Synthesis method of oxy-18 substituted Abedimol precursor

Abstract

The invention provides an oxy-18 substituted Abedimol precursor and a synthesis method thereof, and the synthesis method comprises the following steps: in an inert atmosphere, phenylboronic acid or a derivative thereof shown in a formula (1), halogenated olefin shown in a formula (2) and oxy-18 water react under the action of a rhodium catalyst and alkali to obtain a compound shown in a formula (3); reacting the compound as shown in the formula (3) with 1, 6-dibromohexane under the action of alkali and tetra-tert-butyl ammonium salt to obtain a compound as shown in a formula (4); the compound shown in the formula (4) reacts with 1, 3-dioxoisoindoline-2-amide potassium salt under the action of hexadecyl tributyl phosphorus bromide, and the oxygen-18 substituted Abedimol precursor shown in the formula (5) is obtained. The oxy-18 substituted Abedimol precursor is obtained by adopting three-step reaction, the synthesis method has simple steps, the synthesis steps and time can be greatly shortened, the cost is saved, and the production efficiency is improved.

Description

Technical Field

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

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

[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 agonist (LABA) under development, 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 synthetic method of Abediterol, and the 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 tracking to understand the activity patterns and metabolic pathways of drugs in the body. This traceability study 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 drug efficacy and safety. Therefore, the synthesis of abediterol or its precursor containing oxygen-18 substitution is of great significance for the treatment of asthma.

[0007] However, Abediterol is an important intermediate The chemical name is 6-(2,2-difluoro-2-phenylethoxy)hexane-1-ammonium salt, and it takes five steps to obtain, which is cumbersome. When it is prepared as 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 in the present application has simple steps, which 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, phenylboronic acid or a derivative thereof represented by formula (1), a halogenated olefin represented by formula (2) and oxygen-18 water react in the presence 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) reacting the compound represented by formula (3) with 1,6-dibromohexane in the presence of a base and tetra-tert-butylammonium salt to obtain a compound represented by formula (4);

[0017]

[0018] c) reacting the compound represented by formula (4) with 1,3-dioxoisoindoline-2-amide potassium salt under the action of hexadecyltributylphosphonium bromide to obtain an oxygen-18 substituted abediterol precursor represented by formula (5);

[0019]

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

[0021]

[0022] The present application uses phenylboronic acid or its derivatives shown in formula (1), halogenated olefins shown in formula (2) and oxygen-18 water as raw materials, reacts under an inert atmosphere, under the action of a rhodium catalyst and a base to obtain 2,2-difluoro-1-phenylethanol shown in formula (3), and then reacts with 1,6-dibromohexane under the action of a base and tetra-tert-butylammonium salt to produce oxygen-18 substituted (2-((6-bromohexyl)oxy)-1,1-difluoroethyl)benzene shown in formula (4), and then reacts with 1,3-dioxoisoindoline-2-amide potassium salt under the action of hexadecyltributylphosphonium bromide to produce oxygen-18 substituted Abediterol precursor shown in formula (5). The synthesis method provided in the present application has simple steps, can greatly shorten the synthesis steps and time, save costs, and improve production efficiency. The prepared oxygen-18 substituted Abediterol precursor can be used to synthesize oxygen-18 substituted Abediterol and perform isotope tracking to understand the activity law and metabolic pathway of the drug in the body.

[0023] The present application uses phenylboronic acid or its derivatives shown in formula (1) as raw materials:

[0024]

[0025] Wherein, 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 boric acid ester residue that has lost at least one hydroxyl group, or a borate residue that has lost at least one hydroxyl group, and optionally, the boric acid ester or borate can be substituted by a halogen. In the present application, the M group is used as a leaving group, and 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, so that the phenyl group reacts with the double bond of the halogenated olefin shown in formula (2), and therefore, the present application has no particular restrictions on the boron-containing group.

[0026] In some specific implementations, the phenylboric acid or its derivatives represented by formula (1) include but are not limited to one or more of phenylboric acid, potassium phenyltrifluoroborate, (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene, phenylboronic acid neopentane glycol ester, 2-phenyl-1,3,2-diphenol borane, 5-(4-methoxyphenyl)-4,4-dimethyl-2-phenyl-1,3,2-dioxaborolan, 13,15-dioxa-14-borano[5.0.5.3]pentadecane, 14-phenyl, 2-phenyl-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborolin, preferably phenylboric acid, (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene or potassium phenyltrifluoroborate.

