A method for synthesizing vilanterol and its salt

Abstract

The invention discloses a preparation method of vilanterol and a salt thereof. The method uses 1,6-hexanediol instead of 1,6-dibromohexane, avoids high energy consumption and high pollution caused by high-temperature reduced-pressure distillation, and reduces brominated impurities; adds a salt refining step to improve product purity; the product vilanterol salt has better powder properties, such as more uniform particle size distribution, is not easy to agglomerate, and can meet the needs of different preparations.

Description

Technical Field

[0001] The invention relates to the pharmaceutical field, and in particular to a method for synthesizing vilanterol and a salt thereof. Background Art

[0002] β2-adrenergic receptor agonists are the most widely used drugs for the treatment of asthma and chronic obstructive pulmonary disease in clinical practice. Vilanterol trifenatate is a new ultra-long-acting β2-adrenergic receptor agonist developed by GlaxoSmithKline PLC, which has bronchodilator effect. The chemical name of Vilanterol trifenatate is 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]-ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol trifenatate, and its structural formula is as follows:

[0003]

[0004] The most commonly used route for synthesizing vilanterol triphenylacetate is as follows: (1) reacting the raw material SM1' (2-(bromomethyl)-1,3-dichlorobenzene) with ethylene glycol and distilling to obtain the intermediate 1' (IM1', 2-(2,6-dichlorobenzyloxy)ethanol); (2) reacting the intermediate 1' (IM1') with the raw material SM2' (1,6-dibromohexane) to obtain the intermediate 2' (IM2', 2-((2-((6-bromohexyl) (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one) to generate intermediate 3'(IM3', (5R)-3-{6-[2-(2 ,6-dichlorobenzyloxy)ethoxy]-hexyl}5-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-oxazolidin-2-one); (4) intermediate 3'(IM3') is directly subjected to alkaline ring opening without purification to obtain intermediate 4'(IM4', ((R)-2-((6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl)amino)-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-oxazolidin-2-one); (5) acidic hydrolysis of intermediate 4 (IM4') to obtain intermediate 5' (IM5', 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]-ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol); (6) salting intermediate 5' (IM5') with triphenylacetic acid to generate vilanterol triphenylacetate. The synthetic route is as follows:

[0005]

[0006] Vilanterol Triphenylacetate

[0007] This synthetic route has the following disadvantages: the 1,6-dibromohexane in intermediate 2' (IM2') has a high boiling point and needs to be removed by high vacuum distillation, which consumes a lot of energy and has a long production cycle; the brominated impurities in intermediate 2 (IM2') are potential genotoxic impurities and their content is relatively high; the one-pot method is used for feeding, and the intermediates are all oily substances, which lacks quality control and cannot meet the declaration requirements.

[0008] In view of this, the present invention is proposed. Summary of the invention

[0009] The inventors unexpectedly discovered that in the preparation process of vilanterol salt, using 1,6-hexanediol instead of 1,6-dibromohexane can avoid the high energy consumption and high pollution caused by high-temperature and reduced-pressure distillation, and at the same time avoid the introduction of genotoxic impurities; and, after the intermediate 4 involved undergoes a salt refining step, the one-pot process and increased impurity research can be avoided, and the product quality can be controlled.

[0010] Therefore, in a first aspect, the present invention provides a method for synthesizing vilanterol, the method comprising the steps of:

[0011] 1) Make the raw material 2-(2,6-dichlorobenzyloxy)ethanol

[0012]

[0013] Reaction with 1,6-hexanediol to form intermediate 1, namely 2-[2-(6-hydroxy-hexyloxy)-ethoxymethyl]-1,3-dichlorobenzene:

[0014]

[0015] 2) reacting the intermediate 1 with sulfonyl chloride in the presence of a suitable acid-binding agent to generate a sulfonate of the intermediate 1 as the intermediate 2;

[0016] 3) In the presence of a suitable phase transfer catalyst and a base, the intermediate 2 is reacted with the raw material (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one.

[0017]

[0018] The reaction was carried out at 40°C-80°C to generate intermediate 3, namely (5R)-3-{6-[2-(2,6-dichlorobenzyloxy)-ethoxy]-hexyl}5-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-oxazolidin-2-one:

[0019]

[0020] 4) reacting intermediate 3 with a base at reflux temperature to generate intermediate 4, i.e., (R)-2-((6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl)amino)-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol:

[0021]

[0022] 5) In the presence of a suitable acid, the intermediate 4 is subjected to a hydrolysis reaction to generate vilanterol, i.e., 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]-ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol:

[0023]

[0024] In a second aspect, the present invention provides a method for synthesizing a vilanterol salt, the method comprising the steps of:

[0025] 1) Make the raw material 2-(2,6-dichlorobenzyloxy)ethanol

[0026]

[0027] Reaction with 1,6-hexanediol to form intermediate 1, namely 2-[2-(6-hydroxy-hexyloxy)-ethoxymethyl]-1,3-dichlorobenzene:

[0028]

[0029] 2) reacting the intermediate 1 with sulfonyl chloride in the presence of a suitable acid-binding agent to generate a sulfonate of the intermediate 1 as the intermediate 2;

[0030] 3) In the presence of a suitable phase transfer catalyst and a base, the intermediate 2 is reacted with the raw material (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one.

[0031]

[0032] The reaction was carried out at 40°C-80°C to generate intermediate 3, namely (5R)-3-{6-[2-(2,6-dichlorobenzyloxy)-ethoxy]-hexyl}5-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-oxazolidin-2-one:

[0033]

[0034] 4) reacting intermediate 3 with a base at reflux temperature to generate intermediate 4, i.e.

[0035] (R)-2-((6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl)amino)-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol:

[0036]

[0037] 5) In the presence of a suitable acid, the intermediate 4 is hydrolyzed to produce vilanterol, i.e., 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]-ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol:

[0038]

[0039] 6) reacting vilanterol with an acid at reflux temperature to form a vilanterol salt.

