Process for the synthesis of isomers of a key intermediate of pet precursors and uses thereof

Abstract

The application provides a synthesis method and use of isomers of a PET reagent precursor key intermediate, in particular, provides a compound of formula (I) and a synthesis method and use thereof. The application provides a brand-new synthesis method of isomers of a PET reagent precursor key intermediate, and has the advantages of simple operation, low toxicity and low danger of reagents used.

Description

[0001] This case is a divisional application of the application filed on September 6, 2022, entitled "Method for Synthesizing Isomers of PET Precursor Key Intermediates and Their Uses Thereof", application number 202211085636.1. Technical Field

[0002] This application belongs to the field of biomedicine, specifically relating to a method for synthesizing isomers of a key intermediate of a PET precursor and their uses. Background Technology

[0003] PET (Positron Emission Tomography) is a relatively advanced clinical imaging technique in the field of nuclear medicine. Its general method involves labeling a substance, typically essential for biological metabolism such as glucose, proteins, nucleic acids, and fatty acids, with a short-lived radioactive isotope (e.g., PET). 18 F, 11 (C, etc.) After being injected into the human body, the accumulation of the substance in human tissues is detected to reflect the state of life metabolic activities, thereby achieving the purpose of diagnosis.

[0004] In the basal aerobic metabolism of the myocardium, 70% of ATP is produced by the β-oxidation of fatty acids. Therefore, fatty acids or modified fatty acids are suitable reagents for cardiac positron emission tomography (PET). Because unmodified fatty acids are metabolized too quickly, they accumulate more radioactive atoms in the liver or lungs rather than in the sites required for diagnosis. Modified fatty acids have greater diagnostic value. [18F] CardioPET is an innovative PET reagent that is currently undergoing phase II clinical trials. Its characteristic is the introduction of a cyclopropane ring at the CH2CO2H group, which makes its absorption and accumulation behavior similar to that of fatty acids, but difficult to undergo β-oxidation. Therefore, it can remain in cardiomyocytes and thus can be used for PET imaging. 18 The decay of F produces positrons, which are used in PET-CT scans to create medically usable images for studying cardiac metabolism and diagnosing diseases, particularly coronary artery disease. Compound (I) can react with K produced by isotope irradiation. 18 After undergoing substitution and hydrolysis reactions, compound F is purified by semi-preparative chromatography to obtain compound (a) for diagnostic purposes (References: US7790142, US2004253177).

[0005]

[0006] Summary of the Invention

[0007] To address the aforementioned problems in the existing technology, this application provides a method for synthesizing a key intermediate isomer of a PET reagent precursor.

[0008] Specifically, this application relates to the following aspects:

[0009] 1. A method for preparing a compound of formula (I) using compound 4, wherein

[0010] The compound of formula (I) is shown below:

[0011]

[0012] Compound 4 is shown below:

[0013]

[0014] Wherein, X is a protecting group, preferably selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, tert-butyldimethylsilyl, triisopropylsilyl, and triethylsilyl; more preferably, X is benzyl.

[0015] Y is a protecting group. Preferably, Y is selected from tert-butyldimethylsilyl, benzyl, trimethylsilyl, p-methoxybenzyl, 2-tetrahydropyranyl, and more preferably 2-tetrahydropyranyl.

[0016] 2. The method according to item 1, which includes the step of reducing compound 4 to obtain compound 5:

[0017]

[0018] Preferably, the reduction reaction is carried out in a solvent in the presence of a catalyst.

[0019] The solvent is selected from n-hexane, tetrahydrofuran, 1,4-dioxane, and n-heptane, preferably n-hexane, and the catalyst is selected from Lindela catalyst, Pt, and copper-palladium, preferably Lindela catalyst.

[0020] 3. The method according to item 2, which includes the step of deprotecting compound 5 to obtain compound 6:

[0021]

[0022] Preferably, the deprotecting reaction is carried out using an aqueous reagent selected from the following: sulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, boron trifluoride ether, acetic acid, phosphoric acid, or formic acid, preferably p-toluenesulfonic acid.

[0023] 4. The method according to item 3, comprising the step of subjecting compound 6 to a cyclization reaction to obtain the compound of formula (I):

[0024]

[0025] Preferably, the cyclization reaction is carried out in a solvent in the presence of a cyclizing agent.

[0026] The cyclizing reagent is selected from diiodomethyl zinc, potassium (iodomethyl)trifluoroborate, chloroiodomethane, and diiodomethane, preferably diiodomethane.

