Synthesis of Abediterol Precursors

Abstract

The present application provides a method for preparing a compound represented by formula (II), comprising the following steps: in an inert atmosphere, phenylboronic acid represented by formula (1) or its derivative, halogenated olefin represented by formula (2) and 2-(6-hydroxyhexyl)isoindoline-1,3-dione react under the action of a rhodium catalyst and a base to obtain a compound represented by formula (II). The present application uses phenylboronic acid represented by formula (1) or its derivative, halogenated olefin represented by formula (2) and 2-(6-hydroxyhexyl)isoindoline-1,3-dione as raw materials, reacts under the action of a rhodium catalyst and a base in an inert atmosphere, and can prepare the compound represented by formula (II) in one step, and has a high yield and high purity, which greatly shortens the synthesis steps and time.

Description

Technical Field

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

[0002] Abediterol, with the chemical name (R)-5-[2-[[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino]-1-hydroxyethyl]-8-hydroxy-2(1H)-quinolone and the structural formula shown in Formula I, is an inhaled long-acting β2-adrenoceptor (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. Its efficacy is 10 times that of salmeterol, equivalent to that of formoterol, and has a higher safety profile.

[0003] Formula I.

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

[0005]

[0006] Among them, important intermediates The chemical name is 6-(2,2-difluoro-2-phenylethoxy)hexane-1-ammonium salt. This intermediate requires five steps to obtain, and the steps are cumbersome. Summary of the invention

[0007] In view of this, the purpose of the present application is to provide a method for synthesizing an abediterol precursor. The abediterol precursor provided in the present application can be prepared in one step, and can be used to prepare abediterol, which can greatly shorten the synthesis steps and time, save costs, and improve production efficiency.

[0008] The present application provides a method for preparing a compound represented by formula (II), comprising the following steps:

[0009] In an inert atmosphere, phenylboronic acid or a derivative thereof represented by formula (1), a haloolefin represented by formula (2) and 2-(6-hydroxyhexyl)isoindoline-1,3-dione react in the presence of a rhodium catalyst and a base to obtain a compound represented by formula (II);

[0010] Formula (1);

[0011] Wherein, M is a boron-containing group, and the boron atom is connected to the phenyl group;

[0012] Formula (2);

[0013] Wherein, X is a halogen;

[0014] Formula (II).

[0015] The present application uses phenylboronic acid or its derivatives shown in formula (1), halogenated olefins shown in formula (2) and 2-(6-hydroxyhexyl)isoindoline-1,3-dione as raw materials, reacts in an inert atmosphere under the action of a rhodium catalyst and a base, and can prepare the compound shown in formula (II) in one step with a high yield and high purity, thereby greatly shortening the synthesis steps and time.

[0016] The present application uses phenylboronic acid or its derivatives represented by formula (1) as raw materials:

[0017] Formula (1);

[0018] Wherein, M is a boron-containing group, and the boron atom is connected to the phenyl group, for example, it can be a boronic 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 boric acid salt residue that has lost at least one hydroxyl group, and optionally, the boric acid ester or boric acid salt 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). Therefore, the present application has no special restrictions on the boron-containing group.

[0019] 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]diazaborolline, preferably phenylboric acid, (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene or potassium phenyltrifluoroborate.

[0020] This application uses the halogenated olefin represented by formula (2) as the raw material:

[0021] Formula (2);

[0022] Wherein, X is a halogen, preferably bromine. The present application has no special restrictions on the halogenated olefin represented by the formula (2), and it can be purchased on the market.

[0023] 2-(6-Hydroxyhexyl)isoindoline-1,3-dione has the structure of formula (3):

[0024] Formula (3);

[0025] The present application has no special restriction on the source of the 2-(6-hydroxyhexyl)isoindoline-1,3-dione, which can be purchased from the market.

[0026] 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(I) acetylacetonate, tris(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, tris(triphenylphosphine)rhodium bromide(I), (1,5-cyclooctadiene)2,4-pentanedione rhodium(I), bis[(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 tetrafluoroborate (I), bis (1,5-cyclooctadiene) rhodium (I) hexafluoride antimony salt, (R)-(-)-tert-butylmethyl (di-tert-butylphosphinomethyl) phosphino (1,5-cyclooctadiene) rhodium (I) tetrafluoroborate or more, preferably bis (1,5-cyclooctadiene) rhodium tetrafluoroborate, chlorobis (ethylene) rhodium (I) dimer, acetylacetonato bis (ethylene) rhodium (I) or tris (triphenylphosphine) rhodium bromide (I).

[0027] 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.

[0028] 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, 1,4-dioxane or one or more, preferably p-xylene, tetrahydrofuran, dioxane or dimethyl sulfoxide.

