Preparation method of [18F] fluoroestradiol precursor compound

Abstract

The invention relates to a preparation method of a [18F] fluoroestradiol precursor compound, which is characterized in that chloromethyl methyl ether used in the fifth step in the synthesis process of the existing [18F] fluoroestradiol precursor compound in the market is replaced by bromomethyl methyl ether with lower toxicity. The problem of purchasing highly toxic chloromethyl methyl ether in the synthesis process is successfully solved, the harm of highly toxic product residues brought into human bodies is also solved, and meanwhile, the pollution to the environment in the compound synthesis process is also reduced.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a method for preparing a [18F]fluoroestradiol precursor compound. Background Art

[0002] The synthesis process of [18F] fluoroestradiol precursor compounds currently on the market is divided into six steps, of which the fifth step uses highly toxic chloromethyl methyl ether, and this highly toxic compound is close to the final product in the compound synthesis step. If any residue is introduced into the human body, it will cause great harm to the human body. The toxicological data of chloromethyl methyl ether are: median lethal dose (LD50): 500mg / kg (rat oral), LC50: 182mg / m 3 , 7 hours (rat inhalation), the storage temperature should not exceed 30℃ during storage, the packaging should be sealed and should not be in contact with air. Tearing, sore throat, severe coughing, chest tightness, dyspnea, fever and chills will occur immediately after inhalation of higher concentrations, and the condition will gradually improve after being out of contact. However, after a latent period of several hours to 24 hours, chemical pneumonia and pulmonary edema may occur, and death may occur if rescue is not timely. Contact with eyes and skin may cause burns. Chronic effects: Long-term contact with this product can cause bronchitis. This product can cause lung cancer. The toxicological data of methyl bromide are: median lethal dose (LD50): 2400mg / kg (rat oral); Carcinogenicity: In animal studies, there are only limited signs of carcinogenicity and no other toxicity data. Summary of the invention

[0003] The purpose of the present invention is to provide a method for preparing a [18F]fluoroestradiol precursor compound. The [18F]fluoroestradiol precursor compound MMSE (methoxymethyl-O-sulfonyl-epiestriol) is used for the preparation of a [18F]fluoroestradiol preparation, which is clinically used for PET imaging diagnosis of breast cancer.

[0004] The purpose of the present invention can be achieved by the following technical solutions:

[0005] A method for preparing a [18F]fluoroestradiol precursor compound, comprising the following specific steps:

[0006] S1, using estrone and isopropenyl acetate as raw materials to synthesize the product MMSE-1 with the structure shown in formula I;

[0007] S2, using the product MMSE-1 of the structure shown in formula I obtained in step S1, lead tetraacetate and acetic acid as raw materials to synthesize the product MMSE-2 of the structure shown in formula II;

[0008] S3, using the product MMSE-2 of the structure shown in formula II obtained in step S2 and lithium tri-tert-butoxyaluminum hydride as raw materials to synthesize the product MMSE-3 of the structure shown in formula III or the product MMSE-3' of the structure shown in formula IV;

[0009] S4, using the product MMSE-3 of the structure represented by formula III or the product MMSE-3' of the structure represented by formula IV obtained in step S3 and potassium hydroxide as raw materials to synthesize the product MMSE-4 of the structure represented by formula V;

[0010] S5, using the product MMSE-4 with the structure shown in formula V obtained in step S4, sodium methoxide and bromomethyl methyl ether as raw materials to synthesize the product MMSE-5 with the structure shown in formula VI;

[0011] S6, using the product MMSE-5 of the structure represented by formula VI obtained in step S5 and N,N'-sulfonyldiimidazole as raw materials to synthesize the [18F]fluoroestradiol precursor compound MMSE of the structure represented by formula VII;

[0012] Wherein, the general structural formulas I to IV are as follows:

[0013]

[0014] , in step S1, estrone is added to isopropenyl acetate, and then a catalyst is added, and the reaction is heated. After the reaction is completed, the mixture is cooled, washed, extracted, and dried to obtain a product with the structure shown in formula I.

[0015] In the above, further, estrone: isopropenyl acetate: catalyst = 1 g: 10-20 ml: 0.5-1 ml, preferably estrone: isopropenyl acetate: catalyst = 1 g: 15.3 ml: 0.7 ml.

