CN115010739A - Method for synthesizing F-BPA - Google Patents

Abstract

Embodiments of the invention provide a method of synthesizing F-BPA, comprising: first compound and I ^‑ Reacting to generate a second compound; reacting the second compound with the isopropylidene malonate to generate a third compound; reacting the third compound with tert-butyloxycarbonyl to generate a fourth compound; a fourth compound with F ^‑ Reacting to form a fifth compound; a fifth compound with H ⁺ F-BPA is generated by the reaction. According to the F-BPA synthesis method provided by the embodiment of the invention, the final product can be obtained by only one hydrolysis reaction after the fluorination substitution, so that the synthesis time after the fluorination substitution is shortened, and the yield of the product is improved.

Description

Methods of synthesizing F-BPA

technical field

Embodiments of the present invention relate to the field of boron compounds, in particular to a method for synthesizing F-BPA.

Background technique

Boron neutron capture therapy (BNCT) is an effective method for the treatment of tumors. In boron neutron capture therapy, BPA (Chinese name is p-dihydroxyboronyl phenylalanine or 4-boron-L-phenylalanine) is often used as a drug to treat patients.

In order to monitor the distribution of BPA in patients, a hydrogen atom on the benzene ring of the BPA molecule was replaced with a radioactive ¹⁸ F atom to form F-BPA with ¹⁸ F. Since no new functional groups are introduced into the altered structure, the chemical properties are changed little, and it is easy to be recognized and taken up by cells, so the fluorinated substitution will not change the activity and targeting of BPA.

Methods exist in the prior art to synthesize F-BPA using the nucleophilic substitution method. However, the existing method for synthesizing F-BPA using nucleophilic substitution method still requires multi-step synthesis and separation steps after fluorination substitution, resulting in long total reaction time and low product yield, which is difficult to meet the requirements of clinical application.

SUMMARY OF THE INVENTION

In order to overcome at least one aspect of the above problems, embodiments of the present invention provide a method for synthesizing F-BPA, comprising:

The first compound reacts with I- ^to form the second compound, wherein,

The chemical structural formula of the first compound is:

The chemical structural formula of the second compound is:

The second compound reacts with cyclo()isopropyl malonate to generate the third compound, wherein,

The chemical structural formula of the third compound is:

The third compound reacts with tert-butoxycarbonyl to generate the fourth compound, wherein,

The chemical structural formula of the fourth compound is:

The fourth compound reacts with F- ^to generate the fifth compound, wherein,

The chemical structural formula of the fifth compound is:

The fifth compound reacts with H to generate F ^- BPA, wherein,

The chemical structural formula of the F-BPA is:

In the method for synthesizing F-BPA provided in the embodiments of the present invention, the final product can be obtained by only one step of hydrolysis after fluorination substitution, which shortens the synthesis time after fluorination substitution and improves the yield of the product.

Description of drawings

The above and/or additional aspects and advantages of the present invention will become apparent and readily understood from the following description of embodiments taken in conjunction with the accompanying drawings, wherein:

Fig. 1 is the schematic flow sheet that uses the first compound to synthesize the second compound provided by the embodiment of the present invention;

Fig. 2 is the schematic flow sheet of synthesizing the third compound with the second compound provided by the embodiment of the present invention;

Fig. 3 is the schematic flow sheet of synthesizing the fourth compound with the third compound provided by the embodiment of the present invention;

Fig. 4 is the schematic flow sheet of synthesizing the fifth compound with the fourth compound provided by the embodiment of the present invention;

Fig. 5 is the schematic flow sheet of synthesizing F-BPA with the fifth compound provided by the embodiment of the present invention;

Fig. 6 is the ¹ HNMR spectrum of the second compound provided by the embodiment of the present invention;

Fig. 7 is the ¹ HNMR spectrogram of the third compound provided in the embodiment of the present invention;

Fig. 8 is the ¹ HNMR spectrum of the fourth compound provided in the embodiment of the present invention;

Fig. 9 is the ¹ HNMR spectrogram of the fifth compound provided by the embodiment of the present invention;

Fig. 10 is the ¹ HNMR spectrum of F-BPA provided by the embodiment of the present invention;

FIG. 11 is a radiochemical purity diagram of ¹⁸ F-BPA provided in an example of the present invention.

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the implementations. example. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative work fall within the protection scope of the present invention.

