07, 134.96, 134.63, 132.84, 129.99, 129.80, 127.46, 56.92, 37.79.

Example 11: Preparation of borate compound (11) (two-step method)

Under air atmosphere, (L)-4-dihydroxyboryl phenylalanine (0.05 mmol, 10.45 mg), lithium hydroxide (0.15 mmol, 3.6 mg), DMF (4 mL) and magnetic stirrer were added to 35 mL glass pressure-resistant tube. Then triphenylsilane (0.15 mmol, 39 mg) was added, and the reaction tube was reacted at 90° C. for 12 hours. After the reaction is completed, the reaction system is cooled to room temperature, the reaction vessel is opened at room temperature, and filtered; the obtained solid is recrystallized and separated to obtain the reaction product. The pure product yield of the target product was 72%.

¹ H NMR (500 MHz, Chloroform-d) δ 7.64-7.57 (m, 7H), 7.61-7.53 (m, 1H), 7.39-7.29 (m, 9H), 7.12 (dt, J = 9.5, 1.1 Hz, 1H), 3.05-2.91 (m, 1H).

¹³ C NMR (125 MHz, Chloroform-d) δ 174.88, 139.48, 135.07, 134.68, 133.60, 133.39, 132.18, 129.80, 127.46, 56.92, 37.79.

Example 12: Preparation of borate compound (12) (one-step method)

Under air atmosphere, Tyr-BPA (0.05 mmol, 18.61 mg), sodium triphenylsiliconate (0.1 mmol, 29.84 mg) and a magnetic stir bar were added to a 35 mL glass pressure-resistant tube. Then, toluene (4 mL) was added, and the reaction tube was reacted at 90°C for 12 hours. After the reaction is completed, the reaction system is cooled to room temperature, the reaction vessel is opened at room temperature, and filtered; the obtained solid is recrystallized and separated to obtain the reaction product. The pure product yield of the target product was 90%.

¹ H NMR (500 MHz, Chloroform-d) δ 7.64-7.56 (m, 18H), 7.47-7.41 (m, 2H), 7.37-7.27 (m, 27H), 7.10-7.01 (m, 4H), 6.73- 6.67 (m, 2H), 4.38 (dt, J =9.1, 6.8 Hz, 1H), 3.84 (p, J = 5.9 Hz, 1H), 3.08-3.00 (m, 1H), 3.04-2.95 (m,2H) , 2.84 (m, J = 15.4, 5.8, 1.1 Hz, 1H), 2.70 (dd, J = 7.9, 6.0 Hz, 1H), 2.50 (dd, J = 8.0, 5.9 Hz, 1H).

¹³ C NMR (125 MHz, Chloroform-D) Δ 176.69, 173.61, 156.84, 139.48,135.16, 135.07, 133.60, 132.17, 130.70, 127.46, 127.25,115.38, 54.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.

Example 13: Preparation of borate compound (13) (two-step method)

Under air atmosphere, F-BPA (0.05 mmol, 11.35 mg), sodium hydroxide (0.2 mmol, 8 mg), toluene (4 mL) and a magnetic stirrer were added to a 35 mL glass pressure-resistant tube. Then triphenylsilane (0.15 mmol, 39 mg) was added, and the reaction tube was reacted at 80° C. for 24 hours. After the reaction is completed, the reaction system is cooled to room temperature, the reaction vessel is opened at room temperature, and filtered; the obtained solid is recrystallized and separated to obtain the reaction product. The pure product yield of the target product was 55%.

¹ H NMR (500 MHz, Chloroform-d) δ 7.64-7.56 (m, 8H), 7.43 (dd, J =10.5, 2.0 Hz, 0H), 7.39-7.23 (m, 10H), 3.89 (tt, J = 7.5, 6.6 Hz, 0H), 3.18-3.07 (m, 1H).

¹³ C NMR (125 MHz, Chloroform-d) δ 173.42, 135.07, 133.63, 129.80, 127.46, 32.61, 32.57.

Example 14: Preparation of borate compound (14) (one-step method)

Under air atmosphere, Tyr-BPA (0.05 mmol, 18.61 mg), sodium triphenylsiliconate (0.2 mmol, 59.68 mg) and a magnetic stirrer were added to a 35 mL glass pressure-resistant tube. Subsequently, 1,2-dichloroethane (4 mL) was added, and the reaction tube was reacted at 90° C. for 12 hours. After the reaction is completed, the reaction system is cooled to room temperature, the reaction vessel is opened at room temperature, and filtered; the obtained solid is recrystallized and separated to obtain the reaction product. The pure product yield of the target product was 85%.

