Synthesis method of an oxygen-18 substituted Abediterol precursor

Abstract

The present application provides an oxygen-18 substituted Abediterol precursor and its synthesis method. The synthesis method includes the following steps: Under an inert atmosphere, a benzeneboronic acid or its derivative represented by formula (1), a haloalkene represented by formula (2), and oxygen-18 water react under the action of a rhodium catalyst and a base to obtain a compound represented by formula (3); The compound represented by formula (3) reacts with 1,6-dibromohexane under the action of a base and a tetrabutylammonium salt to obtain a compound represented by formula (4); The compound represented by formula (4) reacts with potassium 1,3-dioxoisoindoline-2-carboxamide under the action of hexadecyltributylphosphonium bromide to obtain an oxygen-18 substituted Abediterol precursor represented by formula (5). The present invention uses three-step reactions to obtain an oxygen-18 substituted Abediterol precursor. The synthesis method has simple steps, can greatly shorten the synthesis steps and time, save costs, and improve production efficiency.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and particularly relates to a method for synthesizing an oxygen-18 substituted Abediterol precursor. Background Art

[0002] Bronchial asthma, abbreviated as asthma, is a common chronic inflammatory airway disease, mainly characterized by recurrent symptoms such as wheezing, shortness of breath, chest tightness or coughing in the airway, often occurring or worsening at night and in the early morning. The symptoms of asthma are mainly wheezing, shortness of breath, chest tightness or coughing, and in severe cases, dyspnea and hypoxemia may occur. Asthma cannot be completely cured at present, but the condition can be controlled by drugs.

[0003] Abediterol, whose chemical name is (R)-5-[2-[[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino]-1-hydroxyethyl]-8-hydroxy-2(1H)-quinolone, is an inhaled long-acting β2-adrenoceptor (LABA) agonist under research, mainly used for asthma and chronic obstructive pulmonary disease (COPD). As a long-acting agonist, Abediterol can dilate airway smooth muscle by activating β2-adrenoceptors, thereby improving respiratory symptoms.

[0004] The prior art discloses a synthesis method of Abediterol, and its route is as follows:

[0005]

[0006] The application of oxygen-18 in drug research is mainly reflected in the use of oxygen-18 for isotope tracing to understand the activity rules and metabolic pathways of drugs in the body. This traceability research is crucial for the development of new drugs because it can help scientists better understand the metabolic process of drugs, thereby optimizing drug design and improving the efficacy and safety of drugs. Therefore, synthesizing oxygen-18 substituted Abediterol or its precursor is of great significance for the treatment of asthma.

[0007] However, an important intermediate of Abediterol with the chemical name of 6-(2,2-difluoro-2-phenylethoxy)hexane-1-ammonium salt requires five steps to obtain, and the steps are cumbersome. When preparing it into an oxygen-18 substituted intermediate, more steps are required. Summary of the Invention

[0008] In view of this, the purpose of the present application is to provide a method for synthesizing an oxygen-18 substituted Abediterol precursor. The synthesis method provided by the present application has simple steps, can greatly shorten the synthesis steps and time, save costs, and improve production efficiency.

[0009] The present application provides a method for synthesizing an oxygen-18 substituted Abediterol precursor, comprising the following steps:

[0010] a) Under an inert atmosphere, a benzeneboronic acid or its derivative represented by formula (1), a haloalkene represented by formula (2), and oxygen-18 water react under the action of a rhodium catalyst and a base to obtain a compound represented by formula (3);

[0011]

[0012] Wherein, M is a boron-containing group, and the boron atom is connected to the phenyl group;

[0013]

[0014] Wherein, X is a halogen;

[0015]

[0016] b) The compound represented by formula (3) reacts with 1,6-dibromohexane under the action of a base and a tetra-tert-butylammonium salt to obtain a compound represented by formula (4);

[0017]

[0018] c) The compound represented by formula (4) reacts with potassium 1,3-dioxoisoindoline-2-carboxamide under the action of hexadecyltributylphosphonium bromide to obtain the oxygen-18 substituted Abediterol precursor represented by formula (5);

[0019]

[0020] The reaction process of the present application is as follows:

[0021]