[0016] In the above, further, the catalyst comprises isopropenyl acetate and concentrated sulfuric acid, and the volume ratio of isopropenyl acetate:concentrated sulfuric acid is 40:1.

[0017] Furthermore, in the above, the heating temperature is 105-115° C. and the heating time is 2-4 hours.

[0018] Furthermore, ethyl acetate and 5% sodium bicarbonate ice water solution were added in sequence for washing.

[0019] In the above method, extraction is further performed with acetic acid and ethyl acetate in sequence.

[0020] The above further comprises drying over anhydrous sodium sulfate.

[0021] Furthermore, in step S2, the product MMSE-1: lead tetraacetate: acetic acid = 1 g: 1-3 g: 15-21 ml, preferably the product MMSE-1: lead tetraacetate: acetic acid = 1 g: 1.98 g: 17.99 ml.

[0022] Furthermore, in step S2, the product MMSE-1 with the structure shown in formula I obtained in step S1, lead tetraacetate and acetic acid are mixed and stirred, diluted and washed after the reaction is completed, and dried to obtain a crude product of MMSE-2, and then methyl tert-butyl ether is added and ultrasonicated, and the product MMSE-2 with the structure shown in synthetic formula II is obtained after filtration.

[0023] In the above, further, the stirring temperature is 30 to 50° C., and the stirring time is 2 to 4 hours.

[0024] The above solution is further diluted with dichloromethane.

[0025] In the above method, 5% sodium thiosulfate and saturated sodium bicarbonate are added in sequence for washing.

[0026] The above further comprises drying over anhydrous sodium sulfate.

[0027] Further, in step S3, the product MMSE-2 of the structure shown in formula II obtained in step S2, lithium tri-tert-butoxyaluminum hydride and anhydrous tetrahydrofuran are mixed and reacted. After the reaction is completed, a mixed solution of ice water and acetic acid is added, and the tetrahydrofuran is removed by rotary evaporation after standing, and extraction is performed. After washing and drying, the product MMSE-3 of the structure shown in synthetic formula III or the product MMSE-3' of the structure shown in formula IV is obtained.

[0028] In the above, the product MMSE-2: lithium tri-tert-butoxyaluminum hydride: anhydrous tetrahydrofuran = 1 g: 2-4 g: 30-50 ml, preferably the product MMSE-2: lithium tri-tert-butoxyaluminum hydride: anhydrous tetrahydrofuran = 1 g: 2.5 g: 40 ml.

[0029] Furthermore, in the above, the volume ratio of ice water to acetic acid in the mixed solution is 1:0.5-1, preferably ice water to acetic acid is 1:0.7.

[0030] In the above method, extraction is performed successively with acetic acid and dichloromethane.

[0031] In the above method, saturated sodium bicarbonate is added for washing.

[0032] The above further comprises drying over anhydrous sodium sulfate.

[0033] Further, in step S4, the product MMSE-3 of the structure represented by formula III or the product MMSE-3' of the structure represented by formula IV obtained in step S3 is dissolved in methanol, potassium hydroxide solution is added, and the reaction is carried out under a nitrogen atmosphere, and the pH is adjusted to 1 by hydrochloric acid, washed with water, and dried in an oven to obtain the product MMSE-4 of the structure represented by formula V.

[0034] In the above, further, the product MMSE-2: methanol: potassium hydroxide solution = 1g: 15-25ml: 15-25ml, preferably the product MMSE-2: methanol: potassium hydroxide solution = 1g: 20ml: 19.6ml.

[0035] In the above further aspect, the concentration of the potassium hydroxide solution is 0.15 to 0.25 g / ml.

[0036] In the above further step, the reaction temperature is 60-70° C. and the reaction time is 4-6 hours.

[0037] Further, in step S5, the product MMSE-4 with the structure shown in formula V obtained in step S4 is added to anhydrous tetrahydrofuran and stirred, and then sodium methoxide and bromomethyl methyl ether solution are added to react. After the reaction is completed, it is spin-dried, ether is added, washed with water, dried, and purified and eluted to obtain the product MMSE-5 with the structure shown in formula VI.