[0027] The present application uses the halogenated olefin represented by formula (2) as raw material:

[0028]

[0029] Wherein, X is a halogen, preferably bromine. The present application has no special restrictions on the halogenated olefin represented by formula (2), and it can be purchased on the market.

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

[0031] H 2 18 O

[0032] The present application has no special restrictions on the oxygen-18 water, which can be purchased on the market.

[0033] In the present application, phenylboronic acid or its derivatives represented by formula (1), halogenated olefin represented by formula (2), oxygen-18 water, rhodium catalyst and base are uniformly mixed in a reaction medium and reacted to obtain a compound represented by formula (3). The reaction route is as follows:

[0034]

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

[0036] The present application uses a rhodium-containing compound as a catalyst. In some specific implementations, the rhodium catalyst includes but is not limited to bis(ethylene)rhodium acetylacetonate (I), tri(triphenylphosphine)carbonyl rhodium hydride (I), dicarbonyl acetylacetonate rhodium (I), carbonyl bis(triphenylphosphine)rhodium chloride (I), (1,5-cyclooctadiene)rhodium chloride (I) dimer, bis(1,5-cyclooctadiene) rhodium tetrafluoroborate, bis(1,5-cyclooctadiene)-trifluoromethanesulfonate rhodium, tri(triphenylphosphine)rhodium bromide (I), (1,5-cyclooctadiene) 2,4-pentanedione rhodium (I), bis[(1,5-cyclooctadiene)(methoxy)rhodium], chlorobis(( One or more of bis(1,5-cyclooctadiene) rhodium (I) tetrafluoroborate, preferably bis(1,5-cyclooctadiene) rhodium tetrafluoroborate, chlorobis(ethylene) rhodium (I) dimer, dipolymerized hydroxy(1,5-cyclooctadiene) rhodium (I), 1,2-bis[(2S,5S)-2,5-diphenylphosphino]ethane(1,5-cyclooctadiene) rhodium tetrafluoroborate (I), bis(1,5-cyclooctadiene) rhodium (I) antimony hexafluoride salt, (R)-(-)-tert-butylmethyl(di-tert-butylphosphinomethyl)phosphino(1,5-cyclooctadiene) rhodium (I) tetrafluoroborate, preferably bis(1,5-cyclooctadiene) rhodium tetrafluoroborate, chlorobis(ethylene) rhodium (I) dimer, acetylacetonatobis(ethylene) rhodium (I) or tris(triphenylphosphine) rhodium bromide (I).

[0037] The preparation method provided in the present application also includes a base, and 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 trihydrogen phosphate, potassium tetrahydrogen phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium trihydrogen phosphate, calcium tetrahydrogen phosphate, sodium phosphate, sodium dihydrogen phosphate, sodium trihydrogen phosphate, sodium tetrahydrogen phosphate, magnesium phosphate, magnesium dihydrogen phosphate, magnesium trihydrogen phosphate, magnesium tetrahydrogen phosphate aluminum phosphate, aluminum dihydrogen phosphate, aluminum trihydrogen phosphate, aluminum tetrahydrogen phosphate, and copper phosphate, copper dihydrogen phosphate, copper trihydrogen phosphate and copper tetrahydrogen phosphate One or more, preferably sodium carbonate, lithium tert-butoxide or cesium carbonate.

[0038] In the preparation method provided by the present application, the solvent used in the reaction includes but is not limited to water / deuterated 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, ethyl ether, acetone, benzene / deuterated benzene, toluene / deuterated toluene, p-xylene, o-xylene, m-xylene, ethylbenzene, chlorobenzene, dichloromethane / deuterated dichloromethane, chloroform / deuterated chloroform, tetrahydrofuran, one or more of 1,4-dioxane, preferably p-xylene, tetrahydrofuran, dioxane or dimethyl sulfoxide.

[0039] In the present application, the molar ratio of the phenylboric acid or its derivative represented by formula (1), the halogenated olefin represented by formula (2), oxygen-18 water, base and 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 implementations, the reaction temperature 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 hours, more preferably 5 hours to 25 hours. In some specific implementations, the reaction is preferably carried out in an oil bath.

