阅读说明：本技术 一种妥洛特罗的制备及纯化方法 (Preparation and purification method of tulobuterol ) 是由 陈龙 余晓磊 张宇 李文明 于 2021-08-30 设计创作，主要内容包括：本发明提供了一种妥洛特罗的制备及纯化方法,其解决了现有方法中存在的安全隐患、后处理繁琐等的技术问题。该方法利用价廉易得的邻氯苯甲醛为原料,经过两步反应和一步精制可得高纯度的妥洛特罗原料药。本发明的反应步骤短,反应条件温和,操作简单,收率高,具有较好的应用开发前景。(The invention provides a method for preparing and purifying tulobuterol, which solves the technical problems of potential safety hazard, complicated post-treatment and the like in the existing method. The method uses cheap and easily-obtained o-chlorobenzaldehyde as a raw material, and the high-purity tulobuterol bulk drug can be obtained through two-step reaction and one-step refining. The method has the advantages of short reaction steps, mild reaction conditions, simple operation, high yield and good application and development prospects.)

1. A method for preparing and purifying tulobuterol, comprising the steps of:

a: taking o-chlorobenzaldehyde (2) as a starting material, and reacting with trimethyl iodide (3) in a water-containing reaction solvent to obtain 2- (2-chlorphenyl) oxirane (4);

b: 2- (2-chlorphenyl) oxirane (4) reacts with tert-butylamine to obtain a tulobuterol crude product;

c: after salifying the crude tulobuterol product, recrystallizing the crude tulobuterol product by using a mixed solvent to obtain tulobuterol salt (5);

d: the tulobuterol salt (5) is dissociated to obtain the tulobuterol (1).

2. The preparation and purification method according to claim 1, wherein the reaction solvent system used in step a is one or more of toluene-water, dichloromethane-water, acetonitrile-water, dimethylsulfoxide-water, and tetrahydrofuran-water, preferably toluene-water.

3. The method according to claim 1, wherein the volume ratio of toluene to water in the reaction solvent system used in step a is 5:1 to 10: 1.

4. The preparation and purification process according to claim 1, wherein the trimethyl iodide (3) in step a is trimethyl sulfoxide iodide or trimethyl sulfonium iodide, preferably trimethyl sulfoxide iodide; the molar ratio of o-chlorobenzaldehyde (2) to trimethyl iodide (3) in reaction a is 1:2.5 to 1:1, preferably 1:2 to 1: 1.1.

5. The method according to claim 1, wherein the solvent used in step b is one or more selected from methanol, ethanol, isopropanol, acetone, acetonitrile and tetrahydrofuran, preferably ethanol.

6. The process according to claim 1, wherein the molar ratio of 2- (2-chlorophenyl) oxirane (4) to tert-butylamine in step b is from 1:10 to 1: 5.

7. The method according to claim 1, wherein the acid used in step c is one of hydrochloric acid, sulfuric acid, benzenesulfonic acid, formic acid, acetic acid, oxalic acid, propionic acid, butyric acid, fumaric acid, maleic acid, and citric acid, preferably acetic acid.

8. The method according to claim 1, wherein the mixed solvent used in step c is one or more selected from methyl acetate-methanol, methyl acetate-ethanol, methyl acetate-isopropanol, ethyl acetate-methanol, methyl acetate-ethanol, ethyl acetate-isopropanol, isopropyl acetate-methanol, isopropyl acetate-ethanol, isopropyl acetate-isopropanol, preferably ethyl acetate-ethanol.

9. The method of claim 1, wherein the base used in step d is one or more selected from the group consisting of ammonia, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate, preferably sodium hydroxide.

10. The method according to claim 1, wherein the extraction solvent used in step d is one or more selected from methyl acetate, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, and dichloromethane, preferably isopropyl acetate.

Technical Field

The invention relates to the field of chemical synthesis, in particular to a novel method and a novel purification method for preparing and synthesizing tulobuterol by taking o-chlorobenzaldehyde as a raw material.