[0038] In the above, the product MMSE-4: anhydrous tetrahydrofuran: sodium methoxide: bromomethyl methyl ether solution = 1 g: 15-25 ml: 0.3-0.5 g: 1-2 ml, preferably the product MMSE-4: anhydrous tetrahydrofuran: sodium methoxide: bromomethyl methyl ether solution = 1 g: 20 ml: 0.4 g: 1.6 ml.

[0039] Furthermore, the volume percentage of the bromomethyl methyl ether solution is 25% v / v.

[0040] The above further comprises drying over anhydrous sodium sulfate.

[0041] Further, in step S6, the product MMSE-5 with the structure shown in formula VI obtained in step S5 is dissolved in anhydrous tetrahydrofuran, and sodium hydride and N,N'-sulfonyldiimidazole solution are added to react. After the reaction is completed, it is extracted and dried, and purified to obtain the [18F]fluoroestradiol precursor compound MMSE with the structure shown in formula VII.

[0042] In the above, the product MMSE-4: anhydrous tetrahydrofuran: sodium hydride: N,N'-sulfuryl diimidazole solution = 1g: 20-30ml: 0.4-0.7g: 7-10ml, preferably the product MMSE-4: anhydrous tetrahydrofuran: sodium hydride: N,N'-sulfuryl diimidazole solution = 1g: 24ml: 0.588g: 8.8ml.

[0043] In the above, further, the concentration of the N,N'-sulfuryldiimidazole solution is 0.05-0.10 g / ml.

[0044] Furthermore, in the above, the reaction time is 1.5 to 2.5 hours.

[0045] In the above method, extraction is further performed twice with ethyl acetate.

[0046] The above further comprises drying over anhydrous sodium sulfate.

[0047] Furthermore, after step S6, step S7 is provided: ethanol recrystallization, adding ethanol to the [18F]fluoroestradiol precursor compound MMSE having the structure shown in formula VII obtained in step S6, heating to dissolve and then placing in a low temperature environment for recrystallization, filtering after precipitating crystals, washing with ethanol and drying to obtain the purified [18F]fluoroestradiol precursor compound MMSE.

[0048] Furthermore, in the above, the temperature of the low temperature environment is lower than 25°C, preferably 4-8°C.

[0049] Compared with the prior art, the present invention has the following beneficial effects:

[0050] 1. The preparation method provided by the present invention replaces the chloromethyl methyl ether used in the fifth step of the synthesis process of the existing [18F] fluoroestradiol precursor compound on the market with bromomethyl methyl ether with lower toxicity, successfully solving the problem of purchasing the highly toxic chloromethyl methyl ether in the synthesis process, and also solving the harm of the highly toxic residues brought into the human body. At the same time, it also reduces the pollution to the environment during the compound synthesis process.

[0051] 2. Chloromethyl methyl ether is difficult to purchase and causes serious environmental pollution, making it unsuitable for mass production. Bromomethyl methyl ether is difficult to purify during the synthesis process, contains many impurities, and has a complicated purification process. The present invention improves the purity of the product by adding ethanol for recrystallization, and the purity of the [18F] fluoroestradiol precursor compound finally prepared is >99%, while the purity of the single column purification is >95%. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 The present invention provides a schematic diagram of the synthesis reaction of the method for preparing the [18F]fluoroestradiol precursor compound. DETAILED DESCRIPTION

[0053] The present invention is described in detail below in conjunction with the accompanying drawings and specific embodiments. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and specific operation process, but the protection scope of the present invention is not limited to the following embodiments.

[0054] A method for preparing a [18F]fluoroestradiol precursor compound, comprising the following specific steps:

[0055] S1, using estrone and isopropenyl acetate as raw materials to synthesize the product MMSE-1 with the structure shown in formula I;

[0056] S2, using the product MMSE-1 of the structure shown in formula I obtained in step S1, lead tetraacetate and acetic acid as raw materials to synthesize the product MMSE-2 of the structure shown in formula II;

[0057] S3, using the product MMSE-2 of the structure shown in formula II obtained in step S2 and lithium tri-tert-butoxyaluminum hydride as raw materials to synthesize the product MMSE-3 of the structure shown in formula III or the product MMSE-3' of the structure shown in formula IV;