The Chinese name of BPA involved in the examples of the present invention is 4-dihydroxyboron-L-phenylalanine. The F-BPA involved in the embodiments of the present invention is a compound formed by replacing one H atom on the benzene ring of BPA with a F atom, and the Chinese name is 2-fluoro-4-dihydroxyboron-L-phenylalanine. The ¹⁸ F-BPA involved in the embodiments of the present invention is F-BPA formed by substituting an F atom with a relative atomic mass of 18 for one H atom on the benzene ring of BPA. F atoms with a relative atomic mass of 18 are radioactive, making ¹⁸ F-BPA or other substances containing F atoms with a relative atomic mass of 18 radioactive.

1 to 5, an embodiment of the present invention provides a method for synthesizing F-BPA, comprising the following steps:

The first compound reacts with I- ^to form the second compound, wherein,

The chemical structural formula of the first compound is:

The chemical structural formula of the second compound is:

The second compound reacts with cyclo()isopropyl malonate to generate the third compound, wherein,

The chemical structural formula of the third compound is:

The third compound reacts with tert-butoxycarbonyl to generate the fourth compound, wherein,

The chemical structural formula of the fourth compound is:

The fourth compound reacts with F- ^to generate the fifth compound, wherein,

The chemical structural formula of the fifth compound is:

The fifth compound reacts with H to generate F ^- BPA, wherein,

The chemical structural formula of the F-BPA is:

The method for synthesizing F-BPA provided by the embodiments of the present invention will be described in detail below.

See Figure 1. In certain embodiments, the first compound 10 is reacted with I ⁻ to form the second compound 20 .

In some embodiments, the first compound 10 is dissolved in dilute hydrochloric acid to obtain the first mixed solution, and the dilute hydrochloric acid is used as the solvent of the first compound 10, and provides an acidic environment for the subsequent reaction. Of course, the present invention is not limited to this. It can also be replaced by other acids, such as dilute sulfuric acid, acetic acid, etc. For the convenience of explaining the present invention, dilute hydrochloric acid is used as an example for illustration below. In some embodiments, the volume of dilute hydrochloric acid may be 10 mL, and of course other suitable volumes may be used. In some embodiments, the concentration of dilute hydrochloric acid may be 0.1 mol/L, and of course it may be other suitable concentrations, for example, 0.09 mol/L, 0.11 mol/L.

In certain embodiments, the I- ^donating compound and hypochlorite are dissolved in water to obtain a second mixed solution. In some embodiments ^, the compound that can provide I- can be a compound formed by I and an active metal, for example ^, the compound that can provide I- can be NaI, KI or other compounds that can ionize I- after being dissolved ⁱⁿ water compound. In certain embodiments, the hypochlorite can be NaClO, KClO, or other suitable hypochlorite. In the following ^, the compound that can provide I- is NaI and the hypochlorite is NaClO as an example to illustrate, the quality of NaI can be 134mg, and the quality of sodium hypochlorite can be 58mg.

In some embodiments, the second mixed solution is added to the first mixed solution to obtain the third mixed solution, of course, the first mixed solution can also be added to the second mixed solution to obtain the third mixed solution.

In some embodiments, concentrated hydrochloric acid is added to the third mixed solution to react to generate the second compound, and the concentrated hydrochloric acid provides a sufficient acidic environment for the reaction, which is favorable for the reaction to proceed.

The reaction mechanism of this step is:

4I ^- +ClO ₂ ^- +4H ⁺ =2I ₂ +Cl ^- +2H ₂ O;

2I ₂ +3ClO ₂ ⁻ =2ICl+2IO ₃ ⁻ +Cl ⁻ ;

ICl reacts with the first compound to form the second compound.

In some embodiments, the concentration of concentrated hydrochloric acid can be 12 mol/L, and of course, it can also be concentrated hydrochloric acid with suitable concentrations. In some embodiments, the volume of concentrated hydrochloric acid may be 0.2 mL, and of course, it may be other suitable concentrated hydrochloric acid. In certain embodiments, concentrated hydrochloric acid is slowly added dropwise to the third mixed solution. In some embodiments, concentrated hydrochloric acid can be slowly added dropwise to the third mixed solution using a dropping funnel. In some embodiments, after the concentrated hydrochloric acid is added to the third mixed solution, stirring can be performed to make the reaction fully proceed. In some embodiments, the reaction temperature is room temperature, and the reaction time can be 6h.