Background

Tulobuterol (tulobuterol), a selective β 2 receptor agonist developed by Abbot corporation of japan, was approved for the market as an anti-asthmatic in japan in 1981. It was used for treating asthma and chronic obstructive disease (COPD) in 1998, and is currently used as a patch for treating children, and has indications of relieving symptoms such as dyspnea caused by airway obstruction diseases such as bronchial asthma, acute bronchitis, chronic bronchitis, emphysema, etc. Tulobuterol, chemically known as 1- (2-chlorophenyl) -2-tert-butylaminoethanol, has the following chemical structure:

the literature reports methods for synthesizing tulobuterol mainly include the following steps:

route one (patent document sho 54-151935):

in the synthesis method, benzene with high toxicity is used as a reaction solvent, strong-irritation and corrosive bromine is used, the harm to a human body is large, and the treatment difficulty in environmental protection is large.

Scheme two (document CN 110590569A):

in the synthesis method, bromination is not easy to control, and quality control is not facilitated in the production of raw material medicines; and in the second step of reaction, sodium borohydride which is an easily explosive compound is used as a reducing agent, so that great potential safety hazard exists.

Scheme three (document CN 110172028A):

although the synthesis method avoids the use of bromine, the intermediate 11 is easy to form hydrate and is not beneficial to quality control in the production of raw material medicines; and the last step uses sodium borohydride which is an easily explosive compound, so that great potential safety hazard exists.

Scheme four (document CN 105439875A):

according to the method, the first-step olefination reaction is completed at a high temperature of 180-210 ℃, the reaction conditions are harsh, and the energy consumption is large; in the second step, m-chloroperoxybenzoic acid (m-CPBA) is used as an oxidant, and is unstable and explosive, so that great hidden danger exists in the aspect of safety.

Scheme five (document CN 111205194A):

although the dibromo hydantoin (DBH) which is cheap, easy to obtain, safe and environment-friendly is adopted as the brominating reagent in the synthesis method, column chromatography is used in the purification process of the final product, so that the production cost is greatly improved, the production efficiency is greatly reduced, and the industrial production is not facilitated.

Disclosure of Invention

The invention aims to solve the defects of potential safety hazard, complicated post-treatment and the like in the prior art, and provides the preparation method of the tulobuterol, which has the advantages of few reaction steps, simple process, mild reaction conditions, cheap and easily obtained raw materials, safe operation and high yield and is suitable for industrial production.

In order to achieve the purpose, the invention adopts the following technical scheme:

the synthesis method comprises the following steps:

the invention provides a method for preparing and purifying tulobuterol, which comprises the following steps:

a: taking o-chlorobenzaldehyde (2) as a starting material, and carrying out a Corey-Chaykovsky reaction with trimethyl iodide (3) in a water-containing reaction solvent to obtain 2- (2-chlorphenyl) oxirane (4);

b: 2- (2-chlorphenyl) oxirane (4) reacts with tert-butylamine to obtain a tulobuterol crude product;

c: after salifying the crude tulobuterol product, recrystallizing the crude tulobuterol product by using a mixed solvent to obtain tulobuterol salt (5);

d: the tulobuterol salt (5) is dissociated to obtain the tulobuterol (1).

The reaction solvent system adopted in the step a is one of toluene-water, dichloromethane-water, acetonitrile-water, dimethyl sulfoxide-water, tetrahydrofuran-water or a mixture thereof, and toluene/water is preferred.

The reaction solvent system employed in step a above is a toluene-water volume ratio of 5:1 to 10:1, and in some embodiments the toluene-water volume ratio is 5:1, 6:1, 7:1, 8:1, 9:1, or 10: 1.

The trimethyl iodide (3) in the step of the reaction a is trimethyl sulfoxide iodide or trimethyl sulfonium iodide, preferably trimethyl sulfoxide iodide.

The molar ratio of o-chlorobenzaldehyde (2) to trimethyl iodide (3) in step a above is 1:2.5 to 1:1, preferably 1:2 to 1:1.1, e.g. 1:2, 1:1.8, 1:1.5, 1:1.2, 1:1.1, further the molar ratio of o-chlorobenzaldehyde (2) to trimethyl sulphoxide iodide (3) is 1:2 to 1:1.1, in some embodiments the molar ratio of o-chlorobenzaldehyde (2) to trimethyl sulphoxide iodide (3) is 1:2, 1:1.5 or 1: 1.1.

The reaction solvent in the step b is one of methanol, ethanol, acetone, acetonitrile or tetrahydrofuran, preferably ethanol.

