CN109678701B - Preparation method of vilanterol intermediate - Google Patents
Preparation method of vilanterol intermediate Download PDFInfo
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- CN109678701B CN109678701B CN201910056501.4A CN201910056501A CN109678701B CN 109678701 B CN109678701 B CN 109678701B CN 201910056501 A CN201910056501 A CN 201910056501A CN 109678701 B CN109678701 B CN 109678701B
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/373—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in doubly bound form
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Abstract
The invention discloses a preparation method of a vilanterol intermediate, belonging to the field of drug synthesis. The method takes 4-hydroxymandelic acid as a raw material to obtain 4-hydroxy-3-formylmandelic acid through formylation reaction, and then reduces aldehyde group to obtain 3-hydroxymethyl-4-hydroxymandelic acid. The invention provides a new intermediate of vilanterol, which has the advantages of easily obtained raw materials, mild synthesis reaction conditions and simple operation, and the synthesis of vilanterol from the intermediate greatly shortens the synthesis route, reduces the production cost and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of medicine synthesis, and relates to a preparation method of an anti-asthma medicine vilanterol intermediate 3-hydroxymethyl-4-hydroxymandelic acid.
Background
Vilanterol trihydronate is a long-acting beta developed by Kulanin Schker (GSK)2A receptor agonist. The compound preparation of the compound preparation and the fluticasone furoate and the compound preparation of the umeclidinium bromide are approved by FDA respectively in 5 months and 12 months in 2013, and are used for treating obstructive pulmonary disease and asthma. Vilanterol has a molecular weight of 486.4, a molecular formula of C24H33Cl2NO5, CAS: 503068-34-6, the Chinese name: chemical name: (R) -4- [2- [ [6- [ (2, 6-dichlorobenzyl) oxy ] phenyl]-ethoxy radical]Ethyl radical]Amino group]-1-hydroxyethyl group]-2-hydroxyethyl]-2-hydroxymethylphenol having the chemical formula shown in the figure:
world patent WO2003024439 relates to a method for synthesizing vilanterol, and the specific synthetic route is as follows:
in the route, vilanterol can be synthesized only through reaction of more than ten steps, wherein two protecting groups are needed, and the reaction steps are increased by protecting and deprotecting functional groups, so that the total yield and the atom utilization rate are reduced. And the construction of the chiral center is difficult, 6 steps of reaction are needed, and the chiral purity meets the quality requirement with certain difficulty. Therefore, a process with short synthetic route, high yield and good quality needs to be designed.
3-hydroxymethyl-4-hydroxymandelic acid is an important intermediate for synthesizing vilanterol, and the vilanterol can be obtained by chiral resolution, condensation with amine and reduction of amido bond. The specific synthetic route is as follows:
the method takes 3-hydroxymethyl-4-hydroxymandelic acid as a raw material to obtain the vilanterol bulk drug through three steps of reactions, greatly shortens the synthesis steps, has relatively high reaction yield in each step, avoids the protection and deprotection of a protective agent, and improves the atom utilization rate. Therefore, 3-hydroxymethyl-4-hydroxymandelic acid is an important intermediate for synthesizing vilanterol.
According to the reports of domestic and foreign documents, no synthetic route of 3-hydroxymethyl-4-hydroxymandelic acid exists at present, so that the synthesis of 3-hydroxymethyl-4-hydroxymandelic acid is very important, the synthetic steps of vilanterol can be reduced, and the production cost is greatly reduced.
Disclosure of Invention
The invention provides a preparation method of an important intermediate 3-hydroxymethyl-4-hydroxymandelic acid of vilanterol aiming at the defects of the prior art for synthesizing vilanterol.