[0029] In the present application, the molar ratio of the phenylboronic acid or its derivative represented by formula (1), the halogenated olefin represented by formula (2), 2-(6-hydroxyhexyl)isoindoline-1,3-dione, the base and the rhodium catalyst is 0.2~1:0.4~4.0:0.4~4.0:1~3:0.01~1, preferably 0.3~0.8:0.5~3.5:0.5~3.5:1.5~2.5:0.1~0.8.

[0030] In the present application, phenylboronic acid or its derivatives represented by formula (1), halogenated olefin represented by formula (2), 2-(6-hydroxyhexyl)isoindoline-1,3-dione, rhodium catalyst and base are uniformly mixed in a reaction medium and reacted to obtain a compound represented by formula (II). The reaction route is as follows:

[0031]

[0032] 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. In some specific implementations, the reaction is preferably carried out under stirring.

[0033] 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 a compound having the structure of formula (II).

[0034] Abediterol can be prepared using the compound of formula (II) as a raw material. The present application has no particular limitation on the preparation process thereof, and the preparation can be prepared by referring to the methods disclosed in existing literature.

[0035] The present application uses phenylboronic acid or its derivatives shown in formula (1), halogenated olefins shown in formula (2) and 2-(6-hydroxyhexyl)isoindoline-1,3-dione as raw materials, reacts in an inert atmosphere under the action of a rhodium catalyst and a base, and can prepare the compound shown in formula (II) in one step with a high yield and high purity, thereby greatly shortening the synthesis steps and time. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 The hydrogen spectrum of the Abediterol precursor provided in Example 1 of the present application;

[0037] Figure 2 The fluorine spectrum of the Abediterol precursor provided in Example 1 of the present application;

[0038] Figure 3 This is the carbon spectrum of the Abediterol precursor provided in Example 1 of the present application. DETAILED DESCRIPTION

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] The present application provides a method for preparing a compound represented by formula (II), comprising the following steps:

[0045] In an inert atmosphere, phenylboronic acid or a derivative thereof represented by formula (1), a haloolefin represented by formula (2) and 2-(6-hydroxyhexyl)isoindoline-1,3-dione react in the presence of a rhodium catalyst and a base to obtain a compound represented by formula (II);

[0046] Formula (1);

[0047] Wherein, M is a boron-containing group, and the boron atom is connected to the phenyl group;

[0048] Formula (2);

[0049] Wherein, X is a halogen;

[0050] Formula (II).

[0051] The present application uses phenylboronic acid or its derivatives shown in formula (1), halogenated olefins shown in formula (2) and 2-(6-hydroxyhexyl)isoindoline-1,3-dione as raw materials, reacts in an inert atmosphere under the action of a rhodium catalyst and a base, and can prepare the compound shown in formula (II) in one step with a high yield and high purity, thereby greatly shortening the synthesis steps and time.

[0052] The synthesis method of the abediterol precursor provided in the present application is further described below in conjunction with the examples.

[0053] Example 1

[0054] Under the protection of an inert atmosphere, 0.3 mmol of phenylboronic acid, 1 mmol of geminal difluorobromoolefin, 1.1 mmol of 2-(6-hydroxyhexyl)isoindoline-1,3-dione, 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 h. After the reaction was completed, the solvent was removed, the residue was eluted by silica gel column chromatography, and the product was collected to obtain the compound represented by formula (II) with a purity of 95% and a yield of 56%.

[0055] The compound of formula (II) was subjected to NMR analysis, and the results are shown in Figure 1 , Figure 2 and Figure 3 , Figure 1 This is the hydrogen spectrum of the Abediterol precursor provided in Example 1 of the present application, Figure 2 The fluorine spectrum of the Abediterol precursor provided in Example 1 of the present application, Figure 3 This is the carbon spectrum of the Abediterol precursor provided in Example 1 of the present application. Its NMR data are as follows:

[0056] 2-(6-(2,2-difluoro-2-phenylethoxy)hexyl)isoindoline-1,3-dione: 1 H NMR(500 MHz, Chloroform-d) δ 7.83 (dd, J = 5.5, 3.0 Hz, 2H), 7.69 (dd, J = 5.5,3.0 Hz, 2H), 7.50 (dd, J = 7.2, 2.6 Hz, 2H), 7.45-7.40 (m, 3H), 3.82 (t, J =13.0 Hz, 2H), 3.64 (t, J = 7.3 Hz, 2H), 3.49 (t, J = 6.5 Hz, 2H), 1.63 (p, J= 7.2 Hz, 2H), 1.52 (p, J = 6.6 Hz, 2H), 1.36-1.28 (m, 4H). 19 F NMR (471 MHz, Chloroform-d) δ -103.69 (t, J = 13.0 Hz). 13C NMR (126 MHz, Chloroform-d) δ168.5, 135.1 (t, J = 25.33 Hz), 133.9, 132.2, 130.0 (d, J = 1.82 Hz), 128.3,125.5 (t, J = 6.21 Hz), 123.2, 120.4 (t, J = 244.32 Hz), 73.2 (t, J = 32.49Hz), 72.4, 37.9, 29.3, 28.5, 26.6, 25.5.