[0058] S4, using the product MMSE-3 of the structure represented by formula III or the product MMSE-3' of the structure represented by formula IV obtained in step S3 and potassium hydroxide as raw materials to synthesize the product MMSE-4 of the structure represented by formula V;

[0059] S5, using the product MMSE-4 with the structure shown in formula V obtained in step S4, sodium methoxide and bromomethyl methyl ether as raw materials to synthesize the product MMSE-5 with the structure shown in formula VI;

[0060] S6, using the product MMSE-5 of the structure represented by formula VI obtained in step S5 and N,N'-sulfonyldiimidazole as raw materials to synthesize the [18F]fluoroestradiol precursor compound MMSE of the structure represented by formula VII;

[0061] Wherein, the general structural formulas I to IV are as follows:

[0062]

[0063]

[0064] Furthermore, in step S1, estrone is added to isopropenyl acetate, and then a catalyst is added, and the reaction is heated. After the reaction is completed, the mixture is cooled, washed, extracted, and dried to obtain a product with the structure shown in formula I.

[0065] In the above, further, estrone: isopropenyl acetate: catalyst = 1 g: 10-20 ml: 0.5-1 ml, preferably estrone: isopropenyl acetate: catalyst = 1 g: 15.3 ml: 0.7 ml.

[0066] In the above, further, the catalyst comprises isopropenyl acetate and concentrated sulfuric acid, and the volume ratio of isopropenyl acetate:concentrated sulfuric acid is 40:1.

[0067] Furthermore, in the above, the heating temperature is 105-115° C. and the heating time is 2-4 hours.

[0068] Furthermore, ethyl acetate and 5% sodium bicarbonate ice water solution were added in sequence for washing.

[0069] In the above method, extraction is further performed with acetic acid and ethyl acetate in sequence.

[0070] The above further comprises drying over anhydrous sodium sulfate.

[0071] Furthermore, in step S2, the product MMSE-1: lead tetraacetate: acetic acid = 1 g: 1-3 g: 15-21 ml, preferably the product MMSE-1: lead tetraacetate: acetic acid = 1 g: 1.98 g: 17.99 ml.

[0072] Furthermore, in step S2, the product MMSE-1 with the structure shown in formula I obtained in step S1, lead tetraacetate and acetic acid are mixed and stirred, diluted and washed after the reaction is completed, and dried to obtain a crude product of MMSE-2, and then methyl tert-butyl ether is added and ultrasonicated, and the product MMSE-2 with the structure shown in synthetic formula II is obtained after filtration.

[0073] In the above, further, the stirring temperature is 30 to 50° C., and the stirring time is 2 to 4 hours.

[0074] The above solution is further diluted with dichloromethane.

[0075] In the above method, 5% sodium thiosulfate and saturated sodium bicarbonate are added in sequence for washing.

[0076] The above further comprises drying over anhydrous sodium sulfate.

[0077] Further, in step S3, the product MMSE-2 of the structure shown in formula II obtained in step S2, lithium tri-tert-butoxyaluminum hydride and anhydrous tetrahydrofuran are mixed and reacted. After the reaction is completed, a mixed solution of ice water and acetic acid is added, and the tetrahydrofuran is removed by rotary evaporation after standing, and extraction is performed. After washing and drying, the product MMSE-3 of the structure shown in synthetic formula III or the product MMSE-3' of the structure shown in formula IV is obtained.

[0078] In the above, the product MMSE-2: lithium tri-tert-butoxyaluminum hydride: anhydrous tetrahydrofuran = 1 g: 2-4 g: 30-50 ml, preferably the product MMSE-2: lithium tri-tert-butoxyaluminum hydride: anhydrous tetrahydrofuran = 1 g: 2.5 g: 40 ml.

[0079] Furthermore, in the above, the volume ratio of ice water to acetic acid in the mixed solution is 1:0.5-1, preferably ice water to acetic acid is 1:0.7.

[0080] In the above method, extraction is performed successively with acetic acid and dichloromethane.

[0081] In the above method, saturated sodium bicarbonate is added for washing.

[0082] The above further comprises drying over anhydrous sodium sulfate.