[0027] The solvent is selected from n-hexane, tetrahydrofuran, toluene, diethyl ether, and 1,4-dioxane, preferably tetrahydrofuran.

[0028] 5. The method according to claim 1 further includes the step of converting compound 3 into compound 4 via a substitution reaction:

[0029]

[0030] Z is selected from bromine and iodine, preferably iodine.

[0031] Preferably, compound 3 is reacted with 2-propyn-1-ol protected by protecting group Y to obtain compound 4.

[0032] 6. The method according to claim 5 further includes the step of converting compound 2 into compound 3 by an Appel reaction:

[0033]

[0034] Preferably, a halogenated reagent is used for the Appel reaction.

[0035] The halogenated reagent is selected from carbon tetrabromide, bromine, and iodine, with iodine being preferred.

[0036] 7. The method according to claim 6 further includes the step of converting compound 1 into compound 2 by Brown's hydroboration-oxidation reaction:

[0037]

[0038] Preferably, the Brown hydroboration-oxidation reaction is carried out in a solvent in the presence of an oxidant.

[0039] The oxidant is selected from m-chloroperoxybenzoic acid, peracetic acid, hydrogen peroxide, pertrifluoroacetic acid, and peroxybenzoic acid, with hydrogen peroxide being preferred.

[0040] The solvent is selected from diethylene glycol dimethyl ether, tetrahydrofuran, diethyl ether, and 1,4-dioxane, preferably tetrahydrofuran.

[0041] 8. A compound of formula (I), wherein the compound of formula (I) is shown below:

[0042]

[0043] Wherein, X is a protecting group, preferably selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, tert-butyldimethylsilyl, triisopropylsilyl, and triethylsilyl; more preferably, X is benzyl.

[0044] 9. The compound according to item 8, which is prepared by any one of items 1-8.

[0045] 10. The use of compound (I) in the preparation of myocardial contrast agents,

[0046] The compound of formula (I) is shown below:

[0047]

[0048] Wherein, X is a protecting group, preferably selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, tert-butyldimethylsilyl, triisopropylsilyl, and triethylsilyl; more preferably, X is benzyl.

[0049] 11. The use according to item 10, characterized in that the myocardial contrast agent is a compound of formula (a).

[0050]

[0051] This application provides a novel method for synthesizing key intermediate isomers of PET precursors, characterized by its simplicity, low reagent toxicity, and low risk. Furthermore, this application discovers that compounds of formula (I) can also be used to prepare myocardial contrast agents, providing a pathway for their application. Attached Figure Description

[0052] Figure 1 This is a scintigraphy of the myocardium in a normal rat.

[0053] Figure 2 This is an imaging image of infarcted myocardium in a rat. Detailed Implementation

[0054] The present application is further illustrated below with reference to embodiments. It should be understood that the embodiments are only used to further illustrate and explain the present application and are not intended to limit the present application.

[0055] Unless otherwise defined, technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art. While similar or identical methods and materials may be applied in experimental or practical applications, materials and methods are described herein. In case of conflict, the definitions included herein shall prevail. Furthermore, materials, methods, and examples are for illustrative purposes only and are not intended to be limiting. The present application is further described below with reference to specific embodiments, but is not intended to limit the scope of the application.

[0056] As mentioned above, the content of impurities, i.e., the content of compound (1), needs to be strictly controlled during the preparation of PET reagent precursors. However, there is currently no relevant method to prepare compound (I).

[0057] The purpose of this application is to provide a method for preparing the compound of formula (I).

[0058]

[0059] The method of this application uses compound 4 as a starting material to prepare compound (I). Compound 4 is shown below:

[0060]

[0061] Wherein, X is a protecting group, preferably selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, tert-butyldimethylsilyl, triisopropylsilyl, and triethylsilyl; more preferably, X is benzyl.

[0062] Y is a protecting group. Preferably, Y is selected from tert-butyldimethylsilyl, benzyl, trimethylsilyl, p-methoxybenzyl, 2-tetrahydropyranyl, and more preferably 2-tetrahydropyranyl.

[0063] A "protecting group" is a group that can covalently bind to a functional group, protecting it from chemical reactions, and can be removed after the reaction to restore the functional group.

[0064] Furthermore, the method of this application also includes the step of reducing compound 4 to obtain compound 5, wherein compound 5 is a cis-alkene. The process of reducing compound 4 to obtain compound 5 is shown below:

[0065]

[0066] "Reduction reaction" refers to a reaction that introduces hydrogen or removes oxygen into the compounds of this application. Specifically, in this application, it refers to the reaction that introduces hydrogen into compound 4.