[0022] This application uses benzeneboronic acid or its derivatives represented by formula (1), haloolefins represented by formula (2), and oxygen-18 water as raw materials. Under an inert atmosphere, the reaction is carried out under the action of a rhodium catalyst and a base to obtain 2,2-difluoro-1-phenylethanol represented by formula (3). Then, it reacts with 1,6-dibromohexane under the action of a base and a tetra-tert-butylammonium salt to form oxygen-18-substituted (2-((6-bromohexyl)oxy)-1,1-difluoroethyl)benzene represented by formula (4). Subsequently, it reacts with potassium 1,3-dioxoisoindoline-2-carboxylate under the action of hexadecyltributylphosphonium bromide to form an oxygen-18-substituted Abediterol precursor represented by formula (5). The synthesis method provided by this application has simple steps, can greatly shorten the synthesis steps and time, save costs, improve production efficiency, and the prepared oxygen-18-substituted Abediterol precursor can be used to synthesize oxygen-18-substituted Abediterol for isotope tracing to understand the activity rules and metabolic pathways of drugs in the body.

[0023] This application uses benzeneboronic acid or its derivatives represented by formula (1) as raw materials:

[0024]

[0025] Among them, M is a boron-containing group, and the boron atom is connected to the phenyl group. For example, it can be a boric acid residue that has lost at least one hydroxyl group, a borate ester residue that has lost at least one hydroxyl group, or a borate residue that has lost at least one hydroxyl group. Optionally, the borate ester or borate can be substituted by a halogen. In this application, the M group serves as a leaving group. As long as the B atom is connected to the phenyl group, it can be removed under the action of a catalyst and a base, enabling the phenyl group to react with the double bond of the haloolefin represented by formula (2). Therefore, this application has no special restrictions on the boron-containing group.

[0026] In some specific implementation manners, the benzeneboronic acid or its derivatives represented by formula (1) include but are not limited to benzeneboronic acid, potassium phenyltrifluoroborate, (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene, neopentyl glycol benzeneboronate, 2-phenyl-1,3,2-benzenediol borane, 5-(4-methoxyphenyl)-4,4-dimethyl-2-phenyl-1,3,2-dioxaborane, 13,15-dioxa-14-boratricyclo[5.0.5.3]pentadecane, 14-phenyl, 2-phenyl-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinine, or one or more of them. Preferably, it is benzeneboronic acid, (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene, or potassium phenyltrifluoroborate.

[0027] This application uses haloolefins represented by formula (2) as raw materials:

[0028]

[0029] Among them, X is a halogen, preferably bromine. There are no special restrictions on the haloolefin represented by the formula (2) in this application, and it can be purchased on the market.

[0030] This application uses oxygen-18 water as a raw material, and its structural formula is as follows:

[0031] H2 18 O

[0032] There are no special restrictions on the oxygen-18 water in this application, and it can be purchased on the market.

[0033] This application mixes the phenylboronic acid or its derivative represented by the formula (1), the haloolefin represented by the formula (2), oxygen-18 water, a rhodium catalyst, and a base evenly in a reaction medium and then conducts a reaction to obtain the compound represented by the formula (3), and its reaction route is as follows:

[0034]

[0035] The compound represented by the formula (3) is oxygen-18 substituted 2,2-difluoro-1-phenylethanol.

[0036] This application uses a rhodium-containing compound as a catalyst. In some specific implementation manners, the rhodium catalyst includes but is not limited to bis(ethylene)rhodium(I) acetylacetonate, tricarbonylhydridorhodium(I) tris(triphenylphosphine), rhodium(I) acetylacetonate dicarbonyl, carbonylbis(triphenylphosphine)rhodium(I) chloride, (1,5-cyclooctadiene)rhodium(I) chloride dimer, bis(1,5-cyclooctadiene)rhodium tetrafluoroborate, bis(1,5-cyclooctadiene)-rhodium trifluoromethanesulfonate, rhodium(I) bromide tris(triphenylphosphine), (1,5-cyclooctadiene)rhodium(I) 2,4-pentanedionate, bis[(1,5-cyclooctadiene)(methoxy)rhodium], dichlorobis(ethylene)rhodium(I) dimer, dihydroxy(1,5-cyclooctadiene)rhodium(I) dimer, 1,2-bis[(2S,5S)-2,5-diphenylphosphino]ethane(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate, bis(1,5-cyclooctadiene)rhodium(I) hexafluoroantimonate, (R)-(-)-tert-butylmethyl(di-tert-butylphosphinomethyl)phosphino(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate, and one or more of them, preferably bis(1,5-cyclooctadiene)rhodium tetrafluoroborate, dichlorobis(ethylene)rhodium(I) dimer, bis(ethylene)rhodium(I) acetylacetonate, or rhodium(I) bromide tris(triphenylphosphine).