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

[0042] After obtaining the oxygen-18 substituted 2,2-difluoro-1-phenylethanol shown in formula (3), it is reacted with 1,6-dibromohexane in the presence of a base and tetra-tert-butylammonium salt to obtain the oxygen-18 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 implementations, 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 trihydrogen phosphate, potassium tetrahydrogen phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium trihydrogen phosphate, calcium tetrahydrogen phosphate, sodium phosphate, sodium dihydrogen phosphate, sodium trihydrogen phosphate, sodium tetrahydrogen phosphate, magnesium phosphate, magnesium dihydrogen phosphate, magnesium trihydrogen phosphate, magnesium tetrahydrogen phosphate, aluminum phosphate, aluminum dihydrogen phosphate, aluminum trihydrogen phosphate, aluminum tetrahydrogen phosphate, and one or more of copper phosphate, copper dihydrogen phosphate, copper trihydrogen phosphate and copper tetrahydrogen phosphate, preferably sodium carbonate, lithium tert-butoxide or cesium carbonate.

[0047] In some specific implementations, the solvent used in the reaction includes but is not limited to water / deuterated 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, ethyl ether, acetone, benzene / deuterated benzene, toluene / deuterated toluene, p-xylene, o-xylene, m-xylene, ethylbenzene, chlorobenzene, dichloromethane / deuterated dichloromethane, chloroform / deuterated chloroform, tetrahydrofuran, one or more of 1,4-dioxane, preferably p-xylene, tetrahydrofuran, dioxane or dimethyl sulfoxide.

[0048] In some specific implementations, the tetra-tert-butylammonium salt is selected from one or more of tetra-tert-butylammonium bromide, tetrabutylammonium chloride or tetrabutylammonium iodide, preferably tetra-tert-butylammonium bromide.

[0049] In the present application, the molar ratio of the compound represented by formula (3), 1,6-dibromohexane, base and tetra-tert-butylammonium 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 implementations, the reaction temperature 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 hours, more preferably 5 hours to 25 hours. In some specific implementations, the reaction is preferably carried out in an oil bath. In some specific implementations, the reaction is preferably carried out under stirring.

[0051] 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 oxygen-18 substituted (2-((6-bromohexyl)oxy)-1,1-difluoroethyl)benzene represented by formula (4).

[0052] After obtaining the compound represented by formula (4), reacting it with 1,3-dioxoisoindoline-2-amide potassium salt under the action of hexadecyltributylphosphonium bromide to obtain the oxygen-18 substituted abediterol precursor represented by formula (5);

[0053]

[0054] The reaction process is as follows:

[0055]

[0056] In some specific implementations, the solvent used in the reaction includes but is not limited to water, deuterated 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, ethyl 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 or one or more, preferably p-xylene, tetrahydrofuran, dioxane or dimethyl sulfoxide.

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

[0058] In some specific implementations, the reaction temperature 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 hours, more preferably 1 hour to 8 hours. In some specific implementations, the reaction is preferably carried out in an oil bath. In some specific implementations, the reaction is preferably carried out under stirring.

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

[0060] The oxygen-18 substituted abediterol precursor shown in formula (5) can be used as a raw material to prepare oxygen-18 substituted abediterol, which can be used for isotope tracking to understand the activity and metabolic pathway of drugs in the body. The present application has no special restrictions on its preparation process, and it can be prepared by referring to the methods disclosed in existing literature.

[0061] The invention adopts three-step reaction to obtain an oxygen-18 substituted abediterol precursor, and the synthesis method has simple steps, which can greatly shorten the synthesis steps and time, save costs, and improve production efficiency. The prepared oxygen-18 substituted abediterol precursor can be used to synthesize oxygen-18 substituted abediterol and perform isotope tracking to understand the activity law and metabolic pathway of the drug in the body. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] Figure 1 This is the hydrogen spectrum of the oxygen-18 substituted Abediterol precursor provided in Example 1 of the present application;

[0063] Figure 2 The fluorine spectrum of the oxygen-18 substituted Abediterol precursor provided in Example 1 of the present application;

[0064] Figure 3 This is the carbon spectrum of the oxygen-18 substituted Abediterol precursor provided in Example 1 of the present application.

