CN113717063B - Preparation and purification method of tulobuterol - Google Patents

Preparation and purification method of tulobuterol Download PDF

Info

Publication number
CN113717063B
CN113717063B CN202111000504.XA CN202111000504A CN113717063B CN 113717063 B CN113717063 B CN 113717063B CN 202111000504 A CN202111000504 A CN 202111000504A CN 113717063 B CN113717063 B CN 113717063B
Authority
CN
China
Prior art keywords
tulobuterol
iodide
reaction
trimethyl
isopropyl acetate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202111000504.XA
Other languages
Chinese (zh)
Other versions
CN113717063A (en
Inventor
陈龙
余晓磊
张宇
李文明
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beijing Tide Pharmaceutical Co Ltd
Original Assignee
Beijing Tide Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beijing Tide Pharmaceutical Co Ltd filed Critical Beijing Tide Pharmaceutical Co Ltd
Priority to CN202111000504.XA priority Critical patent/CN113717063B/en
Publication of CN113717063A publication Critical patent/CN113717063A/en
Application granted granted Critical
Publication of CN113717063B publication Critical patent/CN113717063B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention provides a preparation and purification method of tulobuterol, which solves the technical problems of potential safety hazard, complex post-treatment and the like existing in the existing method. The method uses cheap and easily available o-chlorobenzaldehyde as a raw material, and the high-purity tulobuterol raw material medicine 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 prospect.