The molar ratio of 2- (2-chlorophenyl) oxirane (4) to t-butylamine in reaction b above is 1:10 to 1:5, and in some embodiments the molar ratio of 2- (2-chlorophenyl) oxirane (4) to t-butylamine is 1:10, 1:7, or 1: 5.

The acid used in the step of the reaction c is one or more of hydrochloric acid, sulfuric acid, benzenesulfonic acid, formic acid, acetic acid, oxalic acid, propionic acid, butyric acid, fumaric acid, maleic acid and citric acid, and acetic acid is preferred.

The mixed solvent used in the step c is one or more of methyl acetate-methanol, methyl acetate-ethanol, methyl acetate-isopropanol, ethyl acetate-methanol, methyl acetate-ethanol, ethyl acetate-isopropanol, isopropyl acetate-methanol, isopropyl acetate-ethanol and isopropyl acetate-isopropanol, and preferably ethyl acetate-ethanol.

The alkali used in the step d is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate, and preferably sodium hydroxide.

The extraction solvent used in the step d is one or more of methyl acetate, ethyl acetate, isopropyl acetate, methyl tert-butyl ether and dichloromethane, and isopropyl acetate is preferred.

The invention develops a new method for synthesizing and purifying tulobuterol, the starting material o-chlorobenzaldehyde is cheap and easy to obtain, the technological operation process is simplified, the production efficiency is improved, and the use of bromization reagent with strong irritation and corrosivity in the traditional synthetic route is avoided. Meanwhile, the invention firstly carries out salifying treatment and utilizes a mixed solvent recrystallization method to obtain the tulobuterol salt with the purity of more than 99.8 percent, and finally obtains the high-purity tulobuterol. The method adopted by the invention has the advantages of simple reaction reagent, convenient use, mild reaction condition, no special reagent requirement, simple reaction operation, easy post-treatment and high purity and yield of the product.

Drawings

Figure 1 example 10 tulobuterol X-ray powder diffraction pattern.

Detailed Description

The present invention will be better understood from the following examples. However, one skilled in the art will readily appreciate that the specific material ratios, process conditions, and results thereof described in the examples are merely illustrative of the invention and should not, nor should they, limit the invention as described in detail in the claims.

Example 1: synthesis of 2- (2-chlorophenyl) oxirane (4)

To a 1L reaction flask were added 500 mL of toluene, 60g of o-chlorobenzaldehyde, and the stirring was turned on. 96g of trimethylsulfonium iodide were charged into a reaction flask. Heating is started at a set temperature of 70-75 ℃, the internal temperature is increased to 50 +/-5 ℃, 20% potassium hydroxide aqueous solution is dripped into the reaction bottle, and the dripping speed is controlled to be 30-40 mL/min. After the dripping is finished, the temperature is maintained at 65-75 ℃ for continuous reaction for 3-3.5 h. No more than 0.6% of starting material remains as determined by HPLC. And after the reaction is finished, stopping heating, cooling to 25-30 ℃, and stopping stirring. And (4) carrying out suction filtration, collecting filtrate, transferring the filtrate into a reaction bottle, standing for 30min, separating liquid, and collecting an organic phase. Setting the water bath temperature at 45-60 ℃, the vacuum degree at 50-100mbar and the rotating speed at 60rmp, concentrating the organic phase by using a rotary evaporator under reduced pressure until no obvious liquid drops continuously drip out of the condensation pipe, and obtaining the reddish brown oily substance. Cooling to 20-30 deg.C to separate out white solid in the reddish brown oil, and filtering. The filtrate was concentrated under reduced pressure to give 58 g of 2- (2-chlorophenyl) oxirane (4), yield 95%.

Example 2: synthesis of 2- (2-chlorophenyl) oxirane (4)