[0065] Figure 4 This is the high-resolution mass spectrum of the oxygen-18 substituted Abediterol precursor provided in Example 1 of the present application. DETAILED DESCRIPTION

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

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

[0068] It should be understood that the order of steps or the order in which certain actions are performed is not important as long as the present invention remains operable. In addition, two or more steps or actions may be performed simultaneously.

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

[0070] In addition, the numerical ranges and parameters used to define the present invention are approximate values, and the relevant values ​​in the specific embodiments have been presented as accurately as possible. However, any numerical value inherently inevitably contains standard deviations due to individual test methods. Therefore, unless otherwise expressly stated, it should be understood that all ranges, quantities, values ​​and percentages used in this disclosure are modified by "about". Here, "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] The present application provides a method for synthesizing an oxygen-18 substituted abediterol precursor, comprising the following steps:

[0072] a) under an inert atmosphere, phenylboronic acid or a derivative thereof represented by formula (1), a halogenated olefin represented by formula (2) and oxygen-18 water react in the presence of a rhodium catalyst and a base to obtain a compound represented by 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) reacting the compound represented by formula (3) with 1,6-dibromohexane in the presence of a base and tetra-tert-butylammonium salt to obtain a compound represented by formula (4);

[0079]

[0080] c) reacting the compound represented by formula (4) with 1,3-dioxoisoindoline-2-amide potassium salt under the action of hexadecyltributylphosphonium bromide to obtain an oxygen-18 substituted abediterol precursor represented by formula (5);

[0081]

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

[0083]

[0084] The present application uses phenylboronic acid or its derivatives shown in formula (1), halogenated olefins shown in formula (2) and oxygen-18 water as raw materials, reacts under an inert atmosphere, under the action of a rhodium catalyst and a base to obtain 2,2-difluoro-1-phenylethanol shown in formula (3), and then reacts with 1,6-dibromohexane under the action of a base and tetra-tert-butylammonium salt to produce oxygen-18 substituted (2-((6-bromohexyl)oxy)-1,1-difluoroethyl)benzene shown in formula (4), and then reacts with 1,3-dioxoisoindoline-2-amide potassium salt under the action of hexadecyltributylphosphonium bromide to produce oxygen-18 substituted Abediterol precursor shown in formula (5). The synthesis method provided in the present application has simple steps, can greatly shorten the synthesis steps and time, save costs, and improve production efficiency. The prepared oxygen-18 substituted Abediterol precursor can be used to synthesize oxygen-18 substituted Abediterol and perform isotope tracking to understand the activity law and metabolic pathway of the drug in the body.

[0085] The synthesis method of the oxygen-18 substituted abediterol precursor provided in the present application is further described below in conjunction with the examples.

[0086] Example 1

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

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

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

[0090] The reaction process is as follows:

[0091]

[0092] The results of NMR analysis of the oxygen-18 substituted Abediterol precursor are shown in Figure 1 , Figure 2 and Figure 3 , Figure 1 This is the hydrogen spectrum of the oxygen-18 substituted Abediterol precursor provided in Example 1 of the present application, Figure 2 The fluorine spectrum of the oxygen-18 substituted Abediterol precursor provided in Example 1 of the present application, Figure 3 This is the carbon spectrum of the oxygen-18 substituted Abediterol precursor provided in Example 1 of the present application. Its NMR data are as follows:

[0093] 2-(6-(2,2-difluoro-2-phenylethoxy)hexyl)isoindoline-1,3-dione- 18 O: 1HNMR(500MHz,Chloroform-d)δ7.82(dd,J=5.4,3.0Hz,2H),7.69(dd,J=5.5,3.1Hz,2H),7.49(dd,J=7.2,2.6Hz,2H),7.44-–7.35(m,3H), 3.81(t,J=13.0Hz,2H),3.66-–3.61(m,2H),3.48(t,J=6.5Hz,2H),1.63(p,J=7.4Hz,2H),1.52(p,J=6.7Hz,2H),1.30(hept,J=2.7Hz,4H). 13 C NMR (126MHz, Chloroform-d) δ168.5,133.9,132.2,130.0,128.3,125.6,125.5,125.5,123.2,73.4,73.1,72.3,37.9,29.3,28.5,26.6,25.5. 19 F NMR (471MHz, Chloroform-d) δ-103.71 (t, J = 13.0Hz).