Description

Preparation and purification method of tulobuterol
Technical Field
The invention relates to the field of chemical synthesis, in particular to a novel method for preparing synthetic tulobuterol by taking o-chlorobenzaldehyde as a raw material and a novel purification method.
Background
Tulobuterol (tulobuterol), a selective β2 receptor agonist developed by Abbot corporation of japan, was approved for sale as an anti-asthmatic agent in japan in 1981. In 1998, it was used to treat asthma and chronic obstructive disease (COPD), and is currently used as a patch for treating children with indications such as dyspnea caused by airway obstructive diseases such as bronchial asthma, acute bronchitis, chronic bronchitis, emphysema, etc. Tulobuterol, chemical name 1- (2-chlorophenyl) -2-t-butylaminoethanol, has the following chemical structure:
the method reported in the literature for synthesizing tolterodine mainly comprises the following steps:
synthetic route one (patent document Sho 54-151935):
in the synthesis method, benzene with high toxicity is used as a reaction solvent, bromine with strong irritation and corrosiveness is used, the harm to human bodies is large, and the treatment difficulty in environmental protection is large.
Synthetic route two (document CN110590569 a):
the bromination in the synthesis method is not easy to control, and the quality control is not facilitated in the production of raw materials; in addition, in the second step of reaction, sodium borohydride which is an explosive compound is used as a reducing agent, so that a great potential safety hazard exists.
Synthetic route three (document CN 110172028A):
although the synthetic method avoids the use of bromine, the intermediate 11 is easy to form hydrate, which is unfavorable for quality control in the production of bulk drugs; and the final step uses sodium borohydride which is an explosive compound, so that the potential safety hazard is high.
Synthetic route four (document CN105439875 a):
the first-step olefination reaction of the method needs to be completed at a high temperature of 180-210 ℃, has harsh reaction conditions and consumes large energy; in the second step, m-chloroperoxybenzoic acid (m-CPBA) is used as an oxidant, and the m-chloroperoxybenzoic acid is unstable and easy to explode, so that a great hidden danger exists in the aspect of safety.
Synthetic route five (document CN111205194 a):
in the synthesis method, although the Dibromohydantoin (DBH) which is low in cost, easy to obtain, safe and environment-friendly is adopted as the brominating reagent, the purification process of the final product adopts column chromatography, 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, complex 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, low-cost and easily-obtained raw materials, safe operation, high yield and suitability for industrial production.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the synthesis method of the invention comprises the following steps:
the invention provides a preparation and purification method of tulobuterol, which specifically comprises the following steps:
a: o-chlorobenzaldehyde (2) is taken as a starting material, and reacts with trimethyl iodide (3) in an aqueous reaction solvent to obtain 2- (2-chlorophenyl) ethylene oxide (4);
b:2- (2-chlorphenyl) ethylene oxide (4) reacts with tert-butylamine to obtain a crude tolterodine product;
c: salifying the crude tulobuterol product, and recrystallizing the crude tulobuterol product by a mixed solvent to obtain tulobuterol salt (5);
d: the tolterodine salt (5) is free to obtain the tolterodine (1).
The reaction solvent system used in the step a is one of toluene-water, methylene chloride-water, acetonitrile-water, dimethyl sulfoxide-water, tetrahydrofuran-water or a mixture thereof, preferably toluene/water.
The reaction solvent system toluene-water volume ratio employed in step a above is in the range of 5:1 to 10:1, in some embodiments 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 a is trimethyl sulfoxide iodide or trimethyl sulfonium iodide, preferably trimethyl sulfoxide iodide.
The molar ratio of o-chlorobenzaldehyde (2) to trimethyliodide (3) in reaction a above is from 1:2.5 to 1:1, preferably from 1:2 to 1:1.1, for example 1:2, 1:1.8, 1:1.5, 1:1.2, 1:1.1, the molar ratio of further o-chlorobenzaldehyde (2) to trimethylsulfoxide iodide (3) being from 1:2 to 1:1.1, in certain embodiments the molar ratio of o-chlorobenzaldehyde (2) to trimethylsulfoxide iodide (3) being 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 step 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 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, preferably acetic acid.
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, 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, preferably sodium hydroxide.
The extraction solvent used in the step d is one or more of methyl acetate, ethyl acetate, isopropyl acetate, methyl tertiary butyl ether and methylene dichloride, preferably isopropyl acetate.
The invention develops a new method for synthesizing and purifying tolterodine, the initial raw material o-chlorobenzaldehyde is cheap and easy to obtain, the technical operation process is simplified, the production efficiency is improved, and the use of strong-irritation and corrosive brominating reagents in the previous synthetic route is avoided. Meanwhile, the method obtains the tulobuterol salt with the purity of more than 99.8% by salifying treatment for the first time and by utilizing a mixed solvent recrystallization method, and finally obtains the tulobuterol with high purity. The method adopted by the invention has the advantages of simple reaction reagent, convenient use, mild reaction condition, no special reagent requirement, simple cutting reaction operation, easy post-treatment and high purity and high yield of the product.
Drawings
Figure 1 example 10 tolterodine X-ray powder diffraction pattern.
Detailed Description
The invention will be better understood from the following examples. However, it will be readily understood by those skilled in the art that the specific material ratios, process conditions and results thereof described in the examples are illustrative of the present invention and should not be construed as limiting the invention as detailed in the claims.
Example 1: synthesis of 2- (2-chlorophenyl) oxirane (4)