[0040] In a third aspect, the present invention provides a method for synthesizing vilanterol triphenylacetate, the method comprising the following steps:

[0041] 1) Make the raw material 2-(2,6-dichlorobenzyloxy)ethanol

[0042]

[0043] Reaction with 1,6-hexanediol to form intermediate 1, namely 2-[2-(6-hydroxy-hexyloxy)-ethoxymethyl]-1,3-dichlorobenzene:

[0044]

[0045] 2) In the presence of triethylamine, intermediate 1 is reacted with methanesulfonyl chloride at 0°C to 5°C to form the mesylate of intermediate 1 as intermediate 2a:

[0046]

[0047] 3) In the presence of tetrabutylammonium bromide and potassium hydroxide, the intermediate 2a is reacted with the raw material (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one.

[0048]

[0049] The reaction was carried out at 40°C-80°C to generate intermediate 3, namely (5R)-3-{6-[2-(2,6-dichlorobenzyloxy)-ethoxy]-hexyl}5-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-oxazolidin-2-one:

[0050]

[0051] 4) reacting intermediate 3 with sodium hydroxide at reflux temperature to generate intermediate 4, i.e., (R)-2-((6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl)amino)-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol:

[0052]

[0053] 5) In the presence of hydrochloric acid, the intermediate 4 is subjected to a hydrolysis reaction to generate vilanterol, i.e., 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]-ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol:

[0054]

[0055] 6) reacting vilanterol with triphenylacetic acid at reflux temperature to generate vilanterol triphenylacetate:

[0056]

[0057]

[0058] In a fourth aspect, the present invention provides a vilanterol triphenylacetate, which is prepared by the method described in the second aspect or the third aspect of the present invention, wherein the purity of the vilanterol triphenylacetate is ≥99.7%, and the isomeric impurities it contains are less than 0.1%, and the unknown single impurity is less than 0.1%.

[0059] The beneficial effects of the present invention include one or more of the following:

[0060] 1) 1,6-hexanediol is used instead of 1,6-dibromohexane to avoid high energy consumption and high pollution caused by high-temperature vacuum distillation, while reducing brominated impurities (potential genotoxic impurities). Although the synthetic route of the present invention introduces other impurities (such as ethyl methanesulfonate, ethylene glycol methanesulfonate monoester, ethylene glycol methanesulfonate diester, etc.), its structure is clear and easier to remove;

[0061] 2) Add a salt refining step to avoid the one-pot process, improve the product purity to more than 99.7%, reduce isomer impurities to <0.1%, and reduce unknown single impurities to <0.1%;

[0062] 3) The prepared vilanterol salt, especially vilanterol triphenylacetate, retains the chiral characteristics of the raw material well, has a qualified isomer composition, and has better powder properties, such as a more uniform particle size distribution, and is not easy to agglomerate, and can meet the needs of different preparations. DETAILED DESCRIPTION

[0063] The present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments that can be obtained by those of ordinary skill in the art based on the embodiments of the present invention belong to the scope of protection of the present invention.

[0064] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0065] As mentioned above, the existing synthesis route of vilanterol salt, especially vilanterol triphenylacetate, has high energy consumption and long production cycle; the product contains a large amount of genotoxic impurities; lacks quality control and cannot meet the declaration requirements. Therefore, one of the purposes of the present invention is to provide a new preparation method of vilanterol or its salt, such as triphenylacetate, so as to reduce energy consumption, pollution and impurities in the product and improve product purity.

[0066] Therefore, in a first aspect, the present invention provides a method for synthesizing vilanterol, the method comprising the steps of:

[0067] 1) Make the raw material 2-(2,6-dichlorobenzyloxy)ethanol

[0068]

[0069] Reaction with 1,6-hexanediol to form intermediate 1, namely 2-[2-(6-hydroxy-hexyloxy)-ethoxymethyl]-1,3-dichlorobenzene:

[0070]

[0071] 2) reacting the intermediate 1 with sulfonyl chloride in the presence of a suitable acid-binding agent to generate a sulfonate of the intermediate 1 as the intermediate 2;

[0072] 3) In the presence of a suitable phase transfer catalyst and a base, the intermediate 2 is reacted with the raw material (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one.

[0073]

[0074] The reaction was carried out at 40°C-80°C to generate intermediate 3, namely (5R)-3-{6-[2-(2,6-dichlorobenzyloxy)-ethoxy]-hexyl}5-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-oxazolidin-2-one:

[0075]

[0076] 4) reacting intermediate 3 with a base at reflux temperature to generate intermediate 4, i.e.

[0077] (R)-2-((6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl)amino)-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol:

[0078]

[0079] 5) In the presence of a suitable acid, the intermediate 4 is hydrolyzed to produce vilanterol, i.e., 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]-ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol:

[0080]

[0081] In a second aspect, the present invention provides a method for synthesizing a vilanterol salt, the method comprising the steps of:

[0082] 1) Make the raw material 2-(2,6-dichlorobenzyloxy)ethanol

[0083]

[0084] Reaction with 1,6-hexanediol to form intermediate 1, namely 2-[2-(6-hydroxy-hexyloxy)-ethoxymethyl]-1,3-dichlorobenzene:

[0085]

[0086] 2) reacting the intermediate 1 with sulfonyl chloride in the presence of a suitable acid-binding agent to generate a sulfonate of the intermediate 1 as the intermediate 2;

[0087] 3) In the presence of a suitable phase transfer catalyst and a base, the intermediate 2 is reacted with the raw material (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one.

[0088]

[0089] The reaction was carried out at 40°C-80°C to generate intermediate 3, namely (5R)-3-{6-[2-(2,6-dichlorobenzyloxy)-ethoxy]-hexyl}5-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-oxazolidin-2-one:

[0090]

[0091] 4) reacting intermediate 3 with a base at reflux temperature to generate intermediate 4, i.e.