¹ H NMR (500 MHz, Chloroform-d) δ 7.64-7.55 (m, 18H), 7.59-7.53 (m, 2H), 7.39-7.29 (m, 28H), 7.07 (m, J = 19.2, 8.6, 1.1 Hz, 4H), 6.75-6.69 (m,2H), 4.53 (dt, J = 9.0, 6.7 Hz, 1H), 3.88 (p, J = 5.9 Hz, 1H), 3.06-2.98 (m,1H), 3.00 (d, J = 1.1 Hz, 1H), 3.01-2.96 (m, 1H), 2.89 (m, J = 15.4, 5.7, 1.1Hz, 1H), 2.58 (dd, J = 8.0, 6.0 Hz, 1H), 2.42 (dd, J = 8.0, 5.9 Hz, 1H).

¹³ C NMR (125 MHz, Chloroform-D) Δ 176.69, 173.61, 156.84, 139.48,135.16, 135.07, 133.60, 132.17, 130.70, 127.46, 127.25,115.38, 54.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.

Example 15: Preparation of borate compound (15) (two-step method)

Under air atmosphere, F-BPA derivative (0.05 mmol, 11.35 mg), sodium hydroxide (0.2 mmol, 8 mg), toluene (4 mL) and magnetic stirrer were added to a 35 mL glass pressure-resistant tube. Then triphenylsilane (0.15 mmol, 39 mg) was added, and the reaction tube was reacted at 90° C. for 12 hours. After the reaction is completed, the reaction system is cooled to room temperature, the reaction vessel is opened at room temperature, and filtered; the obtained solid is recrystallized and separated to obtain the reaction product. The pure product yield of the target product was 88%.

¹ H NMR (500 MHz, Chloroform-d) δ 7.61 (dq, J = 8.4, 2.4, 1.9 Hz, 26H), 7.39-7.27 (m, 34H), 4.59 (dt, J = 6.2, 3.7 Hz, 1H) , 4.18-4.08 (m, 2H), 4.03-3.91 (m, 2H), 3.93-3.84 (m, 1H), 3.18-3.07 (m, 2H).

¹³ C NMR (125 MHz, Chloroform-d) δ 174.56, 161.90, 136.15, 136.08,135.54, 135.09, 133.91, 133.72, 133.38, 133.36, 132.29, 131.42, 129.88,128.87, 127.42, 127.40, 122.21, 120.65, 104.54, 77.48, 76.42, 72.57, 64.44, 61.18, 54.64, 30.56.

Example 16: Preparation of borate compound (16) (one-step method)

Under air atmosphere, Tyr-BPA (0.05 mmol, 18.61 mg), sodium triphenylsiliconate (0.2 mmol, 59.68 mg) and a magnetic stirrer were added to a 35 mL glass pressure-resistant tube. Subsequently, N,N-dimethylformamide (4 mL) was added, and the reaction tube was reacted at 100° C. for 3 hours. After the reaction is completed, the reaction system is cooled to room temperature, the reaction vessel is opened at room temperature, and filtered; the obtained solid is recrystallized and separated to obtain the reaction product. The pure yield of the target product was 81%.

¹ H NMR (500 MHz, Chloroform-d) δ 7.64-7.55 (m, 18H), 7.59-7.53 (m, 2H), 7.39-7.29 (m, 28H), 7.07 (m, J = 19.2, 8.6, 1.1 Hz, 4H), 6.75-6.69 (m,2H), 4.53 (dt, J = 9.0, 6.7 Hz, 1H), 3.88 (p, J = 5.9 Hz, 1H), 3.06-2.98 (m,1H), 3.00 (d, J = 1.1 Hz, 1H), 3.01-2.96 (m, 1H), 2.89 (m, J = 15.4, 5.7, 1.1Hz, 1H), 2.58 (dd, J = 8.0, 6.0 Hz, 1H), 2.42 (dd, J = 8.0, 5.9 Hz, 1H).

¹³ C NMR (125 MHz, Chloroform-D) Δ 176.69, 173.61, 156.84, 139.48,135.16, 135.07, 133.60, 132.17, 130.70, 127.46, 127.25,115.38, 54.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.55, 38.

Example 17: Preparation of borate compound (17) (two-step method)

Under air atmosphere, F-BPA derivative (0.05 mmol, 11.35 mg), lithium hydroxide (0.15 mmol, 3.6 mg), N,N-dimethylformamide (4 mL) and magnetic stirrer were added to 35 mL in the glass pressure-resistant tube. Triphenylsilane (0.15 mmol, 39 mg) was then added, and the reaction tube was reacted at 80 °C for 24 hours. After the reaction is completed, the reaction system is cooled to room temperature, the reaction vessel is opened at room temperature, and filtered; the obtained solid is recrystallized and separated to obtain the reaction product. The pure product yield of the target product was 80%.

¹ H NMR (500 MHz, Chloroform-d) δ 7.61 (m, J = 8.4, 2.4, 1.9 Hz, 26H), 7.39-7.27 (m, 34H), 4.59 (dt, J = 6.2, 3.7 Hz, 1H) , 4.18-4.08 (m, 2H), 4.03-3.91 (m, 2H), 3.93-3.84 (m, 1H), 3.18-3.07 (m, 2H).