500. 500 mL toluene and 60g o-chlorobenzaldehyde were added to a 1L reaction flask, and stirring was started. 96g of trimethylsulfonium iodide was added to the reaction flask. Heating is started at the 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, maintaining the temperature of 65-75 ℃ and continuing to react for 3-3.5h. HPLC showed no more than 0.6% starting material remaining. And after the reaction is finished, stopping heating, cooling to 25-30 ℃, and stopping stirring. Suction filtering, collecting filtrate, transferring the filtrate into a reaction bottle, standing for 30min, separating liquid, and collecting organic phase. Setting the water bath temperature to be 45-60 ℃, the vacuum degree to be 50-100mbar, the rotating speed to be 60rmp, and concentrating the organic phase under reduced pressure by using a rotary evaporator until no obvious liquid drops continuously drop out from a condensing tube, thereby obtaining the reddish brown oily substance. Cooling to 20-30deg.C, precipitating white solid in the reddish brown oily substance, and suction filtering. The filtrate was concentrated under reduced pressure to give 2- (2-chlorophenyl) oxirane (4) 58 g in 95% yield.
Example 2: synthesis of 2- (2-chlorophenyl) oxirane (4)
500. 500 mL toluene and 60g o-chlorobenzaldehyde were added to a 1L reaction flask, and stirring was started. 96g of trimethylsulfoxide iodide and 18g of tetrabutylammonium iodide were sequentially added to the reaction flask. Heating is started at the set temperature of 70-75 ℃, the internal temperature is increased to 50+/-5 ℃, 20% sodium hydroxide aqueous solution is dripped into a reaction bottle, and the dripping speed is controlled to be 30-40 mL/min. After the dripping, maintaining the temperature of 65-75 ℃ and continuing to react for 3-3.5h. HPLC showed no more than 0.6% starting material remaining. And after the reaction is finished, stopping heating, cooling to 25-30 ℃, and stopping stirring. Suction filtering, collecting filtrate, transferring the filtrate into a reaction bottle, standing for 30min, separating liquid, and collecting organic phase. Setting the water bath temperature to be 45-60 ℃, the vacuum degree to be 50-100mbar, the rotating speed to be 60rmp, and concentrating the organic phase under reduced pressure by using a rotary evaporator until no obvious liquid drops continuously drop out from a condensing tube, thereby obtaining the reddish brown oily substance. Cooling to 20-30deg.C, precipitating white solid in the reddish brown oily substance, and suction filtering. The filtrate was concentrated under reduced pressure to give 2- (2-chlorophenyl) oxirane (4) 59 g in 97% yield.
Example 3: synthesis of 2- (2-chlorophenyl) oxirane (4)
To a 1L reaction flask was added 500 mL methylene chloride and 60g o-chlorobenzaldehyde, and stirring was started. 96g of trimethylsulfonium iodide and 4.5g of 1, 3-bis [3, 5-bis (trifluoromethyl) phenyl ] urea were successively added to the reaction flask. And (3) dropwise adding 50% sodium hydroxide aqueous solution into the reaction bottle, and controlling the dropping speed to be 30-40 mL/min. After the completion of the addition, the mixture was reacted at room temperature overnight. HPLC showed no more than 0.6% starting material remaining. And after the reaction is finished, stopping heating, cooling to 25-30 ℃, and stopping stirring. Suction filtering, collecting filtrate, transferring the filtrate into a reaction bottle, standing for 30min, separating liquid, and collecting organic phase. Setting the water bath temperature to be 45-60 ℃, the vacuum degree to be 50-100mbar, the rotating speed to be 60rmp, and concentrating the organic phase under reduced pressure by using a rotary evaporator until no obvious liquid drops continuously drop out from a condensing tube, thereby obtaining the reddish brown oily substance. Cooling to 20-30deg.C, precipitating white solid in the reddish brown oily substance, and suction filtering. The filtrate was concentrated under reduced pressure to give 2- (2-chlorophenyl) oxirane (4) 59 g in 93% yield.
Example 4: synthesis of 2- (2-chlorophenyl) oxirane (4)
500 mL acetonitrile and 60g o-chlorobenzaldehyde were added to a 1L reaction flask, and stirring was started. 96g of trimethylsulfonium iodide was added to the reaction flask. Heating is started at the 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, maintaining the temperature of 65-75 ℃ and continuing to react for 3-3.5h. HPLC showed no more than 0.6% starting material remaining. And after the reaction is finished, stopping heating, cooling to 25-30 ℃, and stopping stirring. Suction filtering, collecting filtrate, transferring the filtrate into a reaction bottle, standing for 30min, separating liquid, and collecting organic phase. Setting the water bath temperature to be 45-60 ℃, the vacuum degree to be 50-100mbar, the rotating speed to be 60rmp, and concentrating the organic phase under reduced pressure by using a rotary evaporator until no obvious liquid drops continuously drop out from a condensing tube, thereby obtaining the reddish brown oily substance. Cooling to 20-30deg.C, precipitating white solid in the reddish brown oily substance, and suction filtering. The filtrate was concentrated under reduced pressure to give 2- (2-chlorophenyl) oxirane (4) 57g in 94% yield.
Example 5: synthesis of crude tolterodine acetate (5)
Absolute ethanol 66, mL was added to a 1L reaction flask and stirring was turned on. 42g of 2- (2-chlorophenyl) oxirane (4) were added and 119g of t-butylamine were transferred to a reaction flask. Heating is started, and the internal temperature is maintained at 65-70 ℃ for reaction for 16h. Stopping heating, cooling to 25-30 ℃, adding the reaction liquid into a rotary evaporator when the temperature is reduced to 25-30 ℃, carrying out water bath at 45-60 ℃ and vacuum degree of 50-100mbar, decompressing and desolventizing at the rotating speed of 60rmp, and evaporating to remove ethanol and tert-butylamine. Concentrating until no obvious liquid drops continuously drop out at the condensing tube to obtain white solid.
The 279 mL isopropyl acetate is weighed, the concentrate is sucked into a bottle for concentration, the concentrate is rotated at 45-60 ℃ and evenly dispersed, and the concentrate is transferred to a reaction bottle. The remaining approximately 1/3 isopropyl acetate and 24 mL absolute ethanol were added to the reaction flask and dissolved with stirring. 16g of acetic acid was added, resulting in a white solid. Heating is started, the temperature is raised to 65-70 ℃ and the solution is stirred and kept for 10 minutes. Cooling, and keeping the internal temperature to be 0-5 ℃ for 2 hours. Filtering, and drying the filter cake by blowing at 40+/-5 ℃ for 2-4 hours to obtain 72g of crude tulobuterol acetate (5) with the yield of 92%.
Example 6: synthesis of crude tulobuterol formate (5)