[0092] (R)-2-((6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl)amino)-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol:

[0093]

[0094] 5) In the presence of a suitable acid, the intermediate 4 is hydrolyzed to produce vilanterol, i.e., 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]-ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol:

[0095]

[0096] 6) reacting vilanterol with an acid at reflux temperature to form a vilanterol salt.

[0097] The methods of the first and second aspects of the present invention are described in more detail below.

[0098] Step 1):

[0099] 2-(2,6-dichlorobenzyloxy)ethanol

[0100]

[0101] Reaction with 1,6-hexanediol to form intermediate 1, namely 2-[2-(6-hydroxy-hexyloxy)-ethoxymethyl]-1,3-dichlorobenzene:

[0102]

[0103] In one embodiment, step 1) comprises the following steps:

[0104] a) reacting 1,6-hexanediol with an alkali metal hydroxide at 110° C. to 120° C. to produce 1,6-hexanediol salt, or reacting 1,6-hexanediol with metallic sodium to produce sodium alkoxide;

[0105] b) reacting 2-(2,6-dichlorobenzyloxy)ethanol with sulfonyl chloride in the presence of an acid binding agent to generate a sulfonate of 2-(2,6-dichlorobenzyloxy)ethanol;

[0106] c) reacting the 1,6-hexanediol salt or the sodium alkoxide with a sulfonic acid ester of 2-(2,6-dichlorobenzyloxy)ethanol to produce intermediate 1.

[0107] In step a), an alkali metal hydroxide can be used as a base. As an example, sodium hydroxide, potassium hydroxide, etc. can be used, preferably sodium hydroxide. In addition, metallic sodium can also be used to directly react with 1,6-hexanediol to generate sodium alcoholate and hydrogen. In addition, the reaction of step a) can be carried out in a suitable solvent, and the solvent can be toluene, xylene, chlorobenzene, nitrobenzene, etc., but is not limited thereto, and any solvent suitable for the reaction in this step can be used.

[0108] In step b), triethylamine can be used as an acid binding agent, but other suitable acid binding agents can also be used, for example, N, N-diisopropylethylamine, pyridine or N, N-dimethylaminopyridine (DMAP), preferably, triethylamine is used as an acid binding agent; methanesulfonyl chloride can be used to react with 2-(2,6-dichlorobenzyloxy)ethanol to generate the corresponding mesylate, but other suitable sulfonyl chlorides can also be used, such as p-toluenesulfonyl chloride and trifluoromethanesulfonyl chloride. In addition, the reaction in step b) can be carried out in a suitable solvent, and the solvent can be toluene, xylene, chlorobenzene, nitrobenzene, etc., but is not limited thereto, and any solvent suitable for the reaction of this step can be used. In addition, preferably, step b) can be carried out at 0°C to 5°C, but other temperature conditions that allow the reaction of this step are also possible.

[0109] In step c), the reaction may be carried out at a temperature of 95°C to 105°C.

[0110] It is understood that although the method of the present invention is described herein as step 1), step 2), step 3), etc. or step a), step b), etc., it should be understood that this is only for the purpose of describing the method of the present invention more clearly, and it is not intended to limit the order of the steps relative to each other in this way. In other words, the steps can be performed from front to back, from back to front, simultaneously, or in any other order in numerical or alphabetical order, as long as the method of the present invention can be implemented, unless it can be determined from the context or the invention itself that they must be performed in numerical or alphabetical order. For example, for the sub-steps involved in step 1), those skilled in the art can understand that step a) can be performed first and then step b), or step b) can be performed first and then step a), and then step c).

[0111] As mentioned above, in the traditional method, 1,6-dibromohexane is used as a raw material, and the substance has a high boiling point, so it needs high vacuum distillation to remove it, so there will be problems of high energy consumption and long production cycle; in addition, the brominated impurities in the intermediate 2' (IM2') are potential genotoxic impurities, and their content is relatively high. Different from the traditional synthesis method, in the method of the present invention, the inventor uses 1,6-hexanediol to replace 1,6-dibromohexane, so the problems associated with the use of 1,6-dibromohexane can be perfectly avoided.

[0112] Step 2):

[0113] In the presence of a suitable acid-binding agent, intermediate 1 is reacted with sulfonyl chloride to form a sulfonate ester of intermediate 1 as intermediate 2.

[0114] The reaction in this step can be carried out at 0°C to 5°C. In addition, in this step, triethylamine can be used as the acid binding agent, but other suitable acid binding agents such as N,N-diisopropylethylamine, DMAP, etc. can also be used; in addition, methanesulfonyl chloride can be used as the sulfonyl chloride, but other sulfonyl chlorides such as p-toluenesulfonyl chloride and trifluoromethanesulfonyl chloride can also be used. In addition, this step is carried out in a suitable solvent, and the solvent can be toluene, dichloromethane, tetrahydrofuran, etc., but is not limited thereto, preferably toluene.

[0115] Step 3):

[0116] In the presence of a suitable phase transfer catalyst and a base, intermediate 2 is reacted with the starting material (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one.

[0117]

[0118] The reaction was carried out at 40°C-80°C to generate intermediate 3, namely (5R)-3-{6-[2-(2,6-dichlorobenzyloxy)-ethoxy]-hexyl}5-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-oxazolidin-2-one:

[0119]

[0120] In step 3), tetrabutylammonium bromide can be used as the phase transfer catalyst, but other suitable phase transfer catalysts can also be used, such as tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, or methyltributylammonium chloride; in addition, potassium hydroxide can be used as the base, but other bases can also be used, such as sodium hydroxide, potassium tert-butoxide, or sodium tert-butoxide. In addition, the reaction is carried out in a suitable solvent, which can be ethyl acetate, tetrahydrofuran, or dichloromethane, but is preferably ethyl acetate.

[0121] Step 4):

[0122] Intermediate 3 is reacted with a base at reflux temperature to generate intermediate 4, i.e., (R)-2-((6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl)amino)-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol:

[0123]

[0124] In step 4), sodium hydroxide can be used as the base, but other bases can also be used, for example, potassium hydroxide, sodium tert-butoxide, or potassium tert-butoxide. In addition, this step is carried out in a suitable solvent, and the solvent can be ethanol, methanol, isopropanol, etc., but is not limited thereto, and is preferably ethanol.