In certain embodiments, after the reaction produces the second compound 20, diethyl ether is added to the reaction solution for extraction. In certain embodiments, the volume of ether can be 30 mL. The organic layer was separated after extraction. In some embodiments, the organic layer can be washed twice with water, and the organic layers after the two water washes are combined. In certain embodiments, the organic layer is evaporated to dryness. In certain embodiments, the organic layer can be evaporated to dryness by rotary evaporation. After the organic layer was evaporated to dryness, diethyl ether was added for recrystallization, and the volume of diethyl ether could be 10 mL. The recrystallized solid was filtered off and dried in vacuo to isolate the second compound 20.

The first compound 10 reacted with I- ^to give the second compound 20 in 68% yield. Referring to the ¹ HNMR spectrum of the second compound 20 shown in FIG. 6 , the structure is correct according to the ¹ HNMR spectrum, ¹ HNMR (400 MHz, TFA): δ (ppm) 2.06 (s, 2H, -B-OH), 2.15 (s, 2H, _NH2 ), 3.04 (2H, _-CH2 ), 3.88 (s, 1H, CH), 6.94, 7.29, 7.62 (3H, aromatic hydrogen), 11.14 (s, 1H, -COOH).

See Figure 2. In certain embodiments, the second compound 20 is reacted with cyclo()isopropyl malonate to give the third compound 30.

In certain embodiments, the second compound 20 and m-chloroperoxybenzoic acid (mCPBA) are dissolved in dichloromethane to obtain a fourth mixed solution, and m-chloroperoxybenzoic acid can oxidize the benzene ring in the second compound 20. 1. The oxidized product can participate in subsequent reactions again. In certain embodiments, the mass of the second compound 20 is 335 mg, the volume of dichloromethane is 25 mL, and the mass of m-chloroperoxybenzoic acid is 173 mg. In certain embodiments, after dissolving the second compound 20 and m-chloroperoxybenzoic acid (mCPBA) in dichloromethane, and stirring at room temperature for 0.5 h, a fourth mixed solution is obtained.

In certain embodiments, the fifth mixed solution is obtained after dissolving cyclo(meldrum's Acid) malonate in an alkali solution, and the alkali solution is used for dissolving cyclo()isopropyl malonate, and Provide an alkaline environment for the reaction. In some embodiments, the alkaline solution can be KOH, of course, the alkaline solution can also be NaOH, or other suitable alkaline solutions. In some embodiments, taking the alkali solution as KOH as an example, the mass of cyclo()isopropyl malonate is 144 mg, the concentration of KOH is 5%, and the volume is 1 mL.

In certain embodiments, the fifth mixed solution is added to the fourth mixed solution to react to generate the third compound 30 . In some embodiments, the fifth mixed solution can be slowly added to the fourth mixed solution through a dropping funnel. In some embodiments, the fifth mixed solution is added to the fourth mixed solution, the reaction time may be 5 hours, the reaction temperature may be room temperature, and the third compound 30 is generated by the reaction.

In some embodiments, after the reaction to generate the third compound 30, a large amount of light yellow solid is produced in the reaction solution, and the light yellow solid is the third compound 30. The pale yellow solid was filtered off, rinsed with a small amount of water, and after drying in vacuo, the third compound 30 was isolated.

In certain embodiments, the second compound 20 is reacted with cyclo()isopropyl malonate to form the third compound 30 in 58% yield. Referring to the ¹ HNMR spectrum of the third compound 30 shown in FIG. 7 , the structure is correct according to the ¹ HNMR spectrum, ¹ HNMR (400 MHz, TFA): δ (ppm) 1.79 (s, 1H, CH ₃ ), 2.01s, 2H, _NH2 ), 2.08 (s, 2H, -B-OH), 3.04 (2H, _-CH2 ), 3.88 (1H, -CH), 7.14, 7.26, 7.32 (3H, aromatic hydrogen), 11.1 (s , 1H, -COOH).

See Figure 3. In certain embodiments, the third compound 30 is reacted with a t-butoxycarbonyl group to form the fourth compound 40.