[0094] Mass spectrometry analysis of the oxygen-18 substituted Abediterol precursors is performed at Figure 4 , Figure 4 This is the high-resolution mass spectrum of the oxygen-18 substituted Abediterol precursor provided in Example 1 of the present application. The mass spectrum data are as follows:

[0095]

[0096] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection 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, phenylboronic acid or a derivative thereof represented by formula (1), a halogenated olefin represented by formula (2) and oxygen-18 water react in the presence of a rhodium catalyst and a base to obtain a compound represented by formula (3); Wherein, M is a boron-containing group, and the boron atom is connected to the phenyl group; Wherein, X is a halogen; b) reacting the compound represented by formula (3) with 1,6-dibromohexane in the presence of a base and tetra-tert-butylammonium salt to obtain a compound represented by formula (4); c) reacting the compound represented by formula (4) with 1,3-dioxoisoindoline-2-amide potassium salt under the action of hexadecyltributylphosphonium bromide to obtain an oxygen-18 substituted abediterol precursor represented by formula (5); 2. The preparation method according to claim 1, characterized in that: In the step a), the rhodium catalyst is selected from bis(ethylene) rhodium acetylacetonate (I), tri(triphenylphosphine) carbonyl rhodium hydride (I), dicarbonyl acetylacetonate rhodium (I), carbonyl bis(triphenylphosphine) rhodium chloride (I), (1,5-cyclooctadiene) rhodium chloride (I) dimer, bis(1,5-cyclooctadiene) rhodium tetrafluoroborate, bis(1,5-cyclooctadiene)-trifluoromethanesulfonate rhodium, tri(triphenylphosphine) rhodium bromide (I), (1,5-cyclooctadiene) 2,4-pentanedione rhodium (I), bis[( One or more of: 1,5-cyclooctadiene)(methoxy)rhodium], chlorobis(ethylene)rhodium(I) dimer, dimerized hydroxy(1,5-cyclooctadiene)rhodium(I), 1,2-bis[(2S,5S)-2,5-diphenylphosphino]ethane(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate, bis(1,5-cyclooctadiene)rhodium(I) antimony hexafluoride salt, (R)-(-)-tert-butylmethyl(di-tert-butylphosphinomethyl)phosphino(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate.

3. The preparation method according to claim 1, characterized in that: The base in step a) and step b) is independently selected from 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 trihydrogen phosphate, potassium tetrahydrogen phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium trihydrogen phosphate, calcium tetrahydrogen phosphate, sodium phosphate, sodium dihydrogen phosphate, sodium trihydrogen phosphate, sodium tetrahydrogen phosphate, magnesium phosphate, magnesium dihydrogen phosphate, magnesium trihydrogen phosphate, magnesium tetrahydrogen phosphate, aluminum phosphate, aluminum dihydrogen phosphate, aluminum trihydrogen phosphate, aluminum tetrahydrogen phosphate, and one or more of copper phosphate, copper dihydrogen phosphate, copper trihydrogen phosphate and copper tetrahydrogen phosphate.

4. The preparation method according to claim 1, characterized in that: The solvents used in each reaction of step a), step b) and step c) are independently selected from one or more of water, deuterated 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, ethyl ether, acetone, benzene, deuterated benzene, toluene, deuterated toluene, p-xylene, o-xylene, m-xylene, ethylbenzene, chlorobenzene, dichloromethane, deuterated dichloromethane, chloroform, deuterated chloroform, tetrahydrofuran, and 1,4-dioxane.

5. The preparation method according to claim 1, characterized in that: In the step a), the molar ratio of the phenylboric acid or its derivative represented by formula (1), the halogenated olefin 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 reaction temperature is 0°C to 200°C, and the reaction time is 20 minutes to 36 hours.

6. The preparation method according to claim 5, characterized in that: The phenylboric acid or its derivative represented by formula (1) is selected from one or more of phenylboric acid, potassium phenyltrifluoroborate, (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzene, phenylboronic acid neopentane glycol ester, 2-phenyl-1,3,2-diphenol borane, 5-(4-methoxyphenyl)-4,4-dimethyl-2-phenyl-1,3,2-dioxaborolane, 13,15-dioxa-14-borano[5.0.5.3]pentadecane, 14-phenyl, and 2-phenyl-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborolline.

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

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

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

10. The compound represented by formula (5):

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