[0125] Step 5):

[0126] Intermediate 4 is hydrolyzed in the presence of a suitable acid to produce vilanterol, ie, 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]-ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol:

[0127]

[0128]

[0129] In step 5), hydrochloric acid (such as concentrated hydrochloric acid) can be used as the acid, but other acids can also be used, for example, sulfuric acid (such as 10% sulfuric acid), acetic acid, or phosphoric acid. This step is carried out in a suitable solvent, which can be acetone, methanol, ethanol, or tetrahydrofuran, preferably acetone.

[0130] In a preferred embodiment, the method of the present invention further comprises the following steps between step 4) and step 5):

[0131] i) reacting intermediate 4 with an acid to produce intermediate 5, namely (R)-2-((6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl)amino)-1-(2,2-dimethyl-4H-benzo[1,3]

[0132] salts of 6-dioxin-1)ethanol;

[0133] ii) Intermediate 5 is then reacted in the presence of a suitable acid binder to give intermediate 4.

[0134] Step i) is essentially a salt-forming step, which is used to react the intermediate 4 in the form of an oil with an acid to generate the intermediate 5 in the form of a white solid. In step i), any acid suitable for forming a salt with the intermediate 4 can be used, as an example, fumaric acid, maleic acid, L-tartaric acid, oxalic acid, or succinic acid, etc. can be used, preferably fumaric acid. In addition, step i) is carried out in a suitable solvent, and the solvent can be acetone, butanone, acetonitrile, ethanol, etc., preferably acetone.

[0135] As described above, in the synthesis method of the prior art, all intermediates are oily, lacking quality control, and cannot meet the declaration requirements. However, the method of the present invention further introduces step i) between step 4) and step 5), and by salifying intermediate 4 with an acid such as fumaric acid, a salt intermediate 5 that can be subjected to product quality control can be obtained, so that the method of the present invention can meet the declaration requirements. Of course, those skilled in the art will understand that, in the absence of the need for quality control, the method of the present invention does not need to include step i) and the subsequent step ii), which is entirely within the capabilities of those skilled in the art.

[0136] After step i), in order to further synthesize vilanterol, step ii) is also required, and step ii) is essentially a step of restoring the intermediate 5 in the form of a salt to the intermediate 4 in the form of a free base. In this step, potassium carbonate can be used as an acid binding agent, but other acid binding agents, such as sodium hydroxide, sodium carbonate, or sodium bicarbonate, can also be used. In addition, step ii) is carried out in a suitable solvent, and the solvent can be dichloromethane, ethyl acetate, toluene, or 2-methyltetrahydrofuran, preferably dichloromethane.

[0137] When used as a medicine, vilanterol is usually used in its salt form, particularly in its triphenylacetate form. Therefore, after the synthesis of vilanterol, it can be further reacted with an acid to form a corresponding salt, thereby ultimately being used as a medicine. Therefore, the method of the second aspect of the present invention also includes a step of salifying vilanterol.

[0138] Step 6):

[0139] Vilanterol is reacted with an acid at reflux temperature to form a vilanterol salt.

[0140] In step 6), triphenylacetic acid can be used as the acid, but other acids, such as acetic acid, maleic acid, and fumaric acid, can also be used. Step 6) is carried out in a suitable solvent, which can be toluene, methyl tert-butyl ether, acetone, butanone, ethanol, isopropanol, and methanol, preferably toluene.

[0141] In a preferred embodiment, the acid is triphenylacetic acid, and thus the synthesized vilanterol salt is vilanterol triphenylacetate.

[0142] Currently, vilanterol triphenylacetate is mostly used to treat asthma and chronic obstructive pulmonary disease, etc. Therefore, in a third aspect, the present invention provides a method for synthesizing vilanterol triphenylacetate, the method comprising the following steps:

[0143] 1) Make the raw material 2-(2,6-dichlorobenzyloxy)ethanol

[0144]

[0145] Reaction with 1,6-hexanediol to form intermediate 1, namely 2-[2-(6-hydroxy-hexyloxy)-ethoxymethyl]-1,3-dichlorobenzene:

[0146]

[0147] 2) In the presence of triethylamine, intermediate 1 is reacted with methanesulfonyl chloride at 0°C to 5°C to form the mesylate of intermediate 1 as intermediate 2a:

[0148]

[0149] 3) In the presence of tetrabutylammonium bromide and potassium hydroxide, the intermediate 2a is reacted with the raw material (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one.

[0150]

[0151] The reaction was carried out at 40°C-80°C to generate intermediate 3, namely (5R)-3-{6-[2-(2,6-dichlorobenzyloxy)-ethoxy]-hexyl}5-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-oxazolidin-2-one:

[0152]

[0153] 4) reacting intermediate 3 with sodium hydroxide at reflux temperature to generate intermediate 4, i.e., (R)-2-((6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl)amino)-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol:

[0154]

[0155] 5) In the presence of hydrochloric acid, the intermediate 4 is subjected to a hydrolysis reaction to generate vilanterol, i.e., 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]-ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol:

[0156]

[0157] 6) reacting vilanterol with triphenylacetic acid at reflux temperature to generate vilanterol triphenylacetate:

[0158]

[0159] In a preferred embodiment, step 1) comprises:

[0160] a) In the presence of toluene, 1,6-hexanediol and sodium hydroxide are reacted at 110°C to 120°C.

[0161] The reaction generates a toluene solution of 1,6-hexanediol monosodium;

[0162] b) reacting 2-(2,6-dichlorobenzyloxy)ethanol with methanesulfonyl chloride at 0° C. to 5° C. in the presence of toluene and triethylamine to produce a methanesulfonate / toluene solution of 2-(2,6-dichlorobenzyloxy)ethanol;

[0163] c) A toluene solution of 1,6-hexanediol monosodium salt and a toluene solution of 2-(2,6-dichlorobenzyloxy)ethanol methanesulfonate were reacted at 95° C. to 105° C. to produce Intermediate 1.