[0037] The preparation method provided by the present application further includes an alkali, and the alkali includes but is not limited to lithium trimethylsilanolate, potassium trimethylsilanolate, sodium trimethylsilanolate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium methoxide, sodium methoxide, potassium methoxide, lithium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, sodium thiosulfate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, sodium sulfate, potassium sulfate, potassium dihydrogen phosphate, potassium hydrogen phosphate, potassium tetrahydrogen phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium hydrogen phosphate, calcium tetrahydrogen phosphate, sodium phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium tetrahydrogen phosphate, magnesium phosphate, magnesium dihydrogen phosphate, magnesium hydrogen phosphate, magnesium tetrahydrogen phosphate, aluminum phosphate, aluminum dihydrogen phosphate, aluminum hydrogen phosphate, aluminum tetrahydrogen phosphate, and one or more of copper phosphate, copper dihydrogen phosphate, copper hydrogen phosphate and copper tetrahydrogen phosphate, preferably sodium carbonate, lithium tert-butoxide or cesium carbonate.

[0038] In the preparation method provided by the present application, the solvents used in the reaction include but are not limited to water / deuterium water, ethanol, methanol, isopropanol, n-hexane, n-pentane, cyclopentane, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, methyl tert-butyl ether, diethyl ether, acetone, benzene / deuterated benzene, toluene / deuterated toluene, p-xylene, o-xylene, m-xylene, ethylbenzene, chlorobenzene, dichloromethane / deuterated dichloromethane, chloroform / deuterated chloroform, tetrahydrofuran, 1,4-dioxane, and one or more of them, preferably p-xylene, tetrahydrofuran, dioxane or dimethyl sulfoxide.

[0039] In the present application, the molar ratio of the benzeneboronic acid or its derivative shown in formula (1), the haloalkene shown in formula (2), oxygen-18 water, the alkali and the rhodium catalyst is 0.2-1:0.4-4.0:0.2-100:1-3:0.01-1, preferably 0.3-0.8:0.5-3.5:0.5-80:1.5-2.5:0.1-0.8.

[0040] In some specific implementation manners, the temperature of the reaction is 0°C to 200°C, preferably 50°C to 150°C, more preferably 80°C to 120°C; the reaction time is 20 minutes to 36 hours, preferably 40 minutes to 30 h, more preferably 5 h to 25 h. In some specific implementation manners, the reaction is preferably carried out in an oil bath.

[0041] After the reaction is completed, the reaction medium, that is, the solvent, is removed, and the obtained residue is eluted by silica gel column chromatography, and the oxygen-18 substituted 2,2-difluoro-1-phenylethanol shown in formula (3) can be obtained.

[0042] After obtaining the 18O-substituted 2,2-difluoro-1-phenylethanol shown in formula (3), it reacts with 1,6-dibromohexane under the action of a base and a tetrabutylammonium salt to obtain the 18O-substituted (2-((6-bromohexyl)oxy)-1,1-difluoroethyl)benzene shown in formula (4);

[0043]

[0044] The reaction process is as follows:

[0045]

[0046] In some specific implementation manners, the base includes but is not limited to lithium trimethylsilanolate, potassium trimethylsilanolate, sodium trimethylsilanolate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium methoxide, sodium methoxide, potassium methoxide, lithium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, sodium thiosulfate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, sodium sulfate, potassium sulfate, potassium dihydrogen phosphate, potassium hydrogen phosphate, potassium tetrahydrogen phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium hydrogen phosphate, calcium tetrahydrogen phosphate, sodium phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium tetrahydrogen phosphate, magnesium phosphate, magnesium dihydrogen phosphate, magnesium hydrogen phosphate, magnesium tetrahydrogen phosphate, aluminum phosphate, aluminum dihydrogen phosphate, aluminum hydrogen phosphate, aluminum tetrahydrogen phosphate, and one or more of copper phosphate, copper dihydrogen phosphate, copper hydrogen phosphate, and copper tetrahydrogen phosphate, preferably sodium carbonate, lithium tert-butoxide or cesium carbonate.