[0067] In this application, the reduction reaction is carried out in a solvent in the presence of a catalyst.

[0068] In one specific embodiment, the solvent is selected from n-hexane, tetrahydrofuran, 1,4-dioxane, and n-heptane, preferably n-hexane. The catalyst is selected from Lindela catalyst, Pt, and copper-palladium, preferably Lindela catalyst.

[0069] Furthermore, the method of this application also includes the step of deprotecting compound 5 to obtain compound 6. The process of deprotecting compound 5 to obtain compound 6 is shown below:

[0070]

[0071] "Deprotection reaction" refers to a reaction that removes protecting groups to restore hydroxyl functional groups. The reaction conditions for deprotection are well known to those skilled in the art.

[0072] In one specific embodiment, the deprotection reaction is carried out using an aqueous reagent selected from the following: sulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, boron trifluoride ether, acetic acid, phosphoric acid, or formic acid, preferably p-toluenesulfonic acid.

[0073] Furthermore, the method of this application also includes the step of cyclizing compound 6 to obtain compound (I), wherein compound (I) is compound (I). The process of cyclizing compound 6 to obtain compound (I) is as follows:

[0074]

[0075] "Cycloning reaction" refers to the reaction in which a new carbon ring or heterocycle is formed in an organic compound molecule; it is also called ring closure or cyclization condensation. When forming a carbon ring, the cyclization reaction is completed by forming carbon-carbon bonds. When forming a ring structure containing heteroatoms, the cyclization reaction can be completed by forming carbon-carbon bonds, carbon-heteroatom bonds (CN, CO, CS bonds, etc.), or sometimes by forming bonds between two heteroatoms (NN, NS bonds, etc.).

[0076] The cyclization reaction is carried out in a solvent in the presence of the cyclizing reagent.

[0077] In one specific embodiment, the cyclizing agent is selected from diiodomethylzinc, potassium (iodomethyl)trifluoroborate, chloroiodomethane, and diiodomethane, preferably diiodomethane. The solvent is selected from n-hexane, tetrahydrofuran, toluene, diethyl ether, and 1,4-dioxane, preferably tetrahydrofuran.

[0078] Furthermore, this application also includes a step of converting compound 3 into compound 4 via a substitution reaction. The process for converting compound 3 into compound 4 via a substitution reaction is shown below:

[0079]

[0080] Z is selected from bromine or iodine, with iodine being preferred.

[0081] A substitution reaction is a reaction in which any atom or group of atoms in a compound or organic molecule is replaced by another atom or group of atoms of the same type in a reagent. Substitution reactions can be achieved using a variety of reagents well known in the art.

[0082] Preferably, compound 3 reacts with 2-propyn-1-ol protected by protecting group Y to give compound 4.

[0083] As described above, Y is selected from tert-butyldimethylsilyl, benzyl, trimethylsilyl, p-methoxybenzyl, 2-tetrahydropyranyl, preferably 2-tetrahydropyranyl.

[0084] Furthermore, this application also includes a step of converting compound 2 to compound 3 via an Appel reaction. The process for converting compound 2 to compound 3 via an Appel reaction is shown below:

[0085]

[0086] The "Appel reaction" refers to the conversion of primary and secondary alcohols into alkyl chlorides using halogenating reagents. This reaction is a relatively mild method for introducing halogen atoms.

[0087] In one specific embodiment, the halogenated reagent is selected from carbon tetrabromide, bromine, iodomethane, and iodine, preferably iodine.

[0088] Furthermore, this application also includes a step of converting compound 1 into compound 2 by a Brown hydroboration-oxidation reaction. The flowchart for converting compound 1 into compound 2 by a Brown hydroboration-oxidation reaction is shown below:

[0089]

[0090] The Brown hydroboration-oxidation reaction refers to the concerted cis addition of borane to an alkene from a sterically less hindered carbon to yield an organoboron addition product, which is then oxidized under basic conditions to give an alcohol. The Brown hydroboration-oxidation reaction is carried out in a solvent in the presence of an oxidizing agent.

[0091] In one specific embodiment, the oxidant is selected from m-chloroperoxybenzoic acid, peracetic acid, hydrogen peroxide, peroxytrifluoroacetic acid, and peroxybenzoic acid, preferably hydrogen peroxide. The solvent is selected from diethylene glycol dimethyl ether, tetrahydrofuran, diethyl ether, and 1,4-dioxane, preferably tetrahydrofuran.

[0092] In one specific embodiment, this application provides a method for preparing a compound of formula (I), which includes the following steps:

[0093] Compound 1 was converted into compound 2 by Brown's hydroboration-oxidation reaction.