Absolute ethanol 66, mL was added to a 1L reaction flask and stirring was turned on. 42g of 2- (2-chlorophenyl) oxirane (4) were added and 119g of t-butylamine were transferred to a reaction flask. Heating is started, and the internal temperature is maintained at 65-70 ℃ for reaction for 16h. Stopping heating, cooling to 25-30 ℃, adding the reaction liquid into a rotary evaporator when the temperature is reduced to 25-30 ℃, carrying out water bath at 45-60 ℃ and vacuum degree of 50-100mbar, decompressing and desolventizing at the rotating speed of 60rmp, and evaporating to remove ethanol and tert-butylamine. Concentrating until no obvious liquid drops continuously drop out at the condensing tube to obtain white solid.
The 279 mL isopropyl acetate is weighed, the concentrate is sucked into a bottle for concentration, the concentrate is rotated at 45-60 ℃ and evenly dispersed, and the concentrate is transferred to a reaction bottle. The remaining approximately 1/3 isopropyl acetate and 24 mL absolute ethanol were added to the reaction flask and dissolved with stirring. 12g of formic acid were added and a white solid developed. Heating is started, the temperature is raised to 65-70 ℃ and the solution is stirred and kept for 10 minutes. Cooling, and keeping the internal temperature to be 0-5 ℃ for 2 hours. Filtering, and drying the filter cake by blowing at 40+/-5 ℃ for 2-4 hours to obtain 70g of crude tulobuterol formate (5) with the yield of 94%.
Example 7: synthesis of crude tulobuterol oxalate (5)
Absolute ethanol 66, mL was added to a 1L reaction flask and stirring was turned on. 42g of 2- (2-chlorophenyl) oxirane (4) were added and 119g of t-butylamine were transferred to a reaction flask. Heating is started, and the internal temperature is maintained at 65-70 ℃ for reaction for 16h. Stopping heating, cooling to 25-30 ℃, adding the reaction liquid into a rotary evaporator when the temperature is reduced to 25-30 ℃, carrying out water bath at 45-60 ℃ and vacuum degree of 50-100mbar, decompressing and desolventizing at the rotating speed of 60rmp, and evaporating to remove ethanol and tert-butylamine. Concentrating until no obvious liquid drops continuously drop out at the condensing tube to obtain white solid.
The 279 mL isopropyl acetate is weighed, the concentrate is sucked into a bottle for concentration, the concentrate is rotated at 45-60 ℃ and evenly dispersed, and the concentrate is transferred to a reaction bottle. The remaining approximately 1/3 isopropyl acetate and 24 mL absolute ethanol were added to the reaction flask and dissolved with stirring. 24g of anhydrous oxalic acid was added, resulting in a white solid. Heating is started, the temperature is raised to 65-70 ℃ and the solution is stirred and kept for 10 minutes. Cooling, and keeping the internal temperature to be 0-5 ℃ for 2 hours. Filtering, and drying the filter cake by blowing at 40+/-5 ℃ for 2-4 hours to obtain 82g of crude tulobuterol oxalate (5) with the yield of 95%.
Example 8: synthesis of pure tulobuterol acetate (5)
To a 1L reaction flask was added 199mL of isopropyl acetate and 35mL of absolute ethanol. The stirring was turned on and 72g of crude tulobuterol acetate (5) was added to the reaction flask. Heating to 65-70deg.C. Cooling to crystallize, cooling to 0-5 deg.c, and maintaining crystallization for 2 hr. Filtering, and drying the filter cake by blowing at 40+/-5 ℃ for 2-4 hours to obtain 69g of pure tulobuterol acetate (5), wherein the yield is 95% and the HPLC purity is 99.95%.
Example 9: synthesis of pure tulobuterol oxalate (5)
To a 1L reaction flask was added 199mL of isopropyl acetate and 45mL of isopropyl alcohol. The stirring was started and 70g of crude tulobuterol oxalate (5) was added to the reaction flask. Heating to 65-70deg.C. Cooling to crystallize, cooling to 0-5 deg.c, and maintaining crystallization for 2 hr. Filtering, and drying the filter cake by blowing at 40+/-5 ℃ for 2-4 hours to obtain 67g of pure tulobuterol oxalate (5) with the yield of 95% and the HPLC purity of 99.95%.
Example 10: synthesis of tolote Luo Chunpin
To a 1L reaction flask was added purified water 205 and mL, and 69g of tulobuterol acetate (5) as a pure product was added with stirring. Heating to 30-40deg.C, stirring for dissolving, and cooling to 20-30deg.C. 2M sodium hydroxide solution was added dropwise to the reaction flask, and the pH of the reaction system was maintained at 8-9. The reaction temperature is maintained at 20-30 ℃ and stirred for 20 minutes.
185 mL isopropyl acetate was added to the reaction flask, stirred for 10 minutes, and allowed to stand for 30 minutes for delamination. The aqueous phase was separated. 205mL of purified water was added to the flask, stirred for 10 minutes, allowed to stand for 30 minutes to separate the aqueous phase, and the isopropyl acetate layer was collected. The isopropyl acetate is added into a rotary evaporator in batches, the water bath temperature is 45-60 ℃, the vacuum degree is 50-100mbar, the rotating speed is 60rmp, and the isopropyl acetate is concentrated until no obvious liquid drops continuously drop out from a condensing tube, so that white solid is obtained. 111mL of n-heptane was added to the rotary evaporator and the rotation was started to disperse the white solid uniformly and filter. Vacuum drying the filter cake at 30-45 ℃ for 2-4h to obtain 54g of finished tulobuterol, wherein the yield is 99% and the HPLC purity is 99.98%; 1 H 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 tolote Luo Chunpin
To a 1L reaction flask was added purified water 205 and mL, and 80g of purified tulobuterol oxalate (5) was added with stirring. Heating to 30-40deg.C, stirring for dissolving, and cooling to 20-30deg.C. 2M sodium hydroxide solution was added dropwise to the reaction flask, and the pH of the reaction system was maintained at 8-9. The reaction temperature is maintained at 20-30 ℃ and stirred for 20 minutes.
185 mL isopropyl acetate was added to the reaction flask, stirred for 10 minutes, and allowed to stand for 30 minutes for delamination. The aqueous phase was separated. 205mL of purified water was added to the flask, stirred for 10 minutes, allowed to stand for 30 minutes to separate the aqueous phase, and the isopropyl acetate layer was collected. The isopropyl acetate is added into a rotary evaporator in batches, the water bath temperature is 45-60 ℃, the vacuum degree is 50-100mbar, the rotating speed is 60rmp, and the isopropyl acetate is concentrated until no obvious liquid drops continuously drop out from a condensing tube, so that white solid is obtained. 111mL of cyclohexane was added to the rotary evaporator and the mixture was turned on to disperse the white solid uniformly and filtered. The filter cake is dried in vacuum for 2-4 hours at 30-45 ℃ to obtain 57g of finished tulobuterol with 99% yield and 99.99% purity by HPLC.