[0164] In a further preferred embodiment, the method further comprises between step 4) and step 5):

[0165] i) reacting intermediate 4 with fumaric acid in the presence of acetone to produce intermediate 5a, i.e., fumarate of (R)-2-((6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl)amino)-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol:

[0166]

[0167] ii) Intermediate 5a is reacted in the presence of potassium carbonate to produce intermediate 4.

[0168] In a fourth aspect, the present invention provides a vilanterol triphenylacetate, which is prepared by the method described in the second aspect or the third aspect of the present invention, wherein the purity of the vilanterol triphenylacetate is ≥99.7%, and the isomer impurities it contains are less than 0.1%, and the unknown single impurity is less than 0.1%.

[0169] Since 1,6-dibromohexane is not used in the method for preparing vilanterol triphenylacetate of the present invention, no genotoxic bromide impurities are involved in the synthesis process, and the purity is considerable. In addition, the vilanterol triphenylacetate prepared by the method of the present invention well retains the chiral characteristics of the raw materials, has a qualified isomer composition, and also has better powder properties, such as a more uniform particle size distribution, not easy to agglomerate, and can meet the needs of different preparations.

[0170] Example

[0171] The present invention is described in more detail below in conjunction with the embodiments. The test methods in the following embodiments are conventional methods unless otherwise specified. The test materials used in the following embodiments are obtained by purchasing from conventional reagent stores unless otherwise specified. It should be noted that the above summary of the invention and the detailed description below are only for the purpose of specifically illustrating the present invention and are not intended to limit the present invention in any way.

[0172] The synthetic route of vilanterol triphenylacetate in Example 1-5 is as follows:

[0173]

[0174] Example 1: Synthesis of Intermediate 1 (2-[2-(6-hydroxy-hexyloxy)-ethoxymethyl]-1,3-dichlorobenzene)

[0175]

[0176] Preparation of 1,6-hexanediol monosodium: Add 1,6-hexanediol (13.36g) to a 100ml reaction bottle equipped with a water separator, then add 26ml of solvent toluene, heat to 40℃ to 50℃, add 50% sodium hydroxide solution (2.18g, 1.2eq) dropwise until the solid is dissolved, and heat to 110℃ to 120℃ until the system refluxes and the water separator begins to receive the water generated by the reaction. When the amount of water separated reaches 3.1g, it is considered that the reaction has reached the end point, and the water separation is stopped at this time to obtain a toluene solution of 1,6-hexanediol monosodium, which is cooled and set aside.

[0177] Preparation of 2-(2,6-dichlorobenzyloxy)ethanol mesylate: Add 2-(2,6-dichlorobenzyloxy)ethanol (5.0g) and solvent toluene (50ml) to a 100ml reaction bottle, cool to 0℃ to 5℃, drop acid-binding agent triethylamine (3.43g, 1.5eq), and then drop methanesulfonyl chloride (3.11g, 1.2eq) to react. After TLC monitoring, the reaction is complete, 1N hydrochloric acid (25ml) is added dropwise to quench the reaction, separate the liquids, and discard the aqueous phase. Collect the organic phase, wash once with water (25ml), then separate the liquids and collect the organic phase. The organic phase is concentrated under reduced pressure to an oily substance, and then toluene (25ml) is added to prepare a 2-(2,6-dichlorobenzyloxy)ethanol mesylate / toluene solution.

[0178] Preparation of intermediate 1: Add the methanesulfonate / toluene solution of 2-(2,6-dichlorobenzyloxy)ethanol dropwise into the toluene solution of 1,6-hexanediol monosodium, and heat to 100±5°C for reaction. After the reaction is completed by TLC monitoring, water (40ml*2) is added to the reaction system for washing twice, the liquid is separated, the organic phase is collected and concentrated, and the residue is separated and purified by column chromatography (mobile phase is dichloromethane:methanol=20:1) to obtain intermediate 1 (5.2g), with a yield of 71.57% and a purity of 99.0%; 1 H NMR (400MHz, DMSO-d6) δ7.49(d,J=1.1Hz,1H),7.47(s,1H),7.38(dd,J=8.9,7.2Hz,1H),4.70(s,2H),4.35(t,J=5.2Hz,1 H),3.61(dd,J=5.9,3.7Hz,2H),3.50(dd,J=5.8,3.7Hz,2H),3.41–3.35(m,4H),1.52–1.34(m,4H),1.27(p,J=3.5Hz,4H).

[0179] Example 2: Synthesis of Intermediate 2a (6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl methanesulfonate)

[0180]

[0181] Add intermediate 1 (5.0 g), solvent toluene (50 ml), acid-binding agent triethylamine (2.36 g, 1.5 eq) to a 100 ml reaction bottle, protect with nitrogen and cool to 0°C to 5°C, and drop a toluene solution (25 ml) of methanesulfonyl chloride (2.14 g). After the reaction is completed by TLC monitoring, drop 1N hydrochloric acid (20 ml) to quench the reaction, then separate the liquids, collect the organic phase, and wash it once with water (25 ml). The organic phase is washed once with 10% sodium chloride solution (25 ml), separate the liquids, collect the organic phase, and concentrate to obtain a yellow oil. The crude product is separated and purified by column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain a colorless oil, namely intermediate 2a (5.5 g), with a yield of 88.49% and a purity of 99.2%; 1 H NMR (400MHz, DMSO-d6) δ7.50(d,J=1.0Hz,1H),7.48(s,1H),7.39(dd,J=8.8,7.2Hz,1H),4.70(s,2H),4.17(t,J=6.5Hz,2H),3.61(dd,J=5.8,3.7Hz, 2H),3.51(dd,J=5.8,3.7Hz,2H),3.37(t,J=6.5Hz,2H),3.16(s,3H),1.64 (t, J=6.9Hz, 2H), 1.48 (t, J=6.7Hz, 2H), 1.33 (dq, J=6.8, 4.3, 3.4Hz, 4H).