[0047] In some specific implementation manners, the solvent used in the reaction includes but is not limited to water / deuterium water, ethanol, methanol, isopropanol, n-hexane, n-pentane, cyclopentane, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, methyl tert-butyl ether, diethyl ether, acetone, benzene / deuterated benzene, toluene / deuterated toluene, p-xylene, o-xylene, m-xylene, ethylbenzene, chlorobenzene, dichloromethane / deuterated dichloromethane, chloroform / deuterated chloroform, tetrahydrofuran, 1,4-dioxane, and one or more of them, preferably p-xylene, tetrahydrofuran, dioxane or dimethyl sulfoxide.

[0048] In some specific implementation manners, the tetrabutylammonium salt is selected from one or more of tetrabutylammonium bromide, tetrabutylammonium chloride or tetrabutylammonium iodide, preferably tetrabutylammonium bromide.

[0049] In the present application, the molar ratio of the compound shown in formula (3), 1,6-dibromohexane, the base and the tetrabutylammonium salt is 1-2.5:0.4-4.0:1.0-20.0:0.003-1, preferably 1.5-2:0.5-3.5:2.0-15.0:0.01-0.08.

[0050] In some specific implementation manners, the temperature of the reaction is 0°C to 100°C, preferably 20°C to 80°C, more preferably 40°C to 60°C; the reaction time is 20 minutes to 36 hours, preferably 40 minutes to 30 h, more preferably 5 h to 25 h. In some specific implementation manners, the reaction is preferably carried out in an oil bath. In some specific implementation manners, the reaction is preferably carried out under stirring conditions.

[0051] After the reaction is completed, the reaction medium, that is, the solvent, is removed, and the obtained residue is eluted by silica gel column chromatography to obtain the oxygen-18 substituted (2-((6-bromohexyl)oxy)-1,1-difluoroethyl)benzene shown in formula (4).

[0052] After obtaining the compound shown in formula (4), it is reacted with potassium 1,3-dioxoisoindoline-2-carboxylate in the presence of hexadecyltributylphosphonium bromide to obtain the oxygen-18 substituted Abediterol precursor shown in formula (5);

[0053]

[0054] The reaction process is as follows:

[0055]

[0056] In some specific implementation manners, the solvents used in the reaction include but are not limited to one or more of water, deuterium oxide, ethanol, methanol, isopropanol, n-hexane, n-pentane, cyclopentane, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, methyl tert-butyl ether, diethyl ether, acetone, benzene, deuterated benzene, toluene, deuterated toluene, p-xylene, o-xylene, m-xylene, ethylbenzene, chlorobenzene, dichloromethane, deuterated dichloromethane, chloroform, deuterated chloroform, tetrahydrofuran, 1,4-dioxane, and are preferably p-xylene, tetrahydrofuran, dioxane or dimethyl sulfoxide.

[0057] In the present application, the molar ratio of the compound shown in formula (4), potassium 1,3-dioxoisoindoline-2-carboxylate and hexadecyltributylphosphonium bromide is 1 to 2.5:0.4 to 4.0:0.01 to 0.3, preferably 1.2 to 2.3:0.5 to 3.5:0.05 to 0.25.

[0058] In some specific embodiments, the temperature of the reaction is 0°C to 120°C, preferably 20°C to 100°C, more preferably 40°C to 80°C; the reaction time is 20 minutes to 12 hours, preferably 40 minutes to 10 h, more preferably 1 h to 8 h. In some specific embodiments, the reaction is preferably carried out in an oil bath. In some specific embodiments, the reaction is preferably carried out under stirring conditions.

[0059] After the reaction is completed, the reaction medium, i.e., the solvent, is removed, and the obtained residue is eluted by silica gel column chromatography to obtain the oxygen-18 substituted Abediterol precursor shown in formula (5).

[0060] Using the oxygen-18 substituted Abediterol precursor shown in formula (5) as a raw material, oxygen-18 substituted Abediterol can be prepared, which can be used for isotope tracing to understand the activity rules and metabolic pathways of drugs in the body. There are no special restrictions on its preparation process in this application, and it can be prepared by referring to the methods disclosed in the existing literature.