The invention firstly designs a method for synthesizing 3-hydroxymethyl-4-hydroxymandelic acid by adopting a chloroform/liquid caustic soda system, and the specific synthetic route is as follows:
unfortunately, the synthetic route of the design is not successful, so that the invention takes 4-hydroxymandelic acid as a raw material to obtain 4-hydroxy-3-formylmandelic acid through formylation reaction, and then aldehyde group is reduced to obtain 3-hydroxymethyl-4-hydroxymandelic acid. The specific synthetic route is as follows:
s1, formylation: adding 4-hydroxymandelic acid and urotropine into a three-necked bottle, adding a solvent, reacting for 4h at 70-90 ℃, after TLC (thin layer chromatography) controlled reaction is finished, cooling to room temperature, concentrating the solvent in vacuum, adding ethyl acetate and water into the residue, stirring for half an hour, standing for layering, drying an organic phase, concentrating to obtain a white solid, and recrystallizing with ethanol to obtain 4-hydroxy-3-formylmandelic acid;
s2, reduction reaction: adding 4-hydroxy-3-formyl mandelic acid into a three-necked bottle, adding a solvent, cooling to 5-10 ℃, adding a small amount of reducing agent in batches, and controlling the reaction to be finished by TLC (thin-layer chromatography). Adding water, cooling the system to 0-5 ℃, adjusting the pH value to 2-3 with concentrated hydrochloric acid, concentrating, extracting with ethyl acetate, combining organic phases, sequentially washing with saturated saline water and water, drying with anhydrous magnesium sulfate, filtering, concentrating to obtain a white solid, and recrystallizing with toluene to obtain the 3-hydroxymethyl-4-hydroxymandelic acid.
In step S1, the formylation reagent is urotropin, wherein the molar ratio of 4-hydroxymandelic acid to urotropin is 1:1-1.5, and the preferred molar ratio is 1: 1.1; the formylation solvent is one of trifluoroacetic acid, glacial acetic acid, trichloroacetic acid, polyphosphoric acid and trifluoromethanesulfonic acid, and preferably trifluoroacetic acid; the reaction temperature is 70-90 ℃.
In step S2, the reducing agent is one of sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, potassium borohydride, and lithium borohydride, preferably sodium borohydride; the molar ratio of the 4-hydroxy-3-formylmandelic acid to the reducing agent is 1:1-1.5, preferably 1: 1.1; the solvent is one of methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol and tert-butanol, preferably ethanol; the reaction temperature is 0-5 ℃.
The invention has the beneficial effects that:
the method takes 4-hydroxymandelic acid as a raw material to obtain 4-hydroxy-3-formylmandelic acid through formylation reaction, and then reduces aldehyde group to obtain 3-hydroxymethyl-4-hydroxymandelic acid. The invention synthesizes a new intermediate of vilanterol, the raw materials are easy to obtain, the reaction condition is mild, the operation is simple, the synthesis of vilanterol by the intermediate greatly shortens the synthesis route, reduces the production cost, and is suitable for industrial production.
Detailed Description
Example 1:
preparation of 4-hydroxy-3-formylmandelic acid:
adding 4-hydroxymandelic acid (50.4g) and urotropine (46.2g) into a 500mL three-necked flask, adding trifluoroacetic acid (250mL), heating to 85 ℃ for reaction for 4h, controlling the reaction in TLC, cooling to room temperature, concentrating the solvent in vacuum, adding water (250mL) into the residue, extracting with ethyl acetate (150X 2 mL), combining organic phases, drying, filtering, concentrating to obtain a crude product, adding the crude product into 150mL of ethanol, refluxing for 1 hour, cooling for crystallization, filtering, washing a filter cake with 50mL of ethanol, and drying to obtain 43g of a white solid with the yield of 73%.
3-hydroxymethyl-4-hydroxymandelic acid
Adding 4-hydroxy-3-formylmandelic acid (39.2g) into a 500mL three-necked flask, adding methanol (200mL), cooling to 8 ℃, adding sodium borohydride (7.5g) in small portions within 30 minutes, controlling the reaction in TLC, cooling the system to 0-5 ℃, adding water (200mL), adjusting the pH to 2-3 with concentrated hydrochloric acid, extracting with ethyl acetate of 100X 2mL, combining organic phases, washing with 100mL of saturated saline solution and 100mL of water in sequence, drying with anhydrous magnesium sulfate, filtering, concentrating to obtain a white solid, recrystallizing the crude product with toluene to obtain 37g, wherein the yield is 93%.