[0182] Example 3: Synthesis of Intermediate 3 ((5R)-3-{6-[2-(2,6-dichlorobenzyloxy)-ethoxy]-hexyl}5-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-oxazolidin-2-one)

[0183] In a 100 ml reaction bottle, add the raw material (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (2.6 g), solvent ethyl acetate (39 ml), and intermediate 2a (5.4 g, 1.3 eq). After stirring evenly, add tetrabutylammonium bromide (168 mg) and potassium hydroxide (1.17 g, 2 eq), and heat to 40°C to 80°C for 2 h. The reaction of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one was completed by TLC monitoring. 1N hydrochloric acid (13 ml) and 10% sodium chloride solution (13 ml) were added in sequence for washing. The organic phase was concentrated to obtain a yellow oil. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate=2:1) ​​to obtain a light yellow oil, namely intermediate 3 (4.9 g), with a yield of 85.03% and a purity of 98.5%.1 H NMR (400MHz, DMSO-d6) δ7.50(d,J=1.0Hz,1H),7.48(s,1H),7.38(dd,J=8.8,7.2Hz,1H),7.19(dd ,J=8.4,2.1Hz,1H),7.13(d,J=2.1Hz,1H),6.83(d,J=8.4Hz,1H),5.45(t,J=8.0Hz,1H),4.83(s, 2H),4.69(s,2H),3.88(t,J=8.8Hz,1H),3.61(dd,J=5.9,3.6Hz,2H),3.50(dd,J=5.8,3.7Hz,2H) ,3.43–3.34(m,3H),3.26–3.08(m,2H),1.46(m,6H+4H),1.27(dtq,J=21.7,8.3,5.2,3.0Hz,4H).

[0184] Example 4: Synthesis of Intermediate 5a ((R)-2-((6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl)amino)-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol fumarate)

[0185]

[0186] Synthesis of Intermediate 4: Add Intermediate 3 (4.0 g) and ethanol (20 ml) to a 100 ml reaction bottle, stir to clarify, add 50% sodium hydroxide aqueous solution (5.8 g, 10 eq), heat to reflux and stir for 1 h. TLC monitors the completion of the reaction, filter to remove excess inorganic salts, add dichloromethane (20 ml) to the filtrate for extraction, add dichloromethane (10 ml) to the aqueous phase for extraction again, combine the organic phases, wash with 10% sodium chloride aqueous solution (10 ml), and concentrate the organic phase to obtain a yellow oil, namely Intermediate 4 ((R)-2-((6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl)amino)-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol).

[0187] Synthesis of intermediate 5a: Add solvent acetone (40 ml) and fumaric acid (840 mg) to the oily substance, and after the solid precipitates, heat to 50°C to 60°C, beat for 1 h, and filter while hot to obtain a white solid, namely intermediate 5a (3.0 g), with a yield of 70.92% and a purity of 99.7%; 1H NMR (400MHz, DMSO-d6) δ7.50 (s, 1H), 7.48 (s, 1H), 7.38 (dd, J=8.8, 7.3Hz, 1H), 7.13 (dd, J= 8.4,2.1Hz,1H),7.05(d,J=2.0Hz,1H),6.75(d,J=8.4Hz,1H),6.42(s,0.5H+0.5H,fumaric acid olefin H),4.80(s,2H),4.69(s,2H),4.67(t,1H),3.62–3.59(m,2H),3.51–3.49( m,2H),3.36(s,2H),2.85–2.67(m,4H),1.45(m,6H+4H),1.31–1.23(m,4H).

[0188] Example 5: Synthesis of Vilanterol Triphenylacetate

[0189]

[0190] In a 100 ml reaction flask, add intermediate 5a (2.5 g), dichloromethane (25 ml), and an aqueous solution (25 ml) of potassium carbonate (538 mg), stir until the solid is dissolved, separate the liquids, add a 10% sodium chloride aqueous solution (10 ml) to the organic phase and wash it once, concentrate the organic phase to obtain a light yellow oil, add acetone (10 ml) to dissolve it, and add 6N hydrochloric acid (1.3 ml) dropwise to start the hydrolysis reaction. TLC monitors the completion of the hydrolysis reaction, add 50% sodium hydroxide solution, adjust the pH to 7 to 8, add toluene (25 ml) to extract, extract the aqueous phase with toluene (10 ml) again, combine the organic phases, concentrate under reduced pressure to 10 ml to 15 ml, add triphenylacetic acid (2.24 g), and heat to reflux. After the solid was dissolved, the temperature was lowered to 50°C to 60°C, kept warm for 1 hour, and then lowered to 10°C to 20°C for aging for 2 hours, filtered, and the filter cake was washed with 5ml to 10ml of toluene to obtain vilanterol triphenylacetate (1.1g), with a yield of 72.98% and a purity of 99.8% (isomer impurities <0.1%, unknown single impurities <0.1%); 1H NMR (400MHz, DMSO-d6) δ9.23(s,1H),7.48(s,1H),7.46(s,1H),7.36(dd,J=8.8,7.2Hz,1H),7.31(d,J =2.2Hz,1H),7.26–7.08(m,15H),7.00(dd,J=8.2,2.2Hz,1H),6.74(d,J=8.2Hz,1H),4.82(dd,J=10.2, 2.8Hz,1H),4.69(s,2H),4.48(s,2H),3.61(dd,J=5.9,3.7Hz,2H),3.50(dd,J=5.8,3.7Hz,2H),3.35(t ,J=6.5Hz,2H),2.96(dd,J=12.4,2.8Hz,1H),2.88–2.63(m,3H),1.66–1.37(m,4H),1.31–1.12(m,4H).