[0061] The present invention obtains the oxygen-18 substituted Abediterol precursor through a three-step reaction. The synthesis method has simple steps, can greatly shorten the synthesis steps and time, save costs, improve production efficiency, and the prepared oxygen-18 substituted Abediterol precursor can be used to synthesize oxygen-18 substituted Abediterol for isotope tracing to understand the activity rules and metabolic pathways of drugs in the body. Description of the Drawings

[0062] Figure 1 1H NMR spectrum of the oxygen-18 substituted Abediterol precursor provided in Example 1 of this application;

[0063] Figure 2 19F NMR spectrum of the oxygen-18 substituted Abediterol precursor provided in Example 1 of this application;

[0064] Figure 3 13C NMR spectrum of the oxygen-18 substituted Abediterol precursor provided in Example 1 of this application.

[0065] Figure 4 High-resolution mass spectrum of the oxygen-18 substituted Abediterol precursor provided in Example 1 of this application. Detailed Description of the Invention

[0066] It should be understood that the expression "one or more of..." individually includes each of the recited objects following the expression and various different combinations of two or more of the recited objects, unless otherwise understood from the context and usage. The expression "and / or" in combination with three or more recited objects should be understood to have the same meaning, unless otherwise understood from the context.

[0067] The terms "comprising", "having" or "including", including the use of their grammatical synonyms, should generally be understood as open-ended and non-limiting, for example, not excluding other unrecited elements or steps, unless specifically stated otherwise or understood from the context.

[0068] It should be understood that as long as the present invention remains operable, the order of steps or the order of performing certain actions is not important. In addition, two or more steps or actions can be carried out simultaneously.

[0069] The use of any and all examples or exemplary language herein, such as "for example" or "including", is merely intended to better illustrate the present invention and does not limit the scope of the present invention unless a claim is made. No language in this specification should be construed as indicating that any unclaimed element is essential for the practice of the present invention.

[0070] In addition, the numerical ranges and parameters used to define the present invention are approximate values. The relevant values in the specific embodiments have been presented as precisely as possible herein. However, any numerical value inherently and inevitably contains standard deviations due to individual testing methods. Therefore, unless otherwise clearly stated, it should be understood that all ranges, quantities, numerical values and percentages used in this disclosure are modified by "about". Herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1% or 0.5% of a specific value or range.

[0071] This application provides a method for synthesizing an oxygen-18 substituted Abediterol precursor, comprising the following steps:

[0072] a) Under an inert atmosphere, the phenylboronic acid or its derivative shown in formula (1), the haloolefin shown in formula (2) and oxygen-18 water react under the action of a rhodium catalyst and a base to obtain a compound shown in formula (3);

[0073]

[0074] wherein, M is a boron-containing group, and the boron atom is connected to the phenyl group;

[0075]

[0076] wherein, X is a halogen;

[0077]

[0078] b) The compound shown in formula (3) reacts with 1,6-dibromohexane under the action of a base and a tetrabutylammonium salt to obtain the compound shown in formula (4);

[0079]

[0080] c) The compound shown in formula (4) reacts with potassium 1,3-dioxoisoindoline-2-carboxamide under the action of hexadecyltributylphosphonium bromide to obtain the oxygen-18 substituted Abediterol precursor shown in formula (5);

[0081]

[0082] The reaction process of this application is as follows:

[0083]

[0084] This application uses phenylboronic acid or its derivative shown in formula (1), haloolefin shown in formula (2), and oxygen-18 water as raw materials. Under an inert atmosphere, it reacts under the action of a rhodium catalyst and a base to obtain 2,2-difluoro-1-phenylethanol shown in formula (3). Then, it reacts with 1,6-dibromohexane under the action of a base and a tetrabutylammonium salt to generate oxygen-18 substituted (2-((6-bromohexyl)oxy)-1,1-difluoroethyl)benzene shown in formula (4). Then, it reacts with potassium 1,3-dioxoisoindoline-2-carboxamide under the action of hexadecyltributylphosphonium bromide to generate the oxygen-18 substituted Abediterol precursor shown in formula (5). The synthesis method provided by this application has simple steps, can greatly shorten the synthesis steps and time, save costs, improve production efficiency. The prepared oxygen-18 substituted Abediterol precursor can be used to synthesize oxygen-18 substituted Abediterol for isotope tracing to understand the activity rules and metabolic pathways of drugs in the body.

