Synthesis method of < 18 > F-flumetamol labeled precursor

Abstract

The invention provides a synthesis method of an < 18 > F-flumetazol labeled precursor, which comprises the following steps: by taking N-methyl-4-bromo-2-nitroaniline (compound 9) and 2-bromo-6-methoxybenzothiazole (compound 11) as initial raw materials, firstly carrying out boric acid esterification on the compound 9 to generate a compound 10, carrying out demethylation and ethyoxyl methyl ether protection on the compound 11 to obtain a compound 13, and then carrying out reaction on the compound 13 and the compound 13 to obtain the < 18 > F-flumetazol labeled precursor. Then carrying out Suzuki coupling with a compound 10 to generate a compound 7; and finally, carrying out formylation reaction to obtain a labeled precursor compound 8. The synthesis route is simple in preparation, high in synthesis yield and easy to separate and purify, and the obtained product is relatively high in purity.

Description

Technical Field

[0001] The present invention belongs to the field of chemical synthesis and relates to the synthesis of radioactive fluorine-labeled precursor compounds, and in particular to radioactive drugs. 18 A new synthetic route for the labeled precursor of F-flumetinol. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] 18 F-Flumetinol is a 18 F-labeled thioflavin T-type small molecule drug was approved for marketing in the United States on October 25, 2013. It can be taken up and retained in the brains of patients with Alzheimer's disease (AD), and can display amyloid plaques through positron emission tomography (PET). It can be used to evaluate Alzheimer's disease and dementia in adults. It was also submitted for clinical trials in China in July 2019.

[0004] Patents WO2007020400A1 and CN102731432A reported 18 Synthesis method of F-flumetinol labeled precursor (Compound 8). Using 4-formylamino-3-nitrobenzoic acid as the starting material, the labeled precursor compound is prepared by chlorination, cyclization, methylation, demethylation, etherification and formylation. The synthesis route is as follows:

[0005]

[0006] The literature reported a total yield of 13%, of which the yield of the second step reaction was only 26%. In the actual preparation process, when the intermediate 6 reacts with chloromethyl ether, there are two reaction sites, namely the phenolic hydroxyl group and the methylamino group, which will generate three products, O-substituted (compound 7), N-substituted and disubstituted. The yield of this step is only 35%, and the total yield is much lower than the reported data. At the same time, the polarity of the O-substituted and N-substituted products is similar and it is not easy to separate and purify. Summary of the invention

[0007] In order to solve the above problems, the present invention provides a method for preparing a novel nanostructured carbon nanotube with simple preparation, high synthesis yield and easy separation and purification of the product. 18 A new synthetic method for the labeling precursor of F-flumetinol.

[0008] In order to achieve the above object, the present invention adopts the following technical solution:

[0009] The first aspect of the present invention provides a18 The synthesis method of F-flumetinol labeled precursor is synthesized by the following route 18 F-Flumetazol labeled precursor;

[0010]

[0011] The specific steps of the route include:

[0012] (1) N-methyl-4-bromo-2-nitroaniline (Compound 9) reacts with a palladium catalyst, potassium acetate, and biboronic acid pinacol ester under anhydrous and oxygen-free conditions to undergo Miyaura borate esterification to generate 4-methylamino-3-nitrophenylboronic acid pinacol ester (Compound 10);

[0013]

[0014] (2) Using 2-bromo-6-methoxybenzothiazole (Compound 11) as a raw material, a demethylation reaction was performed to generate 2-bromo-6-hydroxybenzothiazole (Compound 12);

[0015]

[0016] (3) 2-bromo-6-hydroxybenzothiazole (Compound 12) and chloromethyl ether are substituted in the presence of an organic base to generate 2-bromo-6-ethoxymethoxybenzothiazole (Compound 13);

[0017]

[0018] (4) 4-Methylamino-3-nitrophenylboronic acid pinacol ester (Compound 10) and 2-bromo-6-ethoxymethoxybenzothiazole (Compound 13) were subjected to Suzuki coupling in the presence of a palladium catalyst and an inorganic base to obtain a thioflavin compound 2-[3-nitro-4-(methylamino)phenyl]-6-ethoxymethoxybenzothiazole (Compound 7);

[0019]

[0020] (5) 2-[3-nitro-4-(methylamino)phenyl]-6-ethoxymethoxybenzothiazole (Compound 7) is reacted with acetic anhydride and formic acid, and then formylated to obtain the labeled precursor 2-[3-nitro-4-(methylformylamino)phenyl]-6-ethoxymethoxybenzothiazole (Compound 8);

[0021]

[0022] In some embodiments, the palladium catalyst is selected from at least one of tetrakistriphenylphosphine palladium, dichlorobis(triphenylphosphine)palladium, bis(di-cyclohexylphosphine)ferrocene palladium dichloride, and bis(diphenylphosphine)ferrocene palladium dichloride;

[0023] In some embodiments, in step (1), the reaction solvent is selected from at least one of tetrahydrofuran, 1,4-dioxane, acetonitrile or toluene;

[0024] In some embodiments, in step (1), the reaction temperature is 65°C to 100°C.