The English abbreviation of tert-butoxycarbonyl is Boc. In certain embodiments, the third compound 30 reacts with a compound that can provide tert-butoxycarbonyl to form a fourth compound 40. Specifically, the third compound 30 reacts with a compound that can provide tert-butoxycarbonyl. The tert-butoxycarbonyl group in the carbonyl compound reacts to form the fourth compound 40. The compound that can provide tert-butoxycarbonyl can be di-tert-butyl dicarbonate (also called tert-butyl acetate, chemical formula is (Boc) ₂ O), of course, the present invention is not limited to this, and the compound that can provide tert-butoxycarbonyl is also It can be other compounds, such as L-proline tert-butyl ester hydrochloride and the like. For the convenience of explaining the present invention, the following description is given by taking the compound that can provide the tert-butoxycarbonyl group as di-tert-butyl dicarbonate as an example.

In certain embodiments, the third compound 30, NaHCO ₃ and di-tert-butyl dicarbonate are dissolved in dichloromethane to react to generate the fourth compound 40. After NaHCO ₃ is dissolved in dichloromethane, the solution can be made alkaline It can provide a weak alkaline environment for the reaction. Of course, NaHCO ₃ here can be replaced by other substances that make the solution alkaline after dissolving in dichloromethane, such as KHCO ₃ , K ₂ CO ₃ , Na ₂ CO ₃ and so on. In certain embodiments, the mass of the third compound 30 is 481 mg, the mass of NaHCO ₃ is 168 mg, the mass of di-tert-butyl dicarbonate is 202 mg, and the volume of dichloromethane is 25 mL. In certain embodiments, after dissolving the third compound 30, NaHCO ₃ and di-tert-butyl dicarbonate in dichloromethane, react at 0° C. for 1 hour, and then warm to room temperature and stir for 5 hours to generate the fourth compound 40.

In certain embodiments, the third compound 30 is reacted with di-tert-butyl dicarbonate to form the fourth compound 40 in 88% yield. Referring to the ¹ HNMR spectrum of the fourth compound 40 shown in FIG. 8 , the structure is correct according to the ¹ HNMR spectrum, ¹ HNMR (400 MHz, TFA): δ (ppm) 1.40 (s, 3H, Boc-CH ₃ ), 1.79 (s, 3H, _CH3 ), 2.08 (s, 2H, -B-OH), 3.06 (2H, _-CH2 ), 4.85 (1H, -CH), 7.19, 7.23, 7.29 (3H, aromatic hydrogen), 11.6 (s, 1H, -COOH).

See Figure 4. In certain embodiments, the fourth compound 40 is reacted with F ⁻ to form the fifth compound 50 .

In certain embodiments, KF may be used to provide F ⁻ , although NaF or other suitable fluorides may also be used. The following takes KF as an example to illustrate.

In certain embodiments, 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexadecane (abbreviated as K _2.2.2 in English, For ease of writing, K _2.2.2 is used in this application to refer to 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexadecane), K ₂ CO ₃ and KF were dissolved in anhydrous dimethyl sulfoxide (DMSO) to obtain the sixth mixed solution. K _2.2.2 was used as a catalyst for the reaction. After K ₂ CO ₃ was dissolved in anhydrous dimethyl sulfoxide, It can make the solution alkaline and provide a weak alkaline environment for the reaction. Of course, K ₂ CO ₃ here can be replaced with other substances that make the solution alkaline after dissolving in anhydrous dimethyl sulfoxide, such as KHCO ₃ , NaHCO ₃ , Na ₂ CO ₃ and so on. In certain embodiments, the mass of K _2.2.2 is 113 mg, the mass of K ₂ CO ₃ is 41.4 mg, the mass of KF is 17.4 mg, and the mass of anhydrous dimethyl sulfoxide is 10 mL. After dissolving K _2.2.2 , K ₂ CO ₃ , and KF in anhydrous dimethyl sulfoxide, the mixture was heated and stirred for 0.5 h in an oil bath at 120-130° C. to obtain a sixth mixed solution.

In certain embodiments, the fourth compound 40 is dissolved in anhydrous dimethyl sulfoxide to obtain a seventh mixed solution. In certain embodiments, the mass of the fourth compound 40 is 136 mg, and the volume of anhydrous dimethyl sulfoxide is 5 mL.

In some embodiments, the seventh mixed solution is added to the sixth mixed solution, and the fifth compound 50 is formed by the reaction. In some embodiments, the seventh mixed solution can be slowly added to the sixth mixed solution through a dropping funnel. In certain embodiments, with the addition of the seventh mixed solution, the reaction solution turns into a dark caramel color. In some embodiments, the seventh mixed solution is added to the sixth mixed solution, refluxed at 150° C., and stirred for 20 min to react to generate the fifth compound 50 .