To a 1L reaction flask were added 500 mL of toluene, 60g of o-chlorobenzaldehyde, and the stirring was turned on. 96g of trimethyl sulphoxide iodide and 18g of tetrabutylammonium iodide were added successively to the reaction flask. Heating is started at a set temperature of 70-75 ℃, the internal temperature is increased to 50 +/-5 ℃, a 20% sodium hydroxide aqueous solution is dripped into the reaction bottle, and the dripping speed is controlled to be 30-40 mL/min. After the dripping is finished, the temperature is maintained at 65-75 ℃ for continuous reaction for 3-3.5 h. No more than 0.6% of starting material remains as determined by HPLC. And after the reaction is finished, stopping heating, cooling to 25-30 ℃, and stopping stirring. And (4) carrying out suction filtration, collecting filtrate, transferring the filtrate into a reaction bottle, standing for 30min, separating liquid, and collecting an organic phase. Setting the water bath temperature at 45-60 ℃, the vacuum degree at 50-100mbar and the rotating speed at 60rmp, concentrating the organic phase by using a rotary evaporator under reduced pressure until no obvious liquid drops continuously drip out of the condensation pipe, and obtaining the reddish brown oily substance. Cooling to 20-30 deg.C to separate out white solid in the reddish brown oil, and filtering. The filtrate was concentrated under reduced pressure to give 59 g of 2- (2-chlorophenyl) oxirane (4), yield 97%.

Example 3: synthesis of 2- (2-chlorophenyl) oxirane (4)

To a 1L reaction flask were added 500 mL of methylene chloride and 60g of o-chlorobenzaldehyde, and the stirring was turned on. 96g of trimethylsulfonium iodide and 4.5g of 1, 3-bis [3, 5-bis (trifluoromethyl) phenyl ] urea were successively charged into a reaction flask. And (3) dropwise adding a 50% sodium hydroxide aqueous solution into the reaction bottle, and controlling the dropping speed to be 30-40 mL/min. The reaction was carried out overnight at room temperature after dropping. No more than 0.6% of starting material remains as determined by HPLC. And after the reaction is finished, stopping heating, cooling to 25-30 ℃, and stopping stirring. And (4) carrying out suction filtration, collecting filtrate, transferring the filtrate into a reaction bottle, standing for 30min, separating liquid, and collecting an organic phase. Setting the water bath temperature at 45-60 ℃, the vacuum degree at 50-100mbar and the rotating speed at 60rmp, concentrating the organic phase by using a rotary evaporator under reduced pressure until no obvious liquid drops continuously drip out of the condensation pipe, and obtaining the reddish brown oily substance. Cooling to 20-30 deg.C to separate out white solid in the reddish brown oil, and filtering. The filtrate was concentrated under reduced pressure to give 59 g of 2- (2-chlorophenyl) oxirane (4), yield 93%.

Example 4: synthesis of 2- (2-chlorophenyl) oxirane (4)

To a 1L reaction flask was added 500 mL acetonitrile, 60g o-chlorobenzaldehyde, and the stirring was turned on. 96g of trimethylsulfonium iodide were charged into a reaction flask. Heating is started at a set temperature of 70-75 ℃, the internal temperature is increased to 50 +/-5 ℃, 20% potassium hydroxide aqueous solution is dripped into the reaction bottle, and the dripping speed is controlled to be 30-40 mL/min. After the dripping is finished, the temperature is maintained at 65-75 ℃ for continuous reaction for 3-3.5 h. No more than 0.6% of starting material remains as determined by HPLC. And after the reaction is finished, stopping heating, cooling to 25-30 ℃, and stopping stirring. And (4) carrying out suction filtration, collecting filtrate, transferring the filtrate into a reaction bottle, standing for 30min, separating liquid, and collecting an organic phase. Setting the water bath temperature at 45-60 ℃, the vacuum degree at 50-100mbar and the rotating speed at 60rmp, concentrating the organic phase by using a rotary evaporator under reduced pressure until no obvious liquid drops continuously drip out of the condensation pipe, and obtaining the reddish brown oily substance. Cooling to 20-30 deg.C to separate out white solid in the reddish brown oil, and filtering. The filtrate was concentrated under reduced pressure to give 57g of 2- (2-chlorophenyl) oxirane (4), yield 94%.

Example 5: synthesis of crude tulobuterol acetate (5)

66 mL of absolute ethanol was added to the 1L reaction flask, and stirring was turned on. 42g of 2- (2-chlorophenyl) oxirane (4) were added and 119g of tert-butylamine were transferred into the reaction flask. Heating is started, and the internal temperature is maintained at 65-70 ℃ for reaction for 16 h. Stopping heating, cooling to 25-30 ℃, adding the reaction solution into a rotary evaporator, performing desolventizing under reduced pressure at the water bath temperature of 45-60 ℃, the vacuum degree of 50-100mbar and the rotation speed of 60rmp, and evaporating ethanol and tert-butylamine. Concentrating until no obvious liquid drops continuously drip out of the condensing tube to obtain white solid.