[0057] Example 2

[0058] Under the protection of an inert atmosphere, 0.3 mmol of (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene, 1 mmol of geminal difluorobromoolefin, 1.1 mmol of 2-(6-hydroxyhexyl)isoindoline-1,3-dione, 0.03 mmol of acetylacetonatobis(ethylene)rhodium(I) and 1.5 mmol of cesium carbonate were mixed, and 6 mL of tetrahydrofuran was added, and the mixture was stirred in an oil bath at 100 °C for 20 h. After the reaction was completed, the solvent was removed, the residue was eluted by silica gel column chromatography, and the product was collected to obtain a compound with a purity of 93% and a yield of 52%.

[0059] The compound was subjected to nuclear magnetic resonance analysis, and the results showed that it had the structure of formula (II).

[0060] Example 3

[0061] Under the protection of an inert atmosphere, 0.3 mmol of phenylboronic acid, 1 mmol of geminal difluorobromoolefin, 1.1 mmol of 2-(6-hydroxyhexyl)isoindoline-1,3-dione, 0.03 mmol of chlorobis(ethylene)rhodium(I) dimer and 1.5 mmol of lithium tert-butoxide were mixed, and 6 mL of dioxane was added, and the mixture was stirred in an oil bath at 100 °C for 20 h. After the reaction was completed, the solvent was removed, the residue was eluted by silica gel column chromatography, and the product was collected to obtain a compound with a purity of 91% and a yield of 50%.

[0062] The compound was subjected to nuclear magnetic resonance analysis, and the results showed that it had the structure of formula (II).

[0063] Example 4

[0064] Under the protection of an inert atmosphere, 0.3 mmol of potassium phenyl trifluoroborate, 1 mmol of geminal difluoro bromoolefin, 1.1 mmol of 2-(6-hydroxyhexyl)isoindoline-1,3-dione, 0.03 mmol of bis(1,5-cyclooctadiene) tetrafluoroborate rhodium and 1.5 mmol of sodium carbonate were mixed, and 6 mL of dimethyl sulfoxide was added, and the mixture was stirred in an oil bath at 100 °C for 20 h. After the reaction was completed, the solvent was removed, the residue was eluted by silica gel column chromatography, and the product was collected to obtain a compound with a purity of 94% and a yield of 48%.

[0065] The compound was subjected to nuclear magnetic resonance analysis, and the results showed that it had the structure of formula (II).

[0066] 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 preparing a compound represented by formula (II), comprising the following steps: In an inert atmosphere, phenylboronic acid or a derivative thereof represented by formula (1), a haloolefin represented by formula (2) and 2-(6-hydroxyhexyl)isoindoline-1,3-dione react in the presence of a rhodium catalyst and a base to obtain a compound represented by formula (II); Formula (1); Wherein, M is a boron-containing group, and the boron atom is connected to a phenyl group; the phenylboric acid or its derivative represented by the formula (1) is selected from one or more of phenylboric acid, potassium phenyltrifluoroborate, (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene, and phenylboronic acid neopentane glycol ester; Formula (2); Wherein, X is a halogen; Formula (II); The rhodium catalyst is selected from bis(ethylene)rhodium acetylacetonate (I), tris(triphenylphosphine)carbonyl rhodium hydride (I), dicarbonyl acetylacetonate rhodium (I), carbonyl bis(triphenylphosphine)rhodium chloride (I) , (1,5-cyclooctadiene) chlororhodium (I) dimer, bis (1,5-cyclooctadiene) rhodium tetrafluoroborate, bis (1,5-cyclooctadiene) - trifluoromethanesulfonate rhodium, tris (triphenylphosphine) rhodium bromide (I), (1,5-cyclooctadiene) 2,4-pentanedione rhodium (I), bis [(1,5-cyclooctadiene) (methoxy) rhodium], 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) hexafluoride antimony salt, (R) - (-) - tert-butyl methyl (di-tert-butylphosphinomethyl) phosphino (1,5-cyclooctadiene) rhodium (I) tetrafluoroborate one or more; The solvent used in the reaction is selected from one or more of 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, and deuterated chloroform.

2. The preparation method according to claim 1, characterized in that: The base 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, and magnesium hydroxide.

3. The preparation method according to claim 1, characterized in that: The molar ratio of the phenylboronic acid or its derivative represented by formula (1), the halogenated olefin represented by formula (2), 2-(6-hydroxyhexyl)isoindoline-1,3-dione, the base and the rhodium catalyst is 0.2-1:0.4-4.0:0.4-4.0:1-3:0.01-1.

4. The preparation method according to claim 3, characterized in that: The reaction temperature 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 the formula (2), X is bromine.

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