[0094] Compound 2 was converted into compound 3 by the Appel reaction.

[0095] Compound 3 was converted into compound 4 through a substitution reaction.

[0096] Compound 4 was reduced to give compound 5.

[0097] Compound 5 was deprotected to obtain compound 6.

[0098] Compound 6 was subjected to a cyclization reaction to obtain compound (I).

[0099] The reaction reagents and reaction conditions in each of the above steps are as described above.

[0100] In a preferred embodiment, this application provides a method for preparing a compound of formula (I), comprising the following steps:

[0101] Compound 1 was converted into compound 2 by Brown's hydroboration-oxidation reaction.

[0102] Compound 2 was converted into compound 3 by the Appel reaction.

[0103] Compound 3 was converted into compound 4 through a substitution reaction.

[0104] Compound 4 was reduced to give compound 5.

[0105] Compound 5 was deprotected to obtain compound 6.

[0106] Compound 6 was subjected to a cyclization reaction to obtain compound of formula (I).

[0107] Where X is benzyl, Y is 2-tetrahydropyranyl, and Z is iodine.

[0108] The flowchart of the above reaction steps is shown below:

[0109]

[0110] The proposed method for preparing compound (I) is a novel synthetic method, characterized by its simplicity, low toxicity of the reagents used, and low risk.

[0111] This application also provides a compound of formula (I), which is shown below:

[0112]

[0113] Wherein, X is a protecting group, preferably selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, tert-butyldimethylsilyl, triisopropylsilyl, and triethylsilyl; more preferably, X is benzyl.

[0114] As mentioned above, the compound of formula (I) is a key impurity in PET reagent precursors. The preparation, identification and limit control of this substance can provide a better basis for the preparation and detection of PET precursors.

[0115] Furthermore, the compound of formula (I) was prepared by the above-described preparation method.

[0116] This application also provides the use of the compound of formula (I) in the preparation of myocardial contrast agents.

[0117] The compound of formula (I) is shown below:

[0118]

[0119] Wherein, X is a protecting group, preferably selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, tert-butyldimethylsilyl, triisopropylsilyl, and triethylsilyl; more preferably, X is benzyl.

[0120] In one specific embodiment, the myocardial contrast agent is a compound of formula (a).

[0121]

[0122] Example

[0123] The reactions in the following embodiments are carried out according to the flowchart shown below:

[0124]

[0125] Example 1

[0126] 1. Synthesis of Compound 2

[0127] The process for preparing compound 2 from compound 1 is shown below:

[0128]

[0129] The specific steps are as follows:

[0130] Compound 1 (50.0 g, 0.1735 mol) was added to a 500 mL three-necked flask. Under a nitrogen atmosphere, 100 mL of anhydrous tetrahydrofuran was added. At 0-5 °C, 21.4 g (0.2776 mol) of 1N boron dimethyl sulfide solution was added dropwise. After the addition was complete, the reaction system was allowed to rise to room temperature and then heated under reflux for 4 hours. The reaction system was then cooled to 0 °C, and 20 mL of methanol, 30 mL of 4M NaOH solution, and 78 mL of 30% hydrogen peroxide solution were added sequentially. The mixture was stirred at room temperature for 2 hours to carry out the oxidation reaction. Add 200 mL of water and 200 mL of methyl tert-butyl ether to the system, extract, and separate the layers. Wash the organic phase with 100 mL of saturated ammonium chloride solution and separate the layers. Wash the organic phase with 100 mL of saturated sodium chloride solution and separate the layers. Dry the organic phase with anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure, and purify the crude product by silica gel chromatography (elution: cyclohexane / EtOAc 100 / 0 to 80 / 20) to give 38.5 g of product. Yield: 72.5%.

[0131] 1H-NMR (400MHz, CDCl3) δ: 0.86 (t, 3H), 1.24~1.58 (m, 20H), 2.98 (m, 2H), 3.38 (m, 1H), 4.62 (s, 2H), 4.76 (m, 1H), 7.25-7.36 (m, 5H).

[0132] 2. Synthesis of Compound 3

[0133] The process for preparing compound 3 from compound 2 is shown below:

[0134]

[0135] The specific steps are as follows:

[0136] Compound 2 (36.0 g, 0.1175 mol), imidazole (16.0 g, 0.2350 mol), triphenylphosphine (65.2 g, 0.2485 mol), and THF (200 mL) were added to a 1 L three-necked flask. Iodine (63.1 g, 0.2485 mol) was added under a nitrogen atmosphere at 0 °C. After the addition was complete, the mixture was brought to room temperature and stirred overnight. The reaction was quenched with saturated sodium sulfite solution, washed with a combination of ethyl acetate (2 × 200 mL) and water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a viscous oil. This oil was purified by silica gel column chromatography (elution: cyclohexane / EtOAc 100 / 10 to 80 / 20) to give 29.4 g of compound 3. Yield: 80.6%.