[0085] The following further illustrates the synthesis method of the oxygen-18 substituted Abediterol precursor provided by this application in conjunction with examples.

[0086] Example 1

[0087] Under the protection of an inert atmosphere, 0.3 mmol of phenylboronic acid, 1 mmol of gem-difluorobromoolefin, 1.1 mmol of oxygen-18 water, 0.03 mmol of rhodium(I) tris(triphenylphosphine) bromide, and 1.5 mmol of sodium carbonate were mixed, and 6 mL of p-xylene was added. The mixture was stirred and reacted in an oil bath at 100 °C for 20 h. After the reaction was completed, the solvent was removed to obtain the crude reaction solution of oxygen-18 substituted 2,2-difluoro-1-phenylethanol.

[0088] The crude reaction solution of oxygen-18 substituted 2,2-difluoro-1-phenylethanol, 0.1 mol of 1,6-dibromohexane, 0.1 mmol of sodium carbonate, 0.1 mmol of tetrabutylammonium bromide were mixed and 6 mL of p-xylene was added for reaction. After the reaction was completed, the solvent was removed to obtain the crude reaction solution of oxygen-18 substituted (2-((6-bromohexyl)oxy)-1,1-difluoroethyl)benzene.

[0089] The crude reaction solution of oxygen-18 substituted (2-((6-bromohexyl)oxy)-1,1-difluoroethyl)benzene, 0.1 mmol of potassium 1,3-dioxoisoindoline-2-carboxylate and 0.1 mmol of hexadecyltributylammonium bromide were mixed and 6 mL of p-xylene was added for reaction. After the reaction was completed, the solvent was removed, and the residue was eluted by silica gel column chromatography. The product was collected to prepare the oxygen-18 substituted Abediterol precursor, a colorless oily liquid, 46.7 mg, and the total separation yield was 40%( 18 O:93).

[0090] The reaction process is as follows:

[0091]

[0092] Nuclear magnetic resonance analysis was performed on the oxygen-18 substituted Abediterol precursor. The results are shown in Figure 1 , Figure 2 and Figure 3 , Figure 1 is the hydrogen spectrum of the oxygen-18 substituted Abediterol precursor provided in Example 1 of this application, Figure 2 is the fluorine spectrum of the oxygen-18 substituted Abediterol precursor provided in Example 1 of this application, Figure 3 is the carbon spectrum of the oxygen-18 substituted Abediterol precursor provided in Example 1 of this application. The nuclear magnetic data are as follows:

[0093] 2-(6-(2,2-difluoro-2-phenylethoxy)hexyl)isoindoline-1,3-dione- 18 O: 1HNMR(500MHz, Chloroform-d) δ 7.82 (dd, J=5.4, 3.0 Hz, 2H), 7.69 (dd, J=5.5, 3.1 Hz, 2H), 7.49 (dd, J=7.2, 2.6 Hz, 2H), 7.44 - 7.35 (m, 3H), 3.81 (t, J=13.0 Hz, 2H), 3.66 - 3.61 (m, 2H), 3.48 (t, J=6.5 Hz, 2H), 1.63 (p, J=7.4 Hz, 2H), 1.52 (p, J=6.7 Hz, 2H), 1.30 (hept, J=2.7 Hz, 4H). 13 C NMR(126MHz, Chloroform-d) δ 168.5, 133.9, 132.2, 130.0, 128.3, 125.6, 125.5, 125.5, 123.2, 73.4, 73.1, 72.3, 37.9, 29.3, 28.5, 26.6, 25.5. 19 F NMR(471MHz, Chloroform-d) δ -103.71 (t, J=13.0 Hz).

[0094] Mass spectrometry analysis was performed on the oxygen-18 substituted Abediterol precursor, see Figure 4 , Figure 4 which is the high-resolution mass spectrum of the oxygen-18 substituted Abediterol precursor provided in Example 1 of this application. The mass spectrometry data is as follows:

[0095]