279 mL of isopropyl acetate were weighed into a concentration flask, and approximately 2/3 of isopropyl acetate was aspirated into the flask and spun at 45-60 ℃ to disperse the concentrate uniformly and transferred to the reaction flask. The remaining approximately 1/3 g of isopropyl acetate, 24 mL of absolute ethanol were added to the reaction flask and dissolved with stirring. Acetic acid, 16g, was added and a white solid was produced. Heating, heating to 65-70 deg.C, stirring, and standing for 10 min. And (5) cooling, and keeping the internal temperature at 0-5 ℃ for 2 h. Filtering, and drying a filter cake for 2-4h by air blow at 40 +/-5 ℃ to obtain 72g of a tulobuterol acetate crude product (5) with the yield of 92%.

Example 6: synthesis of crude tulobuterol formate (5)

66 mL of absolute ethanol was added to the 1L reaction flask, and stirring was turned on. 42g of 2- (2-chlorophenyl) oxirane (4) were added and 119g of tert-butylamine were transferred into the reaction flask. Heating is started, and the internal temperature is maintained at 65-70 ℃ for reaction for 16 h. Stopping heating, cooling to 25-30 ℃, adding the reaction solution into a rotary evaporator, performing desolventizing under reduced pressure at the water bath temperature of 45-60 ℃, the vacuum degree of 50-100mbar and the rotation speed of 60rmp, and evaporating ethanol and tert-butylamine. Concentrating until no obvious liquid drops continuously drip out of the condensing tube to obtain white solid.

279 mL of isopropyl acetate were weighed into a concentration flask, and approximately 2/3 of isopropyl acetate was aspirated into the flask and spun at 45-60 ℃ to disperse the concentrate uniformly and transferred to the reaction flask. The remaining approximately 1/3 g of isopropyl acetate, 24 mL of absolute ethanol were added to the reaction flask and dissolved with stirring. 12g of formic acid were added and a white solid was produced. Heating, heating to 65-70 deg.C, stirring, and standing for 10 min. And (5) cooling, and keeping the internal temperature at 0-5 ℃ for 2 h. Filtering, and drying the filter cake by air blow for 2-4h at 40 +/-5 ℃ to obtain 70g of a tulobuterol formate crude product (5) with the yield of 94%.

Example 7: synthesis of crude tulobuterol oxalate (5)

66 mL of absolute ethanol was added to the 1L reaction flask, and stirring was turned on. 42g of 2- (2-chlorophenyl) oxirane (4) were added and 119g of tert-butylamine were transferred into the reaction flask. Heating is started, and the internal temperature is maintained at 65-70 ℃ for reaction for 16 h. Stopping heating, cooling to 25-30 ℃, adding the reaction solution into a rotary evaporator, performing desolventizing under reduced pressure at the water bath temperature of 45-60 ℃, the vacuum degree of 50-100mbar and the rotation speed of 60rmp, and evaporating ethanol and tert-butylamine. Concentrating until no obvious liquid drops continuously drip out of the condensing tube to obtain white solid.

279 mL of isopropyl acetate were weighed into a concentration flask, and approximately 2/3 of isopropyl acetate was aspirated into the flask and spun at 45-60 ℃ to disperse the concentrate uniformly and transferred to the reaction flask. The remaining approximately 1/3 g of isopropyl acetate, 24 mL of absolute ethanol were added to the reaction flask and dissolved with stirring. 24g of anhydrous oxalic acid was added and a white solid was produced. Heating, heating to 65-70 deg.C, stirring, and standing for 10 min. And (5) cooling, and keeping the internal temperature at 0-5 ℃ for 2 h. Filtering, and drying a filter cake by air blow for 2-4h at the temperature of 40 +/-5 ℃ to obtain 82g of a tulobuterol oxalate crude product (5), wherein the yield is 95%.

Example 8: synthesis of pure tulobuterol acetate (5)

199mL of isopropyl acetate and 35mL of absolute ethanol were added to a 1L reaction flask. Stirring was turned on and 72g of crude tulobuterol acetate (5) was added to the reaction flask. Heating to 65-70 deg.C to dissolve. Cooling and crystallizing, cooling the inner temperature to 0-5 ℃, and maintaining the crystallization for 2 hours. Filtering, and drying the filter cake by air blow at 40 +/-5 ℃ for 2-4h to obtain 69g of the tulobuterol acetate (5) pure product, wherein the yield is 95 percent, and the HPLC purity is 99.95 percent.