[0137] 1H-NMR (400MHz, CDCl3) δ: 0.88 (t, 3H), 1.24~1.85 (m, 18H), 2.92 (m, 2H) 3.40 (m, 1H), 3.64 (m, 2H), 4.52 (s, 2H), 7.24-7.35 (m, 5H).

[0138] 3. Synthesis of Compound 4

[0139] The process for preparing compound 4 from compound 3 is shown below:

[0140]

[0141] The specific steps are as follows:

[0142] 19.4 g (139.4 mmol) of tetrahydropyranyl-protected 2-propynyl-1-ol and 300 mL of tetrahydrofuran were added to a 1 L three-necked flask. Under a nitrogen atmosphere, at -30 °C, 87.1 mL (139.4 mmol) of n-butyllithium in 1.6 M hexane solution was added, followed by compound 3 (29.0 g (69.68 mmol)). After the addition was complete, the solution was brought to room temperature and reacted for 6 hours. At the end of the reaction, saturated NH₄Cl was added. The resulting mixture was extracted three times with hexane / EtOAc (1:1). The combined extracts were washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography (n-heptane:ethyl acetate = 100:1–50:1) to give 26.5 g of a colorless oily liquid. Yield: 88.8%.

[0143] 1H NMR (400MHz, CDCl3) δ0.86 (m, 3H), 1.12-1.79 (m, 26H), 2.41 (m, 2H), 3.34 (p ,1H),3.72(m,2H),4.08(m,2H),4.56(m,1H),4.60(m,2H),7.26-7.44(m,5H)

[0144] 4. Synthesis of Compound 5

[0145] The process for preparing compound 5 from compound 4 is shown below:

[0146]

[0147] The specific steps are as follows:

[0148] Compound 4 (24.0 g, 56.03 mmol) was added to a 500 mL Parr flask under a nitrogen atmosphere, followed by a Lindela catalyst (1.2 g, 0.5 wt.), then hexane (150 mL), ethanol (150 mL), and quinoline (18.1 g, 140.1 mmol). The mixture was then reduced with hydrogen. The reaction solution was filtered to remove the solid, and the concentrate was used to give 23.5 g of a yellow oily product. Yield: 97.5%.

[0149] 1H NMR (400MHz, CDCl3) δ0.88 (m, 3H), 1.14-1.76 (m, 26H)

[0150] ,2.14(m,2H),3.36(p,1H),3.70(m,2H),4.06(m,2H),4.58(m,2H),4.60(m,1H),5.60-5.64(m,2H),7.28-7.48(m,5H)

[0151] 5. Synthesis of Compound 6

[0152] The process for preparing compound 6 from compound 5 is shown below:

[0153]

[0154] The specific steps are as follows:

[0155] Under nitrogen protection, methanol (200 mL) was added to a 500 mL three-necked flask, along with p-toluenesulfonic acid (0.8 g, 4.0% wt.), 25 mL of water, and compound 5 (20.0 g, 46.47 mmol). The reaction mixture was heated to 60 °C and maintained for 2 hours. It was then cooled to room temperature, diluted with water, and adjusted to pH 7-8 with saturated sodium bicarbonate solution. Extraction was performed with ethyl acetate / n-hexane (1:1, 3 × 100 mL), the organic phase was dried, and the product was concentrated to give a yellow oily product. Purification was achieved by silica gel chromatography (n-heptane:ethyl acetate = 100:1–80:20), filtration at room temperature, and column chromatography to obtain 12.0 g of product. Yield: 74.6%.

[0156] 1H NMR(400MHz, CDCl3)δ0.86(m,3H),1.16-1.64(m,22H),3.39(p,1H),3.50-3.75(m,2H),4.52(d,2H),5.03(m,1H)5.60(m,2H)7.22-7.46(m,5H)

[0157] 6. Synthesis of compound (I)

[0158] The process for preparing compound (I) from compound 6 is shown below:

[0159]

[0160] The specific steps are as follows:

[0161] Using tetrahydrofuran (100 mL) as solvent, diethylzinc solution (17.8 g, 144.4 mmol) and DME (13.0 g, 144.4 mmol) were added sequentially at -30 °C under controlled temperature. Diiodomethane (38.7 g, 144.4 mmol) was then added dropwise to the solution, while maintaining the reaction temperature between -25 °C and -10 °C. Compound 6 (10.0 g, 28.88 mmol) was then added. The reaction was quenched with saturated ammonium chloride after completion. The product was extracted with ethyl acetate, separated, dried over dry organic phase, concentrated, and purified by silica gel chromatography (n-heptane:ethyl acetate = 100:1–80:20) to yield 9.0 g of product. Yield: 86.5%.