In certain embodiments, after the reaction generates the fifth compound 50, the dimethyl sulfoxide is distilled off under reduced pressure to obtain the first residue. In certain embodiments, after the fifth compound 50 is formed by the reaction, it is cooled to room temperature, and the dimethyl sulfoxide is distilled off under reduced pressure to obtain the first residue. In certain embodiments, after dissolving the first residue with methanol, the dissolving solution is added to an activated C18 solid phase extraction column, and eluted with diethyl ether and dichloromethane, respectively, to obtain the first eluent. In certain embodiments, the first eluate is evaporated to dryness to isolate the fifth compound 50, which is a tan solid. In some embodiments, the first eluate can be evaporated to dryness by rotary evaporation. In some embodiments, 5 mL of acetonitrile can be taken to rinse the C18 solid phase extraction column to remove excess liquid, 10 mL of high-purity water can be added to rinse the column, and air can be added to drain the excess liquid to activate the C18 solid phase extraction column.

In certain embodiments, the fourth compound 40 reacts with F ⁻ to form the fifth compound 50 in 51% yield. Referring to the ¹ HNMR spectrum of the fifth compound 50 shown in FIG. 9 , the structure is correct according to the ¹ HNMR spectrum, ¹ HNMR (400 MHz, TFA): δ (ppm) 1.40 (s, 3H, Boc-CH ₃ ), 2.06 (s, 2H, -B-OH), 3.04 (2H, _-CH2 ), 4.86 (1H, -CH), 6.91, 7.03, 7.1 (3H, aromatic hydrogen), 10.8 (s, 1H, -COOH).

See Figure 5. In certain embodiments, the fifth compound 50 reacts with H ⁺ to form F-BPA.

In certain embodiments, hydrochloric acid and dimethyl sulfoxide are mixed to obtain an eighth mixed solution. In some embodiments, the concentration of hydrochloric acid may be 2 mol/L, and the volume ratio of hydrochloric acid to dimethyl sulfoxide is 1:1.

In certain embodiments, the fifth compound 50 is added to the eighth mixed solution to react to generate F-BPA. In certain embodiments, the mass of the fifth compound 50 is 129 mg, and the volume of the eighth mixed solution is 15 mL. In certain embodiments, the fifth compound 50 is added to the eighth mixed solution, the reaction temperature is 100° C., and the reaction time is 0.5 h, and the reaction generates F-BPA.

In certain embodiments, after the reaction generates F-BPA, the reaction solution containing F-BPA is added to an activated silica gel column (Silican column) and an activated C18 solid phase extraction column, and eluted with hydrochloric acid to obtain a second eluent. In certain embodiments, the hydrochloric acid used for elution can be 50 mmol/L.

In some embodiments, 5 mL of n-hexane can be used to rinse the silica gel column to remove excess liquid, 10 mL of toluene can be added to rinse the column body, and air can be added to drain the excess liquid to activate the silica gel column.

In certain embodiments, F-BPA is isolated by evaporating the second eluate to dryness and vacuum drying. In certain embodiments, the second eluate can be evaporated to dryness by rotary evaporation.

In certain embodiments, the fifth compound 50 reacts with H ⁺ to form F-BPA in 60% yield. Referring to the ¹ HNMR spectrum of F-BPA shown in FIG. 10 , the structure is correct according to the ¹ HNMR spectrum, ¹ HNMR (400 MHz, TFA): δ (ppm) 2.03 (s, 2H, -B-OH), 2.12 ( s, 2H, _-NH2 ), 3.04 (2H, _-CH2 ), 3.98 (s, 1H, CH), 7.32, 7.51, 8.12 (3H, aromatic hydrogen), 11.13 (s, 1H, -COOH).

In certain embodiments, when synthesizing ¹⁸ F-BPA, the steps to synthesize the fourth compound 40 using the first compound 10 are the same as the steps to synthesize the fourth compound 40 using the first compound 10 when synthesizing F-BPA.

In certain embodiments, the fourth compound 40 reacts with ¹⁸ F- ^to form the fifth compound 50 when ¹⁸ F-BPA is synthesized.

In certain embodiments, ¹⁸ F ^- solutions can be produced by accelerators using non-radioactive F ^- solutions. In certain embodiments, the < ¹⁸ >F ^- solution has a volume of 400 [mu]L and an activity of about 16 mCi.