[0083] Further, in step S4, the product MMSE-3 of the structure represented by formula III or the product MMSE-3' of the structure represented by formula IV obtained in step S3 is dissolved in methanol, potassium hydroxide solution is added, and the reaction is carried out under a nitrogen atmosphere, and the pH is adjusted to 1 by hydrochloric acid, washed with water, and dried in an oven to obtain the product MMSE-4 of the structure represented by formula V.

[0084] In the above, further, the product MMSE-2: methanol: potassium hydroxide solution = 1g: 15-25ml: 15-25ml, preferably the product MMSE-2: methanol: potassium hydroxide solution = 1g: 20ml: 19.6ml.

[0085] In the above further aspect, the concentration of the potassium hydroxide solution is 0.15 to 0.25 g / ml.

[0086] In the above further step, the reaction temperature is 60-70° C. and the reaction time is 4-6 hours.

[0087] Further, in step S5, the product MMSE-4 with the structure shown in formula V obtained in step S4 is added to anhydrous tetrahydrofuran and stirred, and then sodium methoxide and bromomethyl methyl ether solution are added to react. After the reaction is completed, it is spin-dried, ether is added, washed with water, dried, and purified and eluted to obtain the product MMSE-5 with the structure shown in formula VI.

[0088] In the above, the product MMSE-4: anhydrous tetrahydrofuran: sodium methoxide: bromomethyl methyl ether solution = 1 g: 15-25 ml: 0.3-0.5 g: 1-2 ml, preferably the product MMSE-4: anhydrous tetrahydrofuran: sodium methoxide: bromomethyl methyl ether solution = 1 g: 20 ml: 0.4 g: 1.6 ml.

[0089] Furthermore, the volume percentage of the bromomethyl methyl ether solution is 25% v / v.

[0090] The above further comprises drying over anhydrous sodium sulfate.

[0091] Further, in step S6, the product MMSE-5 with the structure shown in formula VI obtained in step S5 is dissolved in anhydrous tetrahydrofuran, and sodium hydride and N,N'-sulfonyldiimidazole solution are added to react. After the reaction is completed, it is extracted and dried, and purified to obtain the [18F]fluoroestradiol precursor compound MMSE with the structure shown in formula VII.

[0092] In the above, the product MMSE-4: anhydrous tetrahydrofuran: sodium hydride: N,N'-sulfuryl diimidazole solution = 1g: 20-30ml: 0.4-0.7g: 7-10ml, preferably the product MMSE-4: anhydrous tetrahydrofuran: sodium hydride: N,N'-sulfuryl diimidazole solution = 1g: 24ml: 0.588g: 8.8ml.

[0093] In the above, further, the concentration of the N,N'-sulfuryldiimidazole solution is 0.05-0.10 g / ml.

[0094] Furthermore, in the above, the reaction time is 1.5 to 2.5 hours.

[0095] In the above method, extraction is further performed twice with ethyl acetate.

[0096] The above further comprises drying over anhydrous sodium sulfate.

[0097] Furthermore, after step S6, step S7 is provided: ethanol recrystallization, adding ethanol to the [18F]fluoroestradiol precursor compound MMSE having the structure shown in formula VII obtained in step S6, heating to dissolve and then placing in a low temperature environment for recrystallization, filtering after precipitating crystals, washing with ethanol and drying to obtain the purified [18F]fluoroestradiol precursor compound MMSE.

[0098] Furthermore, in the above, the temperature of the low temperature environment is lower than 25°C, preferably 4-8°C.

[0099] In conjunction with the accompanying drawings, some embodiments of the present invention are described in detail below. In the absence of conflict, the following embodiments and features in the embodiments may be combined with each other.