[0096] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A method for synthesizing an oxygen-18 substituted Abediterol precursor, comprising the following steps: a) Under an inert atmosphere, a benzeneboronic acid or its derivative represented by formula (1), a haloalkene represented by formula (2), and oxygen-18 water react under the action of a rhodium catalyst and a base to obtain a compound represented by formula (3); Formula (1); Wherein, M is a boron-containing group, and the boron atom is connected to the phenyl group; Formula (2); Wherein, X is a halogen; Formula (3); The rhodium catalyst is selected from one or more of bis(ethylene)rhodium(I) acetylacetonate, tris(triphenylphosphine)rhodium(I) carbonyl hydride, rhodium(I) dicarbonyl acetylacetonate, carbonylbis(triphenylphosphine)rhodium(I) chloride, (1,5-cyclooctadiene)rhodium(I) chloride dimer, bis(1,5-cyclooctadiene)rhodium tetrafluoroborate, bis(1,5-cyclooctadiene)-rhodium trifluoromethanesulfonate, tris(triphenylphosphine)rhodium(I) bromide, (1,5-cyclooctadiene)rhodium(I) 2,4-pentanedionate, bis[(1,5-cyclooctadiene)(methoxy)rhodium], dichloro(bis(ethylene)rhodium(I)) dimer, dihydroxy(1,5-cyclooctadiene)rhodium(I) dimer, 1,2-bis[(2S,5S)-2,5-diphenylphosphino]ethane(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate, bis(1,5-cyclooctadiene)rhodium(I) hexafluoroantimonate, (R)-(-)-tert-butylmethyl(di-tert-butylphosphinomethyl)phosphino(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate; The base in step a) is selected from one or more of lithium trimethylsilanolate, potassium trimethylsilanolate, sodium trimethylsilanolate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium methoxide, sodium methoxide, potassium methoxide, lithium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide; The benzeneboronic acid or its derivative represented by formula (1) is selected from one or more of benzeneboronic acid, potassium phenyltrifluoroborate, (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene, neopentyl glycol benzeneboronate, 2-phenyl-1,3,2-benzenediolborane, 5-(4-methoxyphenyl)4,4-dimethyl-2-phenyl-1,3,2-dioxaborane; b) The compound represented by formula (3) reacts with 1,6-dibromohexane under the action of a base and a tetra-tert-butylammonium salt to obtain a compound represented by formula (4); Formula (4); c) The compound represented by formula (4) reacts with potassium 1,3-dioxoisoindoline-2-carboxamide under the action of hexadecyltributylphosphonium bromide to obtain the oxygen-18 substituted Abediterol precursor represented by formula (5); Formula (5).

2. The preparation method according to claim 1, wherein The base in step b) is selected from one or more of lithium trimethylsilanolate, potassium trimethylsilanolate, sodium trimethylsilanolate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium methoxide, sodium methoxide, potassium methoxide, lithium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide.

3. The preparation method according to claim 1, characterized in that, The solvents used in each of the reactions of step a), step b) and step c) are independently selected from one or more of water, ethanol, methanol, isopropanol, n-hexane, n-pentane, cyclopentane, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, methyl tert-butyl ether, diethyl ether, acetone, benzene, toluene, p-xylene, o-xylene, m-xylene, ethylbenzene, chlorobenzene, dichloromethane, chloroform.

4. The preparation method according to claim 1, characterized in that, In step a), the molar ratio of the benzeneboronic acid or its derivative represented by formula (1), the haloalkene represented by formula (2), oxygen-18 water, the base and the rhodium catalyst is 0.2~1:0.4~4.0:0.2~100:1~3:0.01~1; The temperature of the reaction is 0 °C to 200 °C, and the reaction time is 20 minutes to 36 hours.

5. The preparation method according to claim 1, characterized in that, In step b), the tetrabutylammonium salt is selected from one or more of tetrabutylammonium bromide, tetrabutylammonium chloride or tetrabutylammonium iodide.

6. The preparation method according to claim 1, wherein In step b), the molar ratio of the compound represented by formula (3), 1,6-dibromohexane, the base and the tetrabutylammonium salt is 1~2.5:0.4~4.0:1.0~20.0:0.003~1; The temperature of the reaction is 0 °C to 100 °C, and the reaction time is 20 minutes to 36 hours.

7. The preparation method according to claim 1, characterized in that, In step c), the molar ratio of the compound represented by formula (4), potassium 1,3-dioxoisoindoline-2-carboxylate and hexadecyltributylphosphonium bromide is 1~2.5:0.4~4.0:0.01~0.3; The temperature of the reaction is 0 °C to 120 °C, and the reaction time is 20 minutes to 12 hours.

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