In certain embodiments, ^{the18F -} solution is added to the activated QMA column (strong anion solid phase extraction column), since ^{the18F -} solution is prepared by ^the18O (p,n) ^18F nuclear reaction by an accelerator, The ¹⁸ F ^- solution will contain trace impurities and the QMA column is used to remove these trace impurities. In some embodiments, 10 mL of 0.5 mol/L Na ₂ CO ₃ solution can be taken to rinse the QMA column, add air to remove excess liquid, then rinse the column with 10 mL of high-purity water, and add air to drain excess liquid to activate the QMA column.

In certain embodiments, after adding the ¹⁸ F ^- solution to the activated QMA column, it is eluted with K _2.2.2 /K ₂ CO ₃ solution to obtain a third eluent with radioactivity, here K ₂ CO ₃ can make the solution alkaline to provide a weak alkaline environment for the reaction, of course, K ₂ CO ₃ here can be replaced with other substances that make the solution alkaline, such as KHCO ₃ , NaHCO ₃ , Na ₂ CO ₃ and so on. In certain embodiments, the K _2.2.2 /K ₂ CO ₃ solution is prepared by dissolving K _2.2.2 , K ₂ CO ₃ in dry acetonitrile. In certain embodiments, the volume of the K _2.2.2 /K ₂ CO ₃ solution is 500 μL and the K _2.2.2 content is 5.66 μmol.

In certain embodiments, after heating the radioactive third eluent to near dryness, acetonitrile is added and heated to near dryness to obtain a second radioactive residue. By heating to near dry is meant heating to almost but not completely dry. In some embodiments, after heating the radioactive third eluent to near dryness, acetonitrile is added and heated to near dryness, and this step can be repeated three times to sufficiently remove water.

In certain embodiments, after the second radioactive residue is cooled to room temperature, the second radioactive residue is added to the seventh mixture obtained by dissolving the fourth compound 40 in anhydrous dimethyl sulfoxide. In the liquid, the reaction generates the fifth compound 50 with ¹⁸ F. In certain embodiments, the seventh mixture can be obtained by dissolving 2.6 mg (3.8 μmol) of the fourth compound 40 in 200 μL of anhydrous dimethyl sulfoxide. In certain embodiments, after adding the second radioactive residue to the seventh mixed solution obtained by dissolving the fourth compound 40 in anhydrous dimethyl sulfoxide, the reaction temperature is 150° C. and the reaction time is 10 min , the reaction generates the fifth compound 50 with ¹⁸ F.

In certain embodiments, ^the fifth compound 50 ^with18F is used to synthesize18F-BPA. In certain embodiments, the fifth compound 50 ^with18F reacts with H ⁺ to ^form18F -BPA.

In certain embodiments, hydrochloric acid and dimethyl sulfoxide are mixed to obtain an eighth mixed solution. In some embodiments, the concentration of hydrochloric acid may be 2 mol/L, and the volume ratio of hydrochloric acid to dimethyl sulfoxide is 1:1.

In certain embodiments, the fifth compound 50 with ¹⁸ F is added to the eighth mixed solution, and the reaction generates ¹⁸ F-BPA. In certain embodiments, the fifth compound 50 with ¹⁸ F is added to the eighth mixed solution, the reaction temperature is 100° C., the reaction time is 0.5 h, and the reaction generates ¹⁸ F-BPA.

In certain embodiments, after the reaction generates ¹⁸ F-BPA, the reaction solution containing ¹⁸ F-BPA is added to the activated silica gel column and the activated C18 solid phase extraction column, and eluted with hydrochloric acid to obtain a radioactive Second eluent. In certain embodiments, the hydrochloric acid used for elution can be 50 mmol/L.

In certain embodiments, the ¹⁸ F-BPA is isolated by evaporating the radioactive second eluate to dryness and vacuum drying. In certain embodiments, the radioactive second eluate can be evaporated to dryness by rotary evaporation.

In certain embodiments, the third compound 30 or the fourth compound 40 can be used as an intermediate to synthesize F-BPA or ¹⁸ F-BPA, and when the third compound 30 or the fourth compound 40 is used as an intermediate, the present invention can be used Examples provide methods to synthesize the third compound 30 or the fourth compound 40.