[0191] Example 6: One-pot synthesis of vilanterol triphenylacetate

[0192]

[0193] Synthesis of intermediate 4 ((R)-2-((6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl)amino)-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol): intermediate 3 (1.0 g) and ethanol (5 ml) were added to a 50 ml reaction bottle, stirred to clarify, and then 50% aqueous sodium hydroxide solution (1.4 g) was added, and the temperature was raised to reflux and stirred for 1 h. The reaction was monitored by TLC, and the excess inorganic salt was removed by filtration. Dichloromethane (5 ml) was added to the filtrate for extraction, and dichloromethane (5 ml) was added to the aqueous phase for extraction again. The organic phases were combined and washed with 10% aqueous sodium chloride solution (5 ml). The organic phase was concentrated to obtain the free base of intermediate 4 (920 mg) as a yellow oil.

[0194] Synthesis of vilanterol (4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]-ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol): intermediate 4 (920 mg) was added to a 50 ml reaction bottle, dissolved with acetone (5 ml), and 6N hydrochloric acid (2.32 ml) was added dropwise to start the hydrolysis reaction. After the hydrolysis reaction was completed by TLC monitoring, 50% sodium hydroxide solution was added, the pH was adjusted to 7 to 8, toluene (10 ml) was added for extraction, the aqueous phase was extracted again with toluene (5 ml), the organic phases were combined, and concentrated under reduced pressure to obtain vilanterol (820 mg) as an oil.

[0195] Synthesis of Vilanterol Triphenylacetate: Add Vilanterol (820 mg) and solvent toluene (5 ml) to a 50 ml reaction bottle, then add triphenylacetic acid (486 mg), and heat to reflux. After the solid is dissolved, cool to 50°C to 60°C, keep warm for 1 hour, then cool to 10°C to 20°C for aging for 2 hours, filter, and wash the filter cake with 5 ml to 10 ml toluene to obtain Vilanterol Triphenylacetate (1.0 g), with a yield of 76.9% and a purity of 99.7% (isomer impurities <0.1%, unknown single impurities <0.1%).

[0196] Particle size analysis of vilanterol triphenylacetate: The synthesized vilanterol triphenylacetate was analyzed by HELOS (H4309) & RODOS / L, R5 instrument. The pressure during particle dispersion was 3 bar, the vacuum was 92 mbar, and the data was analyzed by PAQXOS5.0 software. The synthesized vilanterol triphenylacetate crystal habit was needle-shaped crystals with the following particle diameters: D10: 1.54 μm; D50: 6.26 μm; D90: 18.67 μm; D95: 24.17 μm; Span: 2.74 μm. It is shown that the vilanterol triphenylacetate prepared by the method provided by the present invention has better powder properties.

[0197] The above is a detailed introduction to the synthesis method of vilanterol and its triphenylacetate provided by the present invention. The principles and implementation methods of the present invention are described in detail using specific examples herein. The description of the above examples is only used to help understand the method of the present invention and its core idea. At the same time, for those skilled in the art, according to the idea of ​​the present invention, there will be changes in the specific implementation method and application scope. In summary, the content of this specification should not be understood as limiting the present invention.

Claims

1. A method for synthesizing vilanterol, the method comprising the following steps: 1) Make the raw material 2-(2,6-dichlorobenzyloxy)ethanol Reaction with 1,6-hexanediol to form intermediate 1, namely 2-[2-(6-hydroxy-hexyloxy)-ethoxymethyl]-1,3-dichlorobenzene: 2) reacting the intermediate 1 with sulfonyl chloride in the presence of an acid-binding agent to generate a sulfonate of the intermediate 1 as the intermediate 2; 3) In the presence of a phase transfer catalyst and a base, the intermediate 2 is reacted with the raw material (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one The reaction was carried out at 40°C-80°C to generate intermediate 3, namely (5R)-3-{6-[2-(2,6-dichlorobenzyloxy)-ethoxy]-hexyl}5-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-oxazolidin-2-one: 4) reacting intermediate 3 with a base at reflux temperature to generate intermediate 4, i.e. (R)-2-((6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl)amino)-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol: 5) hydrolyzing the intermediate 4 in the presence of an acid to generate vilanterol, i.e., 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]-ethoxy}hexyl)amino [1-Hydroxyethyl]-2-(hydroxymethyl)phenol:

2. The method according to claim 1, characterized in that Step 2) is carried out at 0°C to 5°C.

3. The method according to claim 1 or 2, characterized in that: The acid in step 5) is hydrochloric acid, sulfuric acid, acetic acid, or phosphoric acid.

4. A method for synthesizing a vilanterol salt, the method comprising the following steps: 1) Make the raw material 2-(2,6-dichlorobenzyloxy)ethanol Reaction with 1,6-hexanediol to form intermediate 1, namely 2-[2-(6-hydroxy-hexyloxy)-ethoxymethyl]-1,3-dichlorobenzene: 2) reacting the intermediate 1 with sulfonyl chloride in the presence of an acid-binding agent to generate a sulfonate of the intermediate 1 as the intermediate 2; 3) In the presence of a phase transfer catalyst and a base, the intermediate 2 is reacted with the raw material (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one The reaction was carried out at 40°C-80°C to generate intermediate 3, namely (5R)-3-{6-[2-(2,6-dichlorobenzyloxy)-ethoxy]-hexyl}5-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-oxazolidin-2-one: 4) reacting intermediate 3 with a base at reflux temperature to generate intermediate 4, i.e. (R)-2-((6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl)amino)-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol: 5) In the presence of an acid, the intermediate 4 is hydrolyzed to produce vilanterol, i.e., 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]-ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol: 6) reacting vilanterol with an acid at reflux temperature to form a vilanterol salt.

5. The method according to claim 4, characterized in that Step 2) is carried out at 0°C to 5°C.

6. The method according to claim 4 or 5, characterized in that: The acid in step 5) is hydrochloric acid, sulfuric acid, acetic acid, or phosphoric acid.

7. The method according to claim 4 or 5, characterized in that: The acid in step 6) is triphenylacetic acid, acetic acid, maleic acid, or fumaric acid.