[0162] 1H NMR (400MHz, CDCl3) δ: -0.20(m,1H),,0.72(m,1H),0.77(m,1H),0.88(t,3H),1.06-1.42( m,19H),1.68(m,4H),3.42(m,2H),4.24(s,1H)4.62(s,2H),4.70(m,1H)7.20-7.45(m,5H)

[0163] 7. Preparation of Compound 7

[0164] The process for preparing compound 7 from compound (I) is shown below:

[0165]

[0166] The specific steps are as follows:

[0167] Compound (I) (8.0 g, 22.19 mmol), imidazole (3.03 g, 44.38 mmol), triphenylphosphine (12.3 g, 46.87 mmol), and THF (44 mL) were added to a 250 mL three-necked flask. Iodine (11.9 g, 46.87 mmol) was added under a nitrogen atmosphere at 0 °C. After the addition was complete, the mixture was brought to room temperature and stirred overnight. The reaction was quenched with saturated sodium sulfite solution, washed with a combination of ethyl acetate (2 × 50 mL) and water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a viscous oil. This oil was purified by silica gel column chromatography (elution: cyclohexane / EtOAc 100 / 10 to 80 / 20) to give 8.5 g of compound 7. Yield: 81.4%.

[0168] 1H NMR (400MHz, CDCl3) δ: -0.18(m,1H),,0.72(m,1H),0.75(m,1H),0.88(t,3H),1.06- 1.44(m,19H),1.66(m,4H),2.82(m,2H),4.62(s,2H),4.72(m,1H)7.20-7.45(m,5H)

[0169] 8. Preparation of Compound 8

[0170] The process for preparing compound 8 from compound 7 is shown below:

[0171]

[0172] The specific steps are as follows:

[0173] Compound (7) (8.0 g, 17.00 mmol) and THF (40 mL) were added to a 100 mL three-necked flask, followed by the addition of tetrabutylamine cyanide (5.5 g, 20.40 mmol). After the addition was complete, the temperature was raised to 60-70 °C and the mixture was stirred for 4 hours. The mixture was then cooled to room temperature, and 20 mL of 1 N sodium hydroxide aqueous solution was added to the reaction solution. The temperature was raised to 80 °C and the mixture was stirred for 4 hours. After cooling to room temperature, the pH of the system was adjusted to 5-6 with 0.1 N dilute hydrochloric acid. The mixture was washed with a combined organic solution of ethyl acetate (2 × 50 mL) with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a viscous oily substance, yielding 5.6 g of compound 8. Yield: 84.8%.

[0174] 1H NMR (400MHz, CDCl3) δ: -0.16(m,1H),,0.70(m,1H),0.75(m,1H),0.88(t,3H),1.06-1.44(m ,19H),1.66(m,4H),2.22(m,2H),4.64(s,2H),4.72(m,1H)7.20-7.45(m,5H),11.28(s,1H)

[0175] 9. Preparation of Compound 9

[0176] The process for preparing compound 9 from compound 8 is shown below:

[0177]

[0178] The specific synthetic steps were as follows: Compound 8 (5 g, 12.87 mmol) was added to a 250 mL three-necked flask, dichloromethane (25 mL) was added to the reaction flask, 4-dimethylaminopyridine (DMAP) (3.1 g) and tert-butanol (tBuOH) (4.8 g, 64.35 mmol) were added, and the reaction system was cooled to about 10 °C. Dicyclohexylcarbodiimide (DCC) (3.2 g dissolved in 30 mL of dichloromethane) was added dropwise. After the addition was complete, the mixture was brought to room temperature and stirred at room temperature for 4 h. 35 mL of dichloromethane and 2 mL of water were added to the system, and the mixture was stirred for 3 h. The mixture was filtered, and the filtrate was concentrated at 30-40 °C. 4.8 g of compound 9 was purified by silica gel chromatography (n-heptane:ethyl acetate = 100:1 to 40:1) by column chromatography, yield: 83.9%.