It should be noted that, although the synthesis of F-BPA or intermediates is described in the form of multiple embodiments in this application, multiple embodiments in this application can be combined with each other under the condition of no conflict. A complete example of the types of reactants, the amount of each reactant, and the reaction conditions (temperature, time, etc.).

In the method for synthesizing F-BPA provided by the embodiments of the present invention, the final product can be obtained by only one step of hydrolysis after fluorination substitution, which shortens the synthesis time after fluorination substitution, and improves the radiochemical yield and specific activity of the product. Spend.

After continuous organic reaction, the total synthesis time of ¹⁸ F-BPA radiochemical (from the fourth compound 40 and ¹⁸ F ^- started to react to the completion of synthesis of ¹⁸ F-BPA) was about 50min, and the synthesis was completed to obtain 142MBq product (corrected by decay), radiochemical The yield is about 32%. The radiochemical purity of the product was measured by thin-layer chromatography, which was spotted on a silica gel thin-layer plate, and developed with a 10 mmol/L ammonium acetate aqueous solution: acetonitrile=30:70 solution as a developing solvent. The radiochemical purity was determined to be about 98% by a tomography scanner, and the radiochemical purity map is shown in FIG. 11 .

The above descriptions are only the embodiments of the present invention, and are not intended to limit the scope of the present invention. Any equivalent structure or equivalent process transformation made by using the contents of the description and drawings of the present invention, or directly or indirectly applied to other related technologies Fields are similarly included in the scope of patent protection of the present invention.

Claims (17)

1. A method of synthesizing F-BPA comprising:

first compound and I ^- Reacting to form a second compound, wherein,

the chemical structural formula of the first compound is as follows:

the chemical structural formula of the second compound is as follows:

reacting the second compound with cycloisopropyl malonate to form a third compound, wherein,

the chemical structural formula of the third compound is as follows:

reacting the third compound with tert-butyloxycarbonyl group to produce a fourth compound, wherein,

the chemical structural formula of the fourth compound is as follows:

the fourth compound and F ^- The reaction produces a fifth compound, wherein,

the chemical structural formula of the fifth compound is:

the fifth compound with H ⁺ The reaction produces F-BPA, wherein,

the chemical structural formula of the F-BPA is as follows:

2. the method of claim 1, wherein,

the first compound and I ^- The step of reacting to form the second compound comprises:

dissolving the first compound in dilute hydrochloric acid to obtain a first mixed solution;

will provide I ^- Dissolving the compound (A) and hypochlorite in water to obtain a second mixed solution, and adding the second mixed solution into the first mixed solution to obtain a third mixed solution;

and adding concentrated hydrochloric acid into the third mixed solution to react to generate the second compound.

3. The method of claim 2, wherein,

after the second compound is generated through the reaction, extracting the reaction liquid to separate an organic layer;

evaporating the organic layer to dryness, and recrystallizing the solid obtained after evaporation to dryness;

and filtering out the solid obtained by recrystallization, and then carrying out vacuum drying to separate out the second compound.

4. The method of claim 1, wherein,

the step of reacting the second compound with the cyclo (isopropylidene) malonate to form a third compound comprises:

dissolving the second compound and m-chloroperoxybenzoic acid in dichloromethane to obtain a fourth mixed solution;

dissolving the cyclopropyl (methylene) isopropyl malonate in the alkali solution to obtain a fifth mixed solution, adding the fifth mixed solution into the fourth mixed solution, and reacting to generate the third compound.

5. The method of claim 4, wherein,

after reacting to produce a third compound, filtering the third compound;

and washing and vacuum drying the third compound obtained by filtering, and separating the third compound.

6. The method of claim 1, wherein,

the step of reacting the third compound with tert-butyloxycarbonyl group to generate a fourth compound comprises:

mixing the third compound, NaHCO ₃ And a compound capable of providing the tert-butoxycarbonyl group is dissolved in dichloromethane and reacted to form the fourth compound.

7. The method of claim 1, wherein,

the fourth compound and F ^- The step of reacting to form a fifth compound comprises:

will K _2.2.2 (4, 7, 13, 16, 21, 24-hexaoxa-1, 10-diazabicyclo [ 8.8.8)]Hexacosane), K ₂ CO ₃ KF is dissolved in anhydrous dimethyl sulfoxide to obtain a sixth mixed solution;

dissolving the fourth compound in anhydrous dimethyl sulfoxide to obtain a seventh mixed solution;

and adding the seventh mixed solution into the sixth mixed solution to react to generate the fifth compound.