Claims (7)

1. A method for preparing and purifying tulobuterol, comprising the steps of:
a: o-chlorobenzaldehyde (2) is taken as a starting material and reacts with trimethyl iodide (3) in toluene-water reaction solvent with the volume ratio of 5:1-10:1, and the mol ratio of the O-chlorobenzaldehyde (2) to the trimethyl iodide (3) is 1:2-1:1.1, so as to obtain 2- (2-chlorophenyl) ethylene oxide (4);
b:2- (2-chlorphenyl) ethylene oxide (4) reacts with tert-butylamine to obtain a crude tolterodine product;
c: reacting the crude tulobuterol product with acid in isopropyl acetate-ethanol solvent to form salt, and recrystallizing the salt by using a mixed solvent to obtain tulobuterol salt (5); wherein the acid is selected from acetic acid or oxalic acid, and the mixed solvent is selected from isopropyl acetate-ethanol or isopropyl acetate-isopropanol;
d: the tolterodine salt (5) is free in sodium hydroxide solution and extracted by isopropyl acetate to obtain the tolterodine (1).
2. The process according to claim 1, wherein the trimethyl iodide (3) in the step a is trimethyl sulfoxide iodide or trimethyl sulfonium iodide.
3. The process according to claim 1, wherein the trimethyl iodide (3) in step a is trimethyl sulfoxide iodide.
4. The process according to claim 1, wherein the reaction solvent in the step b is one or more of methanol, ethanol, isopropanol, acetone, acetonitrile and tetrahydrofuran.
5. The process of claim 1 wherein the reaction solvent in step b is ethanol.
6. The process according to claim 1, wherein the molar ratio of 2- (2-chlorophenyl) oxirane (4) to t-butylamine in step b is from 1:10 to 1:5.
7. The process of claim 1 wherein the acid used in step c is acetic acid.
CN202111000504.XA 2021-08-30 2021-08-30 Preparation and purification method of tulobuterol Active CN113717063B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202111000504.XA CN113717063B (en) 2021-08-30 2021-08-30 Preparation and purification method of tulobuterol