Example 2:
adding 4-hydroxy-3-formylmandelic acid (20g), 10mL of liquid alkali (mass fraction 40%) and chloroform (30g) into a 500mL three-necked flask, heating to 75 ℃ for reaction for 3 hours, controlling the temperature of the liquid phase to be unreacted, continuing heating to 85 ℃ for reaction for 2 hours, and controlling the temperature of the liquid phase to be unreacted.
Although the present invention has been described with reference to the specific embodiments, it should be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.
Claims (5)
1. A preparation method of a vilanterol intermediate 3-hydroxymethyl-4-hydroxymandelic acid comprises the following specific synthetic route:
s1, formylating 4-hydroxymandelic acid with a formylation reagent in a solvent medium to generate 4-hydroxy-3-formylmandelic acid, wherein the formylation reagent is urotropin, and the molar ratio of the 4-hydroxymandelic acid to the formylation reagent is 1:1.1, formylation reaction time is 4 h;
s2: 4-hydroxy-3-formyl mandelic acid and a reducing agent are subjected to reduction reaction in a solvent medium to obtain the 3-hydroxymethyl-4-mandelic acid, wherein the reducing agent is sodium borohydride, and the reduction reaction temperature is 8 ℃.
2. The method for preparing vilanterol intermediate 3-hydroxymethyl-4-hydroxymandelic acid according to claim 1, wherein the solvent medium in step S1 is one of trifluoroacetic acid, glacial acetic acid, trichloroacetic acid, polyphosphoric acid and trifluoromethanesulfonic acid.
3. The method for preparing vilanterol intermediate 3-hydroxymethyl-4-hydroxymandelic acid according to claim 1, wherein the solvent medium in step S2 is one of methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, and tert-butanol.
4. The process for producing vilanterol intermediate 4-hydroxy-3-formylmandelic acid according to claim 1, wherein the reaction temperature in the step S1 is 70 to 90 ℃.
5. The process for preparing 3-hydroxymethyl-4-hydroxymandelic acid as an intermediate of vilanterol according to claim 1, wherein the molar ratio of 4-hydroxy-3-formylmandelic acid to the reducing agent in step S2 is 1:1 to 1.5.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES459339A1 (en) * | 1977-05-31 | 1979-06-01 | Calzada & Co | Alternative procedure, for the synthesis of 2-tercbutilamino-1- (4-hydroxy-3-hydroxymethyl) feniletanol. (Machine-translation by Google Translate, not legally binding) |
| WO2013058824A1 (en) * | 2011-04-07 | 2013-04-25 | Cornell University | Monomers capable of dimerizing in an aqueous solution, and methods of using same |
| CN105585547A (en) * | 2016-03-09 | 2016-05-18 | 中国科学院广州生物医药与健康研究院 | 4-sulfur pentafluoride phenol compound, preparing method and preparing method for sulfur pentafluoride substituted benzopyran compound |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES459339A1 (en) * | 1977-05-31 | 1979-06-01 | Calzada & Co | Alternative procedure, for the synthesis of 2-tercbutilamino-1- (4-hydroxy-3-hydroxymethyl) feniletanol. (Machine-translation by Google Translate, not legally binding) |
| WO2013058824A1 (en) * | 2011-04-07 | 2013-04-25 | Cornell University | Monomers capable of dimerizing in an aqueous solution, and methods of using same |
| CN105585547A (en) * | 2016-03-09 | 2016-05-18 | 中国科学院广州生物医药与健康研究院 | 4-sulfur pentafluoride phenol compound, preparing method and preparing method for sulfur pentafluoride substituted benzopyran compound |
Non-Patent Citations (1)
| Title |
|---|
| Membrane Interaction and Protein Kinase C‑C1 Domain Binding Properties of 4‑Hydroxy-3-(hydroxymethyl) Phenyl Ester Analogues;Dipjyoti Talukdar等;《J. Phys. Chem. B》;20141231;第118卷;第7541-7553页 * |
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