8. The method of claim 7, wherein,

after the fifth compound is generated by reaction, removing dimethyl sulfoxide by reduced pressure distillation to obtain a first residue;

dissolving the first residue with methanol, adding the dissolved solution into an activated C18 solid phase extraction column, and eluting with diethyl ether and dichloromethane respectively to obtain a first eluent;

evaporating the first eluate to dryness and isolating the fifth compound.

9. The method of claim 1, wherein,

the fifth compound with H ⁺ The step of reacting to form F-BPA comprises:

mixing hydrochloric acid and dimethyl sulfoxide to obtain an eighth mixed solution;

and adding the fifth compound into the eighth mixed solution, and reacting to generate the F-BPA.

10. The method of claim 9, wherein,

after F-BPA is generated through reaction, adding reaction liquid containing the F-BPA into an activated silica gel column and an activated C18 solid phase extraction column, and eluting with hydrochloric acid to obtain a second eluent;

and evaporating the second eluent to dryness and performing vacuum drying to separate the F-BPA.

11. Synthesis of ¹⁸ A process for F-BPA comprising,

first compound and I ^- Reacting to form a second compound, wherein,

the chemical structural formula of the first compound is as follows:

the chemical structural formula of the second compound is as follows:

reacting the second compound with cycloisopropyl malonate to generate a third compound, wherein,

the chemical structural formula of the third compound is as follows:

reacting the third compound with tert-butyloxycarbonyl group to produce a fourth compound, wherein,

the chemical structural formula of the fourth compound is as follows:

the fourth compound and ¹⁸ F ^- reaction of the product with ¹⁸ A fifth compound of F wherein,

said belt is ¹⁸ The fifth compound of F has the chemical formula:

said belt is ¹⁸ Fifth compound of F with H ⁺ Reaction to form ¹⁸ F-BPA, wherein,

the above-mentioned ¹⁸ The chemical structural formula of F-BPA is:

12. the method of claim 11, wherein,

the fourth compound and ¹⁸ F ^- reaction of the product with ¹⁸ The step of the fifth compound of F comprises:

will be provided with ¹⁸ F ^- Adding the solution into an activated QMA column, and adding K _2.2.2 /K ₂ CO ₃ Eluting the solution to obtain a third eluent with radioactivity;

heating the third eluent with radioactivity to be nearly dry, adding acetonitrile, and heating to be nearly dry to obtain a second residue with radioactivity;

adding the second residue with radioactivity into a seventh mixed solution obtained by dissolving the fourth compound in anhydrous dimethyl sulfoxide, and reacting to generate the second residue with radioactivity ¹⁸ A fifth compound of F.

13. The method of claim 12, wherein,

reacting to form the band ¹⁸ Heating to remove dimethyl sulfoxide to obtain a third residue with radioactivity;

dissolving the third residue with radioactivity in methanol, adding the solution into a C18 solid phase extraction column, and eluting with diethyl ether and dichloromethane respectively to obtain a fourth eluate with radioactivity;

evaporating the fourth eluate to dryness to separate the product ¹⁸ A fifth compound of F.

14. The method of claim 13, wherein,

and heating the third eluent with radioactivity to be nearly dry, adding acetonitrile, heating to be nearly dry, and repeating the steps for multiple times to obtain a second residue with radioactivity.

15. The method of claim 12, wherein,

said K _2.2.2 /K ₂ CO ₃ The solution is prepared by mixing K _2.2.2 And K ₂ CO ₃ Dissolving in anhydrous acetonitrile.

16. The method of claim 11, wherein,

said belt is ¹⁸ Fifth compound of F with H ⁺ Reaction to form ¹⁸ The step of F-BPA comprises:

mixing hydrochloric acid and dimethyl sulfoxide to obtain an eighth mixed solution;

will be provided with ¹⁸ Adding a fifth compound of F into the eighth mixed solution to react to generate the ¹⁸ F-BPA。

17. The method of claim 16, wherein,

react to form ¹⁸ After F-BPA, will contain ¹⁸ Adding the reaction solution of F-BPA into an activated silica gel column and an activated C18 solid phase extraction column, and eluting with hydrochloric acid to obtain a second eluent with radioactivity;

evaporating the second eluate to dryness and vacuum drying to separate the second eluate ¹⁸ F-BPA。

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