[0100] Example

[0101] See also Figure 1 This embodiment provides a method for preparing a [18F]fluoroestradiol precursor compound, and the specific steps are as follows:

[0102] (1) Add 30g of estrone and 300mL of isopropenyl acetate to a 1000ml eggplant-shaped bottle, stir, add 13mL of catalyst (32mL of isopropenyl acetate and 0.8mL of concentrated sulfuric acid are evenly mixed), heat and reflux at 105℃-115℃ for 1 hour, slowly evaporate about 50mL of solution within 1 hour, add 80mL of isopropenyl acetate and 4mL of catalyst, then slowly evaporate about 50mL of solution within 1 hour at 105-115℃; add 80mL of isopropenyl acetate and 4mL of catalyst, then slowly evaporate about 50mL of solution within 1 hour at 105-115℃. After the reaction is completed, cool to room temperature, add 300mL of ethyl acetate, wash with 200mL of 5% sodium bicarbonate ice water solution, add 100mL of acetic acid, extract to obtain a brown solution; extract again with 300mL of ethyl acetate, combine the extract solution, dry over anhydrous sodium sulfate, and spin dry. 120 ml of methanol was added to the spin-dried crude product and ultrasonicated until there was no agglomeration in the suspension and it was dispersed in the solution in the form of fine powder, filtered, and washed with a small amount of methanol to obtain MMSE-1.

[0103]

[0104] (2) 27.8 g MMSE-1, 48 g lead tetraacetate, 500 ml acetic acid, stir at 40°C for 3 hours. Add 7 g lead tetraacetate and react until the raw material spot disappears by TLC. Dilute with 1500 ml dichloromethane, wash twice with 400 ml 5% sodium thiosulfate, wash twice with 200 ml saturated sodium bicarbonate, dry with anhydrous sodium sulfate to remove water, and spin dry. Add 40 ml methyl tert-butyl ether to the collected MMSE-2 crude product, sonicate until there is no agglomeration and it is distributed in the solution in the form of fine powder, filter, and wash the sample with a small amount of methyl tert-butyl ether to obtain MMSE-2.

[0105]

[0106] (3) 12.5 g MMSE-2, 31.25 g lithium tri-tert-butoxyaluminum hydride, 500 ml anhydrous tetrahydrofuran were reacted for 5 hours, and a sample was taken for TLC detection. If the raw material point was still obvious, the reaction time was extended until the raw material point basically disappeared. After the reaction was terminated, a mixed solution of 300 ml ice water and 210 ml acetic acid was prepared, and the reaction solution was poured into the mixed solution under stirring and allowed to stand for 5 min. The tetrahydrofuran was removed by rotary evaporation, and 100 ml acetic acid was added and extracted with 1500 ml dichloromethane. The extract was washed twice with 400 ml saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and spin-dried to obtain compound MMSE-3.

[0107]

[0108] (4) The compound MMSE-3 or MMSE-3' obtained in the third step was dissolved in 250 mL of methanol, and potassium hydroxide solution (45 g of potassium hydroxide dissolved in 200 mL of water) was added, and the mixture was reacted at 65° C. for 5 hours under a nitrogen atmosphere. Half of the reaction solution was spun off and the pH was adjusted to 1 with 4 M hydrochloric acid. The mixture was filtered, washed with water, and dried in a vacuum oven to obtain MMSE-4.

[0109]

[0110] (5) Add 2.5 g MMSE-4 and 50 mL anhydrous tetrahydrofuran to a 100 ml eggplant-shaped bottle and stir for 5 min. Add 1.00 g sodium methoxide and stir for 15 minutes. Add bromomethyl methyl ether solution (1 ml bromomethyl methyl ether dissolved in 3 ml anhydrous tetrahydrofuran) dropwise and monitor by spot plate until the raw material spot disappears. Add 30 ml ethanol to quench the reaction. Spin dry, add 200 ml ether, wash with water, collect the ether extract, and dry over anhydrous sodium sulfate. Spin dry and set aside. Purify the sample by column purification and start elution with eluent (PE:EA, 10:0 to 3:1) to obtain the target compound MMSE-5.

[0111]

[0112] (6) Dissolve MMSE-5 in 60 ml of anhydrous tetrahydrofuran, add 1.47 g of sodium hydride, and stir for 10 minutes. Add N,N'-sulfuryl diimidazole solution (2.1 g dissolved in 20 mL of anhydrous tetrahydrofuran) dropwise, and continue to react for 2 hours. Add 50 ml of water to quench, extract with 200 ml of ethyl acetate twice, dry over anhydrous sodium sulfate, and spin dry. Purify the crude product by column purification to collect the target compound MMSE.