Example 9: synthesis of tulobuterol oxalate (5) pure product

199mL of isopropyl acetate and 45mL of isopropyl alcohol were added to a 1L reaction flask. Stirring was turned on and 70g of the crude tulobuterol oxalate (5) was added to the reaction flask. Heating to 65-70 deg.C to dissolve. Cooling and crystallizing, cooling the inner temperature to 0-5 ℃, and maintaining the crystallization for 2 hours. Filtering, and drying filter cakes by air blow for 2-4h at 40 +/-5 ℃ to obtain 67g of the tulobuterol oxalate (5) pure product, wherein the yield is 95 percent, and the HPLC purity is 99.95 percent.

Example 10: synthesis of pure tulobuterol

To a 1L reaction flask, 205mL of purified water was added, stirring was turned on, and 69g of tulobuterol acetate (5) neat was added. Heating to 30-40 deg.C, stirring to dissolve, and cooling to 20-30 deg.C. A 2M sodium hydroxide solution was added dropwise to the reaction flask to maintain the reaction system pH = 8-9. The reaction temperature is maintained at 20-30 ℃ and stirring is carried out for 20 minutes.

185 mL of isopropyl acetate was added to the reaction flask, stirred for 10 minutes, and allowed to stand for 30 minutes to separate. The aqueous phase was separated off. Then, 205mL of purified water was added to the reaction flask, and the mixture was stirred for 10 minutes, allowed to stand for 30 minutes to separate a water phase, and an isopropyl acetate layer was collected. Adding isopropyl acetate into a rotary evaporator in batches, wherein the water bath temperature is 45-60 ℃, the vacuum degree is 50-100mbar, and the rotating speed is 60rmp, concentrating until no obvious liquid drops continuously drip out of a condenser pipe, and obtaining a white solid. 111mL of n-heptane was added to the rotary evaporator and the rotation was started to disperse the white solid uniformly and filtered. Vacuum drying the filter cake at 30-45 deg.C 2Obtaining 54g of finished product tulobuterol after 4h, wherein the yield is 99 percent, and the HPLC purity is 99.98 percent;¹H NMR (400 MHz, DMSO-d ₆) δ 7.61 (dd, J = 7.7, 1.8 Hz, 1H), 7.35 (qd, J = 7.6, 1.4 Hz, 2H), 7.26 (td, J = 7.6, 1.8 Hz, 1H), 5.46 (brs, 0.5H), 4.89 (dd,J = 8.8, 3.0 Hz, 1H), 2.69 (dd, J = 11.4, 3.1 Hz, 1H), 2.46 (dd, J = 11.4, 8.7 Hz, 1H), 1.53 (brs, 0.5H), 1.02 (s, 9H)。

example 11: synthesis of pure tulobuterol

To a 1L reaction flask, 205mL of purified water was added, stirring was turned on, and 80g of the pure tulobuterol oxalate (5) was added. Heating to 30-40 deg.C, stirring to dissolve, and cooling to 20-30 deg.C. A 2M sodium hydroxide solution was added dropwise to the reaction flask to maintain the reaction system pH = 8-9. The reaction temperature is maintained at 20-30 ℃ and stirring is carried out for 20 minutes.

185 mL of isopropyl acetate was added to the reaction flask, stirred for 10 minutes, and allowed to stand for 30 minutes to separate. The aqueous phase was separated off. Then, 205mL of purified water was added to the reaction flask, and the mixture was stirred for 10 minutes, allowed to stand for 30 minutes to separate a water phase, and an isopropyl acetate layer was collected. Adding isopropyl acetate into a rotary evaporator in batches, wherein the water bath temperature is 45-60 ℃, the vacuum degree is 50-100mbar, and the rotating speed is 60rmp, concentrating until no obvious liquid drops continuously drip out of a condenser pipe, and obtaining a white solid. 111mL of cyclohexane was added to the rotary evaporator and the rotation was turned on to disperse the white solid uniformly and the mixture was filtered. And (3) drying the filter cake for 2-4h at 30-45 ℃ in vacuum to obtain 57g of finished tulobuterol, wherein the yield is 99% and the HPLC purity is 99.99%.