8. The method according to claim 7, characterized in that The acid in step 6) is triphenylacetic acid.

9. The method according to claim 1, 2, 4 or 5, characterized in that: Step 1) includes: a) reacting 1,6-hexanediol with an alkali metal hydroxide at 110° C. to 120° C. to produce 1,6-hexanediol salt, or reacting 1,6-hexanediol with metallic sodium to produce sodium alkoxide; b) reacting 2-(2,6-dichlorobenzyloxy)ethanol with sulfonyl chloride in the presence of an acid binding agent to generate a sulfonate of 2-(2,6-dichlorobenzyloxy)ethanol; c) reacting the 1,6-hexanediol salt or the sodium alkoxide with a sulfonic acid ester of 2-(2,6-dichlorobenzyloxy)ethanol to produce intermediate 1.

10. The method according to claim 9, characterized in that The hydroxide in step a) is sodium hydroxide or potassium hydroxide.

11. The method according to claim 9, characterized in that The acid binding agent in step b) is triethylamine, N,N-diisopropylethylamine, pyridine or N,N-dimethylaminopyridine.

12. The method according to claim 11, characterized in that The acid binding agent in step b) is triethylamine.

13. The method according to claim 9, characterized in that The sulfonyl chloride in step b) is methanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoromethanesulfonyl chloride.

14. The method according to claim 13, characterized in that The sulfonyl chloride in step b) is methanesulfonyl chloride.

15. The method according to claim 9, characterized in that Step b) is carried out at 0°C to 5°C.

16. The method according to claim 9, characterized in that Step c) is carried out at 95°C to 105°C.

17. The method according to claim 1, 2, 4 or 5, characterized in that The method further comprises between step 4) and step 5): i) reacting intermediate 4 with an acid to form intermediate 5, i.e., a salt of (R)-2-((6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl)amino)-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol; ii) Intermediate 5 is then reacted in the presence of an acid binder to produce intermediate 4.

18. The method according to claim 17, characterized in that The acid in step i) is fumaric acid, maleic acid, L-tartaric acid, oxalic acid, or succinic acid.

19. The method according to claim 18, characterized in that The acid in step i) is fumaric acid.

20. The method according to claim 17, characterized in that The acid binding agent in step ii) is potassium carbonate, sodium hydroxide, sodium carbonate, or sodium bicarbonate.

21. The method according to claim 20, characterized in that The acid binding agent in step ii) is potassium carbonate.

22. The method according to claim 1, 2, 4 or 5, characterized in that In step 2), the acid-binding agent is triethylamine, N,N-diisopropylethylamine, or N,N-dimethylaminopyridine; and the sulfonyl chloride is methanesulfonyl chloride, p-toluenesulfonyl chloride, or trifluoromethanesulfonyl chloride.

23. The method according to claim 22, characterized in that The acid binding agent is triethylamine.

24. The method according to claim 22, characterized in that The sulfonyl chloride is methanesulfonyl chloride.

25. The method according to claim 1, 2, 4 or 5, characterized in that In step 3), the phase transfer catalyst is tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, or methyltributylammonium chloride; the base is potassium hydroxide, sodium hydroxide, potassium tert-butoxide, or sodium tert-butoxide.

26. The method according to claim 25, characterized in that The phase transfer catalyst is tetrabutylammonium bromide.

27. The method according to claim 25, characterized in that The base is potassium hydroxide.

28. The method according to claim 1, 2, 4 or 5, characterized in that In step 4), the base is sodium hydroxide, potassium hydroxide, sodium tert-butoxide, or potassium tert-butoxide.

29. The method according to claim 28, characterized in that The base is sodium hydroxide.

30. A method for synthesizing vilanterol triphenylacetate, the method comprising the following steps: 1) Make the raw material 2-(2,6-dichlorobenzyloxy)ethanol Reaction with 1,6-hexanediol to form intermediate 1, namely 2-[2-(6-hydroxy-hexyloxy)-ethoxymethyl]-1,3-dichlorobenzene: 2) In the presence of triethylamine, intermediate 1 is reacted with methanesulfonyl chloride at 0°C to 5°C to form the mesylate of intermediate 1 as intermediate 2a: 3) In the presence of tetrabutylammonium bromide and potassium hydroxide, the intermediate 2a is reacted with the raw material (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one. The reaction was carried out at 40°C-80°C to generate intermediate 3, namely (5R)-3-{6-[2-(2,6-dichlorobenzyloxy)-ethoxy]-hexyl}5-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-oxazolidin-2-one: 4) reacting intermediate 3 with sodium hydroxide at reflux temperature to generate intermediate 4, i.e., (R)-2-((6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl)amino)-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol: 5) In the presence of hydrochloric acid, the intermediate 4 is hydrolyzed to generate vilanterol, i.e., 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]-ethoxy}hexyl)amino [1-Hydroxyethyl]-2-(hydroxymethyl)phenol: 6) reacting vilanterol with triphenylacetic acid at reflux temperature to generate vilanterol triphenylacetate:

31. The method according to claim 30, characterized in that Step 1) includes: a) reacting 1,6-hexanediol with sodium hydroxide at 110° C. to 120° C. in the presence of toluene to generate a toluene solution of 1,6-hexanediol monosodium; b) reacting 2-(2,6-dichlorobenzyloxy)ethanol with methanesulfonyl chloride at 0° C. to 5° C. in the presence of toluene and triethylamine to produce a methanesulfonate / toluene solution of 2-(2,6-dichlorobenzyloxy)ethanol; c) A toluene solution of 1,6-hexanediol monosodium salt and a toluene solution of 2-(2,6-dichlorobenzyloxy)ethanol methanesulfonate were reacted at 95° C. to 105° C. to produce Intermediate 1.

32. The method according to claim 30 or 31, characterized in that The method further comprises between step 4) and step 5): i) reacting intermediate 4 with fumaric acid in the presence of acetone to produce intermediate 5a, i.e., fumarate of (R)-2-((6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl)amino)-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol: ii) Intermediate 5a is reacted in the presence of potassium carbonate to produce intermediate 4.

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