¹³ C NMR (125 MHz, Chloroform-d) δ 174.56, 161.90, 136.15, 136.08,135.54, 135.09, 133.91, 133.72, 133.38, 133.36, 132.29, 131.42, 129.88,128.87, 127.42, 127.40, 122.21, 120.65, 104.54, 77.48, 76.42, 72.57, 64.44, 61.18, 54.64, 30.56.

Example 18: Preparation of borate compound (18) (one-step method)

Under air atmosphere, F-BPA derivative (0.05 mmol, 11.35 mg), sodium triphenylsiliconate (0.2 mmol, 59.68 mg) and a magnetic stirrer were added to a 35 mL glass pressure-resistant tube. Subsequently, 1,2-dichloroethane (4 mL) was added, and the reaction tube was reacted at 90° C. for 12 hours. After the reaction is completed, the reaction system is cooled to room temperature, the reaction vessel is opened at room temperature, and filtered; the obtained solid is recrystallized and separated to obtain the reaction product. The pure product yield of the target product was 78%.

¹ H NMR (500 MHz, Chloroform-d) δ 7.64-7.56 (m, 6H), 7.44 (dd, J =10.6, 1.8 Hz, 1H), 7.39-7.31 (m, 5H), 7.34-7.27 (m, 4H), 7.26 (s, 1H), 7.11(m, J = 10.5, 5.0, 1.0 Hz, 1H), 4.59-4.52 (m, 2H), 4.49 (dd, J = 7.3, 6.6 Hz, 1H), 4.27 (dd, J = 7.3, 6.6 Hz, 1H), 4.15 (t, J = 6.2 Hz, 1H), 4.06 (s, 1H), 4.01-3.94 (m, 2H), 3.97-3.84 (m, 2H), 3.78-.68 (m, 2H), 3.46 (d, J = 5.1 Hz, 1H), 3.20-3.06 (m, 2H).

¹³ C NMR (125 MHz, Chloroform-d) δ 173.42, 161.19, 159.18, 135.07,133.94, 133.88, 133.67, 131.79, 131.72, 129.80, 128.72, 128.70, 127.46,123.85, 123.69, 122.75, 122.59, 98.00, 78.45, 72.97, 72.74, 62.44, 60.93, 55.32, 55.30, 32.74, 32.70.

【Detection of borate uptake in CAL27 cells】

CAL27 cells in logarithmic growth phase at 60-75% cell content were seeded into ⁶ -well plates (1 x 106 cells per well). After the cells adhered, the control group BPA or borate compounds were used to act on the cells for 48 h respectively (3 parallel experiments were set for each group, and a blank control group was set). After the action was completed, the culture medium was discarded, and the cells were washed three times with PBS; then, 1 mL of pronase solution with a concentration of 2 mg/mL was added to each well and incubated at 4 °C for 4 h. The pronase-containing solution was discarded, the cells were washed 3 times with PBS, the cells were lysed with RIPA lysis buffer, the cell lysate was collected, and the supernatant was collected by centrifugation. The concentration of ¹⁰ B in the supernatant was detected by ICP-MS.

Table 1 Test results of uptake content of borate compounds in CAL27 cells

(should be compared to normal cell results)

As shown in Table 1, the uptake of borate compounds prepared by the present invention in CAL27 cells is positively correlated with the concentration, and the uptake of borate compounds in CAL27 cells is higher than that of the positive control group BPA at the same concentration.

Claims (2)

1. a borate compound for cancer boron neutron capture therapeutic drug, characterized in that: the structural formula of the borate compound is as follows:

. 2. the preparation method of the borate compound used for cancer boron neutron capture therapeutic drug as claimed in claim 1, is characterized in that: adding boric acid compound, strong base and reaction solvent in reaction vessel, at 25～180 ℃ After reacting for 30 s to 48 h, a stabilizing reagent is added, and the reaction is cooled to room temperature to obtain a reaction solution B; the reaction solution B is filtered to obtain a solid B, and the solid B is recrystallized and separated to obtain a borate compound B ; the molar ratio of the boric acid compound to the strong base is 1:0.5~1:10; the molar ratio of the boric acid compound to the stabilizing reagent is 1:0.5~5; The structural formula of the boronic acid compound is one of the following:

; The strong base refers to one of NaOH, KOH, LiOH, sodium methoxide, sodium ethoxide, disodium ethylene glycol, sodium glycerol, and sodium salt of sugar; the stabilizing reagent refers to sodium pentafluorophenyl , phenylsilane, diphenylsilane, triphenylsilane, 2-(trimethylsilyl)phenyltrifluoromethanesulfonic acid, hexamethyldisilane, hexaphenyldisilane, tert-butyldimethyl chloride One of silane, diethylsilane, triethylsilane, trimethylsilanol, triethylsilanol reagents; the reaction solvent includes but is not limited to dimethyl sulfoxide, N,N-dimethylmethane One or more of amide, tetrahydrofuran, acetonitrile, methanol, dioxane, N-methylpyrrolidone, toluene, xylene, and mesitylene.