[0025] In some embodiments, in step (2), the deprotection reagent used in the demethylation reaction is boron tribromide or aqueous hydrogen bromide solution.

[0026] In some embodiments, in step (3), the organic base is selected from at least one of triethylamine, pyridine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylenediamine (DABCO), and N-methylmorpholine;

[0027] In some embodiments, in step (3), the reaction solvent is selected from at least one of dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, dimethylformamide, and acetonitrile;

[0028] In some embodiments, in step (3), the reaction temperature is 0°C to room temperature (20-25°C).

[0029] In some embodiments, in step (4), the palladium catalyst is selected from at least one of tetrakistriphenylphosphine palladium, dichlorobis(triphenylphosphine)palladium, bis(di-cyclohexylphosphine)ferrocenepalladium dichloride, and bis(diphenylphosphine)ferrocenepalladium dichloride.

[0030] In some embodiments, in step (4), the inorganic base is potassium carbonate, cesium carbonate or potassium phosphate.

[0031] In some embodiments, in step (4), the reaction solvent is selected from at least one of tetrahydrofuran, 1,4-dioxane, dimethylformamide, acetonitrile, and toluene.

[0032] In some embodiments, in step (4), the reaction temperature is 75-130°C.

[0033] In some embodiments, in step (5), the reaction solvent used in the formyl reaction is selected from at least one of dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, and toluene.

[0034] The second aspect of the present invention provides the method prepared by the above method 18 F-Flumetazol labeling precursor.

[0035] Beneficial effects of the present invention

[0036] The synthesis method of the invention avoids substitution selectivity during the reaction, improves the reaction yield, and is easy to separate and purify. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] The accompanying drawings constituting a part of the present invention are used to provide a further understanding of the present invention, and the exemplary embodiments of the present invention and their description are used to explain the present invention and do not constitute improper limitations on the present invention.

[0038] Figure 1 The synthetic route used in the specific embodiment;

[0039] Figure 2 is the mass spectrum of the labeled precursor (compound 8);

[0040] Figure 3 This is the HPLC purity diagram of the labeled precursor (Compound 8). DETAILED DESCRIPTION

[0041] It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0042] The present invention will be further described in detail below in conjunction with specific embodiments. It should be noted that the specific embodiments are intended to explain the present invention rather than to limit it.

[0043] Example 1: Synthesis of 4-methylamino-3-nitrophenylboronic acid pinacol ester (Compound 10)

[0044] N-methyl-4-bromo-2-nitroaniline (compound 9, 2.31 g, 10 mmol), potassium acetate (1.96 g, 20 mmol), biphenylboronic acid pinacol ester (3.81 g, 15 mmol) and anhydrous 1,4-dioxane (150 mL) were added to a three-necked flask, and after stirring evenly, the nitrogen was switched to vacuum 3 times. Dichlorobis(triphenylphosphine)palladium (351 mg, 0.5 mmol) was added under nitrogen protection, and the reaction was carried out at 90° C. for 12 hours. After the reaction, most of the solvent was removed by rotation, the mixture was diluted with water, and extracted with ethyl acetate 3 times. The combined organic phase was washed with brine and dried with sodium sulfate, and then 4-methylamino-3-nitrophenylboronic acid pinacol ester (compound 10, orange solid, 2.42 g, yield 87%) was obtained by silica gel column chromatography. 1 H NMR (400MHz, CDCl3) δ8.61 (s, 1H), 7.80 (d, J = 8.6Hz, 1H), 6.78 (d, J = 8.6Hz, 1H), 3.02 (s, 3H), 1.31 (s, 12H). 13C NMR (101MHz, CDCl3) δ148.0,141.8,134.4,132.0,112.7,75.2,29.8,24.9.