[0179] H-NMR (400MHz, CDCl3) δ: -0.18 (m, 2H), 0.45 (m, 1H), 0.64 (m, 1H), 0.88 (t, 3H) , 1.19-1.44(m, 31H), 2.03(m, 2H), 3.28(m, 1H), 4.62(s, 2H), 7.28-7.32(m, 5H)

[0180] 10. Preparation of Compound 10

[0181] The process for preparing compound 10 from compound 9 is shown below:

[0182]

[0183] The specific synthesis steps are as follows: Compound 9 (4.0 g, 9.0 mmol) was added to a 200 mL high-pressure reactor, along with methanol (80 mL) and 0.8 g of 10% palladium on carbon (Pd / C) catalyst. The system was replaced with hydrogen three times, and the reaction was carried out at 40-50 °C with hydrogen for 4 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure at 30-40 °C to obtain 3.0 g of compound 10, with a yield of 94.1%.

[0184] 1H-NMR (400MHz, CDCl3) δ: -0.18 (m, 2H), 0.47 (m, 1H), 0.68 (m, 1H), 0.88 (t, 3H), 1.21-1.49 (m, 31H), 1.90-2.12 (m, 2H), 3.44 (m, 1H), 4.84 (m, H).

[0185] 10. Synthesis of Compound 11

[0186] The process for preparing compound 11 from compound 10 is shown below:

[0187]

[0188] The specific synthetic steps were as follows: Compound 10 (2.5 g, 7.1 mmol) was added to a 100 mL three-necked flask, followed by dichloromethane (30 mL), pyridine (5.6 g), and methanesulfonyl chloride (MsCl) (1.1 g, 9.23 mmol). The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel chromatography (n-heptane:ethyl acetate = 100:1–20:1) to obtain 2.5 g of the product, with a yield of 82.0%.

[0189] 1H-NMR (400MHz, CDCl3) δ: -0.16 (m, 1H), 0.72 (m, 1H), 0.76 (m, 1H), 0.89 (t, 3H), 1.06 (m, 1H), 1.17 (m, 1H), 1.28 (m, 11), 1.42 (m, 6H) 1.46 (s, 9H), 1.68 (m, 4H), 2.18 (m, 2H), 3.00 (s, 3H) 4.70 (m, 1H).

[0190] 13 C-NMR (400MHZ, CDCl3) δ: 10.70, 11.57, 14.09, 15.21, 22.64, 24.88, 24.97, 28.13, 28.64 ,29.20,29.39,29.40,29.64,31.82,34.46,34.48,35.12,38.68,80.09,84.30,173.10.

[0191] MS: [M+H]+=433.62, [M+Na]+=455.5

[0192] Compound 11 was reacted to obtain the developer compound (a), i.e., compound (a).

[0193]

[0194] The specific reaction route is as follows:

[0195]

[0196] Example

[0197] Fluorine-containing 18 F] ions oxygen[ 18 O] water, passing it through an ion exchange column activated with K2CO3, removes fluoride [ 18 F] ions are enriched into the column.

[0198] K₂₂ and K₂CO₃ were mixed to prepare an acetonitrile / water solution, which was then used to elute the above column. 18The F / K222 complex was eluted into a reaction flask, and the solvent was dried under a nitrogen stream to obtain the activated product. 18 F ions.

[0199] An acetonitrile solution of compound 11 was added to the reaction flask, and the reaction was heated for 50 min. Compound 11 reacts with K... 18 F / K222 undergoes a nucleophilic substitution reaction to generate compound 12.

[0200] TFA / ACN solution was added to the reaction flask, and the reaction was heated for 20 min to remove the tert-butyl ester protecting group. After the reaction was completed, the TFA / ACN was removed by heating under a nitrogen stream. The sample was then purified by ethanol and water onto a chromatographic column to obtain compound (a).

[0201] Test case

[0202] 1. Imaging study of normal rat myocardium: SD rats were anesthetized with isoflurane and fixed in a prone position on a small animal PET bed. Compound (a) (0.15–0.25 mCi / rat) was injected via the tail vein. Following administration, dynamic continuous PET images were acquired from the myocardium for 0–60 minutes in a single bed, obtaining (a) images showing the dynamic changes in radioactivity concentration in the myocardium of SD rats over time. Results showed that significant and uniform uptake occurred in the myocardium 5 minutes after administration, resulting in clear myocardial imaging. The complete morphology of the left ventricle was clearly visible in coronal, axial, and sagittal views. While the radioactivity concentration in the myocardium decreased over time, relatively clear myocardial imaging was still obtained at 60 minutes.