[0113]

[0114] (7) Ethanol recrystallization: add ethanol to the target compound MMSE after column purification, heat and stir until the MMSE sample is completely dissolved, place the dissolved sample in a refrigerator at 4-8°C for recrystallization, filter out excess liquid after crystals precipitate, wash with a small amount of ethanol and dry to obtain the purified [18F]fluoroestradiol precursor compound MMSE.

[0115] By mass spectrometry (LC-MS), hydrogen spectroscopy ( 1 H-NMR) and other methods were used to confirm the structure of the compound, which was determined to be MMSE, a precursor compound of [18F]estradiol compounds.

[0116] The mass spectrometry test result is [M+Na] + :417.13±0.5; hydrogen spectrum method ( 1H-NMR) identification results: δ0.89 (s, 3H); δ2.79-2.78 (m, 2H); δ3.35 (s, 3H); δ4..97 (m, 1H); δ5.12 (s, 2H); δ5.36 (m, 1H); δ6.72 (d, 1H); δ6.79 (dd, 1H); δ7.18 (d, 1H).

[0117] The purity of the compound was >99.5% as determined by liquid chromatography.

[0118] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. A method for preparing a [18F]fluoroestradiol precursor compound, characterized in that: The specific steps are as follows: S1, using estrone and isopropenyl acetate as raw materials to synthesize the product MMSE-1 with the structure shown in formula I; S2, using the product MMSE-1 of the structure shown in formula I obtained in step S1, lead tetraacetate and acetic acid as raw materials to synthesize the product MMSE-2 of the structure shown in formula II; S3, using the product MMSE-2 of the structure shown in formula II obtained in step S2 and lithium tri-tert-butoxyaluminum hydride as raw materials to synthesize the product MMSE-3 of the structure shown in formula III or the product MMSE-3' of the structure shown in formula IV; S4, using the product MMSE-3 of the structure represented by formula III or the product MMSE-3' of the structure represented by formula IV obtained in step S3 and potassium hydroxide as raw materials to synthesize the product MMSE-4 of the structure represented by formula V; S5, using the product MMSE-4 with the structure shown in formula V obtained in step S4, sodium methoxide and bromomethyl methyl ether as raw materials to synthesize the product MMSE-5 with the structure shown in formula VI; S6, using the product MMSE-5 of the structure represented by formula VI obtained in step S5 and N,N'-sulfonyldiimidazole as raw materials to synthesize the [18F]fluoroestradiol precursor compound MMSE of the structure represented by formula VII; Wherein, the general structural formulas I to IV are as follows:

2. The method for preparing a [18F]fluoroestradiol precursor compound according to claim 1, characterized in that: In step S1, estrone is added to isopropenyl acetate, and then a catalyst is added, and the mixture is heated for reaction. After the reaction is completed, the mixture is cooled, washed, extracted, and dried to obtain a product having a structure shown in formula I; Estrone: isopropenyl acetate: catalyst = 1g: 10-20ml: 0.5-1ml, The catalyst comprises isopropenyl acetate and concentrated sulfuric acid, wherein the volume ratio of isopropenyl acetate to concentrated sulfuric acid is 40:

1. The heating temperature is 105-115°C and the heating time is 2-4h. Ethyl acetate and 5% sodium bicarbonate ice water solution were added successively for washing. Extraction was carried out successively with acetic acid and ethyl acetate. Drying was performed over anhydrous sodium sulfate.

3. The method for preparing a [18F]fluoroestradiol precursor compound according to claim 1, characterized in that: In step S2, product MMSE-1: lead tetraacetate: acetic acid = 1 g: 1-3 g: 15-21 ml; The product MMSE-1 with the structure shown in formula I obtained in step S1, lead tetraacetate and acetic acid are mixed and stirred, diluted and washed after the reaction is completed, and dried to obtain a crude product of MMSE-2, and then methyl tert-butyl ether is added and ultrasonicated, and the product MMSE-2 with the structure shown in synthetic formula II is obtained after filtration.

4. The method for preparing a [18F]fluoroestradiol precursor compound according to claim 3, characterized in that: The stirring temperature is 30-50°C and the stirring time is 2-4 hours. Dilute with dichloromethane, 5% sodium thiosulfate and saturated sodium bicarbonate were added successively for washing. Drying was performed over anhydrous sodium sulfate.