[0045] Example 2: Synthesis of 2-bromo-6-hydroxybenzothiazole (Compound 12)

[0046] To a round-bottom flask, 100 mL of dichloromethane and 2-bromo-6-methoxybenzothiazole (compound 11, 2.44 g, 10 mmol) were added. After cooling to -20 °C, boron tribromide (3.85 mL, 40 mmol) was slowly added dropwise, and then the reaction was restored to room temperature for 5 hours. After the reaction was completed, ammonium chloride solution was added to quench the reaction, and the organic phase was separated and concentrated to obtain 2-bromo-6-hydroxybenzothiazole (compound 12, white solid, 1.87 g, yield 81%) by column chromatography. 1 H NMR (400MHz, CDCl3) δ7.83 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 2.5 Hz, 1H), 6.98 (dd, J = 8.8, 2.5 Hz, 1H).

[0047] Example 3: Synthesis of 2-bromo-6-ethoxymethoxybenzothiazole (Compound 13)

[0048] 2-Bromo-6-ethoxymethoxybenzothiazole (compound 12, 1.73 g, 7.5 mmol) and diisopropylethylamine (2 mL, 11.5 mmol) were dissolved in 100 mL of dichloromethane in a round-bottom flask, stirred under an ice-water bath, and chloromethoxyethyl ether (1 mL, 10.8 mmol) was slowly added dropwise, and then the reaction was restored to room temperature for 8 hours. After the reaction was completed, ammonium chloride solution was added to quench the reaction, and the organic phase was separated, concentrated, and purified by column chromatography to obtain 2-bromo-6-ethoxymethoxybenzothiazole (compound 13, colorless liquid, 1.95 g, yield 90%). 1 H NMR (400MHz, CDCl3) δ7.86(d,J=8.9Hz,1H),7.48(d,J=2.4Hz,1H),7.15(dd,J=8.9,2.4Hz,1H),5.27(s,2H),3.75(q,J=7.0Hz,2H),1.23(t,J=7.0Hz,3H). 13 CNMR (101MHz, CDCl3) δ155.9,147.6,138.6,136.3,123.4,117.4,107.0,93.8,64.7,15.2.

[0049] Example 4: Synthesis of 2-[3-nitro-4-(methylamino)phenyl]-6-ethoxymethoxybenzothiazole (Compound 7)

[0050] 4-Methylamino-3-nitrophenylboronic acid pinacol ester (Compound 10, 1.39 g, 5 mmol), 2-bromo-6-ethoxymethoxybenzothiazole (Compound 13, 1.44 g, 5 mmol), potassium carbonate aqueous solution (20 mmol) and toluene (50 mL) were added to a three-necked flask, and the mixture was stirred evenly and then switched to nitrogen three times under vacuum. Tetrakistriphenylphosphine palladium (231 mg, 0.2 mmol) was added under nitrogen protection, and the mixture was reacted at 110° C. for 12 hours. After the reaction, most of the solvent was removed by rotation, the mixture was diluted with water, and extracted three times with ethyl acetate. The combined organic phases were washed with brine and dried with sodium sulfate, and then 2-[3-nitro-4-(methylamino)phenyl]-6-ethoxymethoxybenzothiazole (Compound 7, orange solid, 1.47 g, yield 82%) was obtained by silica gel column chromatography. 1 H NMR (400MHz, CDCl3) δ8.79(d,J=2.2Hz,1H),8.31(d,J=5.1Hz,1H),8.21(dd,J=8.9,2.2Hz,1H),7.90(d,J=8.9Hz,1H),7.56(d,J=2.5Hz, 1H),7.17(dd,J=8.9,2.5Hz,1H),6.96(d,J=8.9Hz,1H),5.30(s,2H),3.78(q,J=7.0Hz,2H),3.11(d,J=5.1Hz,3H),1.26(t,J=7.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ164.4,155.5,149.4,147.4,136.0,134.6,131.8,126.1,123.4,121.7,117.2,114.1,107.8,93.9,64.6,30.1,15.3.

[0051] Example 5: Synthesis of the labeling precursor 2-[3-nitro-4-(methylformamido)phenyl]-6-ethoxymethoxybenzothiazole (Compound 8)

[0052] In an ice-water bath, 4 mL of formic acid and 8 mL of acetic anhydride were added to a round-bottom flask in sequence. After stirring at 60°C for half an hour, the mixture was cooled in an ice-water bath again. A dichloromethane solution (100 mL) of 2-[3-nitro-4-(methylamino)phenyl]-6-ethoxymethoxybenzothiazole (compound 7, 1.8 g, 5 mmol) was slowly added dropwise, and then heated under reflux for 24 hours. After the reaction was completed, the mixture was cooled, and the reaction solution was washed with 100 mL of sodium carbonate solution and 100 mL of water in sequence. The organic phase was concentrated and purified by column chromatography to obtain the labeled precursor (compound 8, light yellow solid, 1.37 g, yield 71%). ESI-MS: [M+H] +,388.29;[2M+H] + ,775.60.

[0053] The total yield of the target product labeled precursor was 37%, which was higher than the literature receipt, and the purity of the compound was 99.53%.

[0054] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A 18 The method for synthesizing a F-flumetinol labeled precursor is characterized in that: The following synthesis route was used 18 F-Flumetazol labeled precursor; The specific steps of the route include: Step (1): N-methyl-4-bromo-2-nitroaniline reacts with a palladium catalyst, potassium acetate and biboronic acid pinacol ester under anhydrous and oxygen-free conditions to undergo Miyaura borate esterification to generate 4-methylamino-3-nitrophenylboronic acid pinacol ester; Step (2): using 2-bromo-6-methoxybenzothiazole as a raw material, and subjecting it to a demethylation reaction to generate 2-bromo-6-hydroxybenzothiazole; Step (3): 2-bromo-6-hydroxybenzothiazole and chloromethyl ether are substituted in the presence of an organic base to generate 2-bromo-6-ethoxymethoxybenzothiazole; Step (4): 4-methylamino-3-nitrophenylboronic acid pinacol ester and 2-bromo-6-ethoxymethoxybenzothiazole are subjected to Suzuki coupling in the presence of a palladium catalyst and an inorganic base to obtain a thioflavin compound 2-[3-nitro-4-(methylamino)phenyl]-6-ethoxymethoxybenzothiazole; Step (5): 2-[3-nitro-4-(methylamino)phenyl]-6-ethoxymethoxybenzothiazole is reacted with acetic anhydride and formic acid, and formylated to obtain the labeled precursor 2-[3-nitro-4-(methylformamido)phenyl]-6-ethoxymethoxybenzothiazole.

2. The method according to claim 1 18 The method for synthesizing a F-flumetinol labeled precursor is characterized in that: The palladium catalyst is selected from at least one of tetrakistriphenylphosphine palladium, dichlorobis(triphenylphosphine)palladium, bis(di-cyclohexylphosphine)ferrocene palladium dichloride, and bis(diphenylphosphine)ferrocene palladium dichloride; Or, in step (1), the reaction solvent is selected from at least one of tetrahydrofuran, 1,4-dioxane, acetonitrile or toluene; Alternatively, in step (1), the reaction temperature is 65°C to 100°C.

3. The method according to claim 1 18 The method for synthesizing a F-flumetinol labeled precursor is characterized in that: In step (2), the deprotection reagent used in the demethylation reaction is boron tribromide or aqueous hydrogen bromide solution.

4. The method according to claim 1 18 The method for synthesizing a F-flumetinol labeled precursor is characterized in that: In step (3), the organic base is selected from at least one of triethylamine, pyridine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylenediamine, and N-methylmorpholine; Or, in step (3), the reaction solvent is selected from at least one of dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, dimethylformamide, and acetonitrile; Alternatively, in step (3), the reaction temperature is from 0°C to room temperature.

5. The method according to claim 1 18 The method for synthesizing a F-flumetinol labeled precursor is characterized in that: In step (4), the palladium catalyst is selected from at least one of tetrakistriphenylphosphine palladium, dichlorobis(triphenylphosphine)palladium, bis(di-cyclohexylphosphine)ferrocene palladium dichloride, and bis(diphenylphosphine)ferrocene palladium dichloride.

6. The method according to claim 1 18 The method for synthesizing a F-flumetinol labeled precursor is characterized in that: In step (4), the inorganic base is potassium carbonate, cesium carbonate or potassium phosphate.

7. The method according to claim 1 18 The method for synthesizing a F-flumetinol labeled precursor is characterized in that: In step (4), the reaction solvent is selected from at least one of tetrahydrofuran, 1,4-dioxane, dimethylformamide, acetonitrile and toluene.

8. The method according to claim 1 18 The method for synthesizing a F-flumetinol labeled precursor is characterized in that: In step (4), the reaction temperature is 75-130°C.

9. The method according to claim 1 18 The method for synthesizing a F-flumetinol labeled precursor is characterized in that: In step (5), the reaction solvent used in the formyl reaction is at least one selected from dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, and toluene.

10. The method according to any one of claims 1 to 9 prepared 18 F-Flumetazol labeling precursor.

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