[0203] 2. Imaging study of myocardial infarction in rats: Rats with myocardial infarction were anesthetized with isoflurane and fixed in a small animal PET bed. Compound (a) (0.15–0.25 mCi / rat) was injected via the tail vein. Immediately after administration, single-bed PET dynamic continuous imaging was performed from 0 to 60 minutes, using the myocardium as the target organ, to obtain images showing the dynamic changes in the radioactive concentration of compound (a) in the myocardium of SD rats over time. The results, as shown in the figure below, showed that 5 minutes after administration, normal myocardial tissue in the rat myocardial infarction model showed significant and uniform uptake, resulting in clear myocardial imaging. In the infarcted myocardium (the extensive apical region innervated by the left anterior descending coronary artery), compound (a) was not uptaken, and obvious radioactive defects were visible in the imaging. Furthermore, the extent of radioactive defects in the infarcted area remained relatively consistent from 5 to 60 minutes after injection. The morphology of the left ventricle and the defect area were clearly visible in coronal, transverse, and sagittal views.

[0204] Early myocardial imaging can be achieved after injection of compound (a), with clear images obtained within 5 minutes of administration. Compound (a) exhibits radioactive defects at the infarcted myocardium, indicating that it is not taken up by the infarcted myocardium. This property of compound (a) can be used to assess cardiomyocyte viability; therefore, compound (a) can be used as a reagent for myocardial imaging. That is, the compound of formula (I) of this application can be used to prepare a myocardial imaging agent.

[0205] Although the embodiments of this application have been described above in conjunction with the specific embodiments described, this application is not limited to the specific embodiments and application fields described above. The specific embodiments described above are merely illustrative and instructive, and not restrictive. Those skilled in the art can make many other forms based on the teachings of this specification and without departing from the scope of protection of the claims of this application, and these are all within the scope of protection of this application.

Claims

1. The use of compound 4 in the preparation of compound 7, wherein The compound of formula (I) is shown below: （I） Compound 4 is shown below: in, X is a protecting group, selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, tert-butyldimethylsilyl, triisopropylsilyl, and triethylsilyl. Y is a protecting group, selected from tert-butyldimethylsilyl, benzyl, trimethylsilyl, p-methoxybenzyl, and 2-tetrahydropyranyl; The uses include: Compound 4 was reduced to give compound 5. Compound 5 was deprotected to obtain compound 6. Compound 6 was subjected to a cyclization reaction to obtain compound of formula (I). The reduction reaction takes place in a solvent in the presence of a catalyst. The solvent is selected from n-hexane, tetrahydrofuran, 1,4-dioxane, and n-heptane. The catalysts were selected from Lindela catalysts, Pt, and copper-palladium catalysts; The deprotection reaction is carried out using an aqueous reagent selected from the following: sulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, boron trifluoride ether, acetic acid, phosphoric acid, or formic acid; The cyclization reaction is carried out in a solvent in the presence of a cyclizing agent. The cyclizing reagent is selected from diiodomethyl zinc, potassium (iodomethyl)trifluoroborate, chloroiodomethane, and diiodomethane. The solvent is selected from n-hexane, tetrahydrofuran, toluene, diethyl ether, and 1,4-dioxane; The use also includes the preparation of compound 7 from the compound of formula (I): The preparation of compound 7 from compound (I) includes the following steps: 22.19 mmol of compound (I), 44.38 mmol of imidazole, 46.87 mmol of triphenylphosphine and 44 mL of THF are added to a 250 mL three-necked flask, and 46.87 mmol of iodine is added under a nitrogen atmosphere at 0 °C. After the addition is complete, the mixture is brought to room temperature and stirred overnight.

2. The use according to claim 1, further comprising the step of converting compound 3 into compound 4 via a substitution reaction: in, Z is selected from bromine and iodine. Compound 3 reacts with 2-propyn-1-ol protected by protecting group Y to give compound 4.

3. The use according to claim 2, further comprising the step of converting compound 2 into compound 3 by an Appel reaction: Appel reaction was performed using halogenated reagents. The halogenated reagents are selected from carbon tetrabromide, bromine, and iodine.

4. The use according to claim 3, further comprising the step of converting compound 1 into compound 2 by Brown's hydroboration-oxidation reaction: Brown's hydroboration-oxidation reaction is carried out in a solvent in the presence of an oxidant. The oxidizing agent is selected from m-chloroperoxybenzoic acid, peracetic acid, hydrogen peroxide, peroxytrifluoroacetic acid, and peroxybenzoic acid. The solvent is selected from diethylene glycol dimethyl ether, tetrahydrofuran, diethyl ether, and 1,4-dioxane.

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