5. The method for preparing a [18F]fluoroestradiol precursor compound according to claim 1, characterized in that: In step S3, the product MMSE-2 with the structure shown in formula II obtained in step S2, lithium tri-tert-butoxyaluminum hydride and anhydrous tetrahydrofuran are mixed and reacted. After the reaction is completed, a mixed solution of ice water and acetic acid is added, and the tetrahydrofuran is removed by rotary evaporation after standing, and extraction is performed. After washing and drying, the product MMSE-3 with the structure shown in synthetic formula III or the product MMSE-3' with the structure shown in formula IV is obtained.

6. The method for preparing a [18F]fluoroestradiol precursor compound according to claim 5, characterized in that: Product MMSE-2: lithium tri-tert-butoxyaluminum hydride: anhydrous tetrahydrofuran = 1g: 2-4g: 30-50ml, By volume ratio, ice water: acetic acid in the mixed solution = 1: 0.5~1, Extraction was performed with acetic acid and dichloromethane in sequence. Add saturated sodium bicarbonate to wash. Drying was performed over anhydrous sodium sulfate.

7. The method for preparing a [18F]fluoroestradiol precursor compound according to claim 1, characterized in that: In step S4, the product MMSE-3 of the structure represented by formula III or the product MMSE-3' of the structure represented by formula IV obtained in step S3 is dissolved in methanol, potassium hydroxide solution is added, and the reaction is carried out under a nitrogen atmosphere, and the pH is adjusted to 1 by hydrochloric acid, washed with water, and dried in an oven to obtain the product MMSE-4 of the structure represented by formula V; Product MMSE-2: methanol: potassium hydroxide solution = 1g: 15-25ml: 15-25ml, The concentration of the potassium hydroxide solution is 0.15-0.25 g / ml, The reaction temperature is 60-70° C. and the reaction time is 4-6 hours.

8. The method for preparing a [18F]fluoroestradiol precursor compound according to claim 1, characterized in that: In step S5, the product MMSE-4 with a structure represented by formula V obtained in step S4 is added to anhydrous tetrahydrofuran and stirred, and then sodium methoxide and bromomethyl methyl ether solution are added to react. After the reaction is completed, the product is spin-dried, ether is added, washed with water, dried, purified and eluted to obtain the product MMSE-5 with a structure represented by formula VI; Product MMSE-4: anhydrous tetrahydrofuran: sodium methoxide: bromomethyl methyl ether solution = 1g: 15-25ml: 0.3-0.5g: 1-2ml, The volume percentage of the bromomethyl methyl ether solution is 25% v / v, Drying was performed over anhydrous sodium sulfate.

9. The method for preparing a [18F]fluoroestradiol precursor compound according to claim 1, characterized in that: In step S6, the product MMSE-5 of the structure shown in formula VI obtained in step S5 is dissolved in anhydrous tetrahydrofuran, and sodium hydride and N,N'-sulfonyldiimidazole solution are added to react. After the reaction is completed, the product is extracted and dried, and purified to obtain the [18F]fluoroestradiol precursor compound MMSE of the structure shown in formula VII; Product MMSE-4: anhydrous tetrahydrofuran: sodium hydride: N,N'-sulfonyldiimidazole solution = 1g: 20-30ml: 0.4-0.7g: 7-10ml; The concentration of the N,N'-sulfuryldiimidazole solution is 0.05-0.10 g / ml. The reaction time is 1.5 to 2.5 hours. Extraction was performed twice with ethyl acetate. Drying was performed over anhydrous sodium sulfate.

10. The method for preparing a [18F]fluoroestradiol precursor compound according to claim 1, characterized in that: After step S6, step S7 is provided: ethanol recrystallization, adding ethanol to the [18F]fluoroestradiol precursor compound MMSE having a structure shown in formula VII obtained in step S6, heating to dissolve, and then placing in a low temperature environment for recrystallization, filtering after precipitating crystals, washing with ethanol and drying to obtain a purified [18F]fluoroestradiol precursor compound MMSE; The temperature of the low temperature environment is lower than 25°C.

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