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202111000504.XA CN113717063B (en) 2021-08-30 2021-08-30 Preparation and purification method of tulobuterol

Publications (2)

Publication Number Publication Date
CN113717063A CN113717063A (en) 2021-11-30
CN113717063B true CN113717063B (en) 2023-08-08

Family

ID=78678796

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202111000504.XA Active CN113717063B (en) 2021-08-30 2021-08-30 Preparation and purification method of tulobuterol

Country Status (1)

Country Link
CN (1) CN113717063B (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116082133A (en) * 2021-11-08 2023-05-09 上海医药工业研究院 Synthetic method of tulobuterol
CN117129595B (en) * 2023-08-25 2024-05-10 正大制药（青岛）有限公司 Analysis method of tolote Luo Zhong related substances

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110590569A (en) * 2019-10-08 2019-12-20 杭州百诚医药科技股份有限公司 Method for synthesizing tulobuterol

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0827076A (en) * 1994-07-15 1996-01-30 Ohara Yakuhin Kogyo Kk Tulobuterol and method for producing its acid adduct

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110590569A (en) * 2019-10-08 2019-12-20 杭州百诚医药科技股份有限公司 Method for synthesizing tulobuterol

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Synthesis of the β2-Agonist Tulobuterol and Its Metabolite 4-Hydroxytulobuterol;Glushkova, M. A. 等;《Russian Journal of Organic Chemistry》;第56卷(第3期);第391页图解1和第392页实验部分 *

Also Published As

Publication number Publication date
CN113717063A (en) 2021-11-30

Similar Documents

Publication Publication Date Title
CN113717063B (en) Preparation and purification method of tulobuterol
CN101307015A (en) Process for preparing cilastatin sodium
CN114380879A (en) Method for preparing progesterone intermediate and progesterone by using microchannel reactor
CN102603843B (en) Preparation method of dexamethasone intermediate
CN1356903A (en) Synthesis and crystallization of piperazine ring-contg. compounds
EP3728167B1 (en) A process for the preparation of crisaborole
CN106279207A (en) A kind of synthetic method of cefdinir
CN114195844B (en) Preparation method of dehydroepiandrosterone
CN115557928A (en) Synthetic method of 2-chlorothiophene-5-formic acid
CN111269149B (en) Production process of 5- (3,3-dimethylguanidino) -2-oxopentanoic acid
CN112645945B (en) Preparation method of Wumei ammonium bromide intermediate
CN114671859A (en) Preparation method of rosuvastatin calcium and intermediate thereof
JP6124562B2 (en) 4 '-[[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid ammonium salt crystal
CN112250586A (en) Preparation method of terbutaline sulfate and B crystal form thereof
CN112279817A (en) Preparation method of high-purity pramipexole dihydrochloride
CN113461508A (en) Preparation method of alpha-ketophenylalanine calcium
CN109956958B (en) Synthesis method of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid
CN106892879B (en) Synthetic method of anti-gout drug febuxostat
CN110845354B (en) Preparation method of cilastatin sodium intermediate
CN101020626A (en) Prepn process of high-purity optically active (-)-or(+)-gossypol
CN115043816B (en) Chiral resolution method of selenium octanoic acid
CN114315588B (en) Preparation method of o-nitrobenzaldehyde
CN113788750B (en) Preparation method of sodium phenoxyacetate
CN114957288B (en) Synthesis method of tetramisole hydrochloride
CN111100093B (en) Cytoxazone and preparation method of intermediate thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant