CN104744270A - New synthesis method of long-acting beta2 receptor agonist vilanterol - Google Patents
New synthesis method of long-acting beta2 receptor agonist vilanterol Download PDFInfo
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- CN104744270A CN104744270A CN201310729837.5A CN201310729837A CN104744270A CN 104744270 A CN104744270 A CN 104744270A CN 201310729837 A CN201310729837 A CN 201310729837A CN 104744270 A CN104744270 A CN 104744270A
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Abstract
The present invention discloses a new synthesis method of a long-acting beta2 receptor agonist vilanterol, and provides a completely-new synthesis method of a long-acting beta2 receptor agonist vilanterol. According to the method, the idea that the Schiff base is firstly produced and then reduction is performed is adopted to effectively avoid disadvantages of harsh reaction conditions (such as anhydrous reaction), expensive reagents and the like of the existing process, and the method has characteristics of easily available raw materials, short route, high yield, and market competitiveness.
Description
Technical field
The invention belongs to pharmacy synthesis technology field, specifically relate to a kind of new synthetic method of synthesis Wei Lanteluo (Vilanterol).
Background technology
Chronic obstructive pulmonary disease (Chronic obstructive pulmonary disease, COPD) not exclusively limited with air-flow and increase the weight of as feature in Progressive symmetric erythrokeratodermia, become the fifth-largest cause of disease causing death, and actively controlled symptom, improve pulmonary function to be the important goal that this disease is treated.At present, the medicine being used for alleviating COPD patient symptom is mainly the Long-effect β_2 reactant excitomotor agent such as the formoterol that needs 2 medications every day and Salmeterol.
Vilanterol is a kind of long-acting beta 2 adrenergic receptor agonists (LABA), and in vitro tests shows, and its functionally selective is similar to Salmeterol.Beta 2 adrenoreceptor excitomotor (comprising Vilanterol) pharmacological action is at least partly because of adenylate cyclase in its irritation cell, and this enzyme can promote that adenosine triphosphate (ATP) is converted into cyclic amp (cAMP).CAMP raises the release of can relax bronchial smooth muscle the middle immediate hypersensitivity medium of T suppression cell (especially mastocyte).
Compound dry powder inhalation Breo Ellipta(adrenocortical hormone fluticasone 100ug+Long-effect β_2 reactant excitomotor agent Wei Lanteluo 25ug that U.S. FDA is developed jointly in mid-May, 2013 approval by GlaxoSmithKline PLC and Theravance two company), every day 1 time, for chronic obstructive pulmonary disease (COPD), comprises bronchitis and emophysematous long term maintenance therapy.Getting permission of this Breo Ellipta is some the clinical trial positive findingses based on relating to patients of severe COPD in 7700.Wherein, the small-scale test display carried out in 410 patients, compared with placebo, 1 forced expiratory volume in the second (FEV1) of this product treatment group experimenter improves 173 ~ 209ml.Other tests then show, and compare with placebo, in this product treatment group COPD serious attack number of times reduce 20% experimenter's ratio significantly higher, though and the ratio reducing 35% increases, there was no significant difference.
The mechanism of action high due to Wei Lanteluo (Vilanterol) selectivity and preferably curative effect and less side effect, thus have good market outlook.
Following formula is the structure of Wei Lanteluo (Vilanterol).
The synthetic route of patent WO2003024439 report is as follows.
Wei Lanteluo synthetic route
This route be compound 4 with compound 5 under the effect of sodium hydride, generate compound 6, then remove formyl radical with expensive trimethyl silicane potassium alcoholate, in acetic acid, finally remove propylidene protection obtain Wei Lanteluo.The reagent such as sodium hydride, trimethyl silicane potassium alcoholate is employed, reaction needed anhydrous response in this technique.And the preparation of starting compound 5 is very loaded down with trivial details, with parahydroxyacet-ophenone or the bromo-phenyl aldehyde of 2-hydroxyl-4-for prepared by raw material, need could obtain through the reaction of 7-8 step, not only step is long, and yield is low, wherein need to use bromine, butyllithium, sodium hydride etc. to be not suitable for the reagent of industrialization amplification.These industry all constraining Wei Lanteluo are amplified.Therefore be necessary that finding a kind of raw material is easy to get, operating procedure synthesis technique that is simple, that easily amplify.
Summary of the invention
The object of the invention is to invent a kind of brand-new Wei Lanteluo (Vilanterol) synthetic method.
Specifically, invention provides a kind of novel process of synthesis Wei Lanteluo (Vilanterol).
Synthetic route of the present invention is as follows:
Wherein compound 1 is Wei Lanteluo (Vilanterol), and concrete operation step is as follows:
1) compound 4 and compound 3 react, and obtain compound 2.
The method that wherein compound 3 can be provided by document Tetrahedron:Asymmetry 22 (2011) 1395 – 1399 obtains. and compound 5 of comparing, compound 3 is more easily prepared, and cost is lower.The method that compound 4 can be provided by WO200302443 obtains.L in compound 4 is general leavings group, as chlorine, bromine, iodine, alkyl sulfonic ester, aromatic base sulphonate etc., considers, the preferred bromine atoms of the present invention from economy and reactive behavior.Specific to the present invention, be applicable to the solvent of this reaction and have amide solvent if DMF etc., sulfone class or sulfoxide type solvents are if DMSO etc., lower alcohol, hydrochloric ether are if methylene dichloride, chloroform etc., ether solvent are if tetrahydrofuran (THF), dioxane etc., acetonitrile, esters solvent are if ethyl acetate etc., arene are as the mixture etc. of the mixture of toluene, chlorobenzene etc. or several solvent, aprotic polar solvent and water, consider from economy and speed of reaction, prioritizing selection DMF of the present invention.The alkali being applicable to this reaction has tertiary amines organic bases as triethylamine, DIPEA, N-methylmorpholine etc., and mineral alkali, as sodium carbonate, salt of wormwood etc., is considered from economy and speed of reaction, prioritizing selection salt of wormwood of the present invention or triethylamine.The reaction of this step can be carried out smoothly between-20 DEG C to solvent reflux temperature, and consider from the angle of reaction efficiency and energy consumption, the preferred room temperature 25-30 of the present invention DEG C as temperature of reaction.
2) compound 2 goes protection to obtain Wei Lanteluo in acid condition.
Specific to the present invention, be applicable to the solvent of this reaction and have lower alcohol, water, ether solvent if tetrahydrofuran (THF), dioxane, glycol dimethyl ether, ethylene glycol monomethyl ether etc., amide solvent are as the mixed solvent of DMF etc., methyl-sulphoxide etc. or a few kind solvent, consider from economy and reactive behavior, prioritizing selection water of the present invention.Be applicable to the acid of this reaction can be organic acid as acetic acid, propionic acid, tartrate, citric acid etc., or mineral acid example hydrochloric acid, sulfuric acid, phosphoric acid etc., consider from economy and reactive behavior, prioritizing selection acetic acid of the present invention.The ratio of acetic acid in water is between 0-100%, prioritizing selection 2:1 of the present invention.The temperature of reaction being applicable to this reaction is between-20 DEG C to solvent reflux temperature, and consider from the angle of reaction efficiency and energy consumption, the preferred room temperature 25-30 of the present invention DEG C as temperature of reaction.
Contrast known synthetic method, synthetic route reaction conditions milder of the present invention, reagent is cheap, and main raw material is easy to get, and reactions steps is shorter, yield is higher, is more suitable for industrialization and amplifies.
Specific embodiment
Embodiments of the invention given below are to explanation of the present invention instead of restriction.
Embodiment 1
(2R) preparation of-hydroxyl-2-(2,2-dimethyl-4H-1,3-Ben Bing dioxine-6-base)-N-3-[6-[2-[(2,6-dichlorophenyl) methoxyl group] oxyethyl group] hexyl]-ethamine
300ml DMF is joined in the there-necked flask of 500ml, 38.4g2-({ 2-[(the bromo-hexyloxy of 6-)]-oxyethyl group } methyl)-1 is added successively under stirring, 3-dichlorobenzene 22.3g (2R)-hydroxyl-2-(2,2-dimethyl-4H-1,3-Ben Bing dioxine-6-base)-ethamine, slowly drip 11.1g triethylamine, finally add 4.5g sodium iodide.Stirring at room temperature is about 6h, and TLC monitors reaction and completes.To add in 900ml water in reaction solution, stir 30min, add isopropyl ether and extract 3 times, saturated salt washes 3 times, anhydrous sodium sulfate drying, dry concentrating under reduced pressure is done, resistates column chromatography purification obtains (2R)-hydroxyl-2-(2,2-dimethyl-4H-1,3-Ben Bing dioxine-6-base)-N-3-[6-[2-[(2,6-dichlorophenyl) methoxyl group] oxyethyl group] hexyl]-ethamine 45.3g, yield 86.2%.
Embodiment 2
4-{ (1R)-2-[(6-{2-[(2,6-dichlorophenyl) methoxyl group] oxyethyl group } hexyl) amine]-1-hydroxyethyl } preparation of-2-(methylol) phenol (Wei Lanteluo)
By (2R)-hydroxyl-2-(2,2-dimethyl-4H-1,3-Ben Bing dioxine-6-base)-N-3-[6-[2-[(2,6-dichlorophenyl) methoxyl group] oxyethyl group] hexyl]-ethamine 45.3g adds in 200ml acetic acid, add 100ml water again, stirring at room temperature 7-8h, TLC monitor reaction and complete.Concentrating under reduced pressure, adds 400ml methylene dichloride, is adjusted to pH7-8 with saturated sodium bicarbonate in resistates, separatory, organic phase saturated salt is washed once, anhydrous sodium sulfate drying, after concentrating under reduced pressure, resistates column chromatography purification obtains 38.2g Wei Lanteluo, yield about 91.5%.
Claims (8)
1. the novel process of synthesis Wei Lanteluo (compound 1)
Synthetic route of the present invention is as follows:
Wherein compound 1 is Wei Lanteluo (Vilanterol), and concrete operation step is as follows:
1) compound 4 and compound 3 react, and obtain compound 2;
2) compound 2 goes protection to obtain Wei Lanteluo in acid condition.
2. method according to claim 1,1) L in compound 4 used in step is general leavings group, as chlorine, bromine, iodine, alkyl sulfonic ester, aromatic base sulphonate etc., the preferred bromine atoms of the present invention.
3. method according to claim 1,1) solvent used has amide solvent if DMF etc., sulfone class or sulfoxide type solvents are if DMSO etc., lower alcohol, hydrochloric ether are if methylene dichloride, chloroform etc., ether solvent are if tetrahydrofuran (THF), dioxane etc., acetonitrile, esters solvent are if ethyl acetate etc., arene are as the mixture etc. of the mixture of toluene, chlorobenzene etc. or several solvent, aprotic polar solvent and water, prioritizing selection DMF of the present invention in step.
4. method according to claim 1,1) alkali used has tertiary amines organic bases as triethylamine, DIPEA, N-methylmorpholine etc. in step, mineral alkali as sodium carbonate, salt of wormwood etc., prioritizing selection salt of wormwood of the present invention or triethylamine.
5. method according to claim 1,1) temperature of reaction in step is between-20 DEG C to solvent reflux temperature, the preferred room temperature 25-30 of the present invention DEG C as temperature of reaction.
6. method according to claim 1,2) solvent used has lower alcohol, water, ether solvent if tetrahydrofuran (THF), dioxane, glycol dimethyl ether, ethylene glycol monomethyl ether etc., amide solvent are as the mixed solvent of DMF etc., methyl-sulphoxide etc. or a few kind solvent, prioritizing selection water of the present invention in step.
7. method according to claim 1,2) in step acid used can be organic acid as acetic acid, propionic acid, tartrate, citric acid etc., or mineral acid example hydrochloric acid, sulfuric acid, phosphoric acid etc., prioritizing selection acetic acid of the present invention,
The ratio of acetic acid in water is between 0-100%, prioritizing selection 2:1 of the present invention.
8. method according to claim 1,2) temperature of reaction in step is between-20 DEG C to solvent reflux temperature, the preferred room temperature 25-30 of the present invention DEG C as temperature of reaction.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111377822A (en) * | 2018-12-29 | 2020-07-07 | 天津药业研究院有限公司 | Preparation method of vilanterol |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1585633A (en) * | 2001-09-14 | 2005-02-23 | 葛兰素集团有限公司 | Phenethanolamine derivatives for treatment of respiratory diseases |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1585633A (en) * | 2001-09-14 | 2005-02-23 | 葛兰素集团有限公司 | Phenethanolamine derivatives for treatment of respiratory diseases |
Non-Patent Citations (2)
| Title |
|---|
| PANAYIOTIS A. PROCOPIOU ET AL.: "Synthesis and Structure-Activity Relationships of Long-acting β2 Adrenergic Receptor Agonists Incorporating Metabolic Inactivation: An Antedrug Approach", 《J. MED. CHEM.》, vol. 53, 31 December 2010 (2010-12-31), pages 4522 - 4530, XP 055251075, DOI: doi:10.1021/jm100326d * |
| PANAYIOTIS A. PROCOPIOU ET AL.: "The discovery of long-acting saligenin b2 adrenergic receptor agonists incorporating hydantoin or uracil rings", 《BIOORG. MED. CHEM.》, vol. 19, 31 December 2011 (2011-12-31), pages 4192 - 4201, XP 055045528, DOI: doi:10.1016/j.bmc.2011.05.064 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111377822A (en) * | 2018-12-29 | 2020-07-07 | 天津药业研究院有限公司 | Preparation method of vilanterol |
| CN111377822B (en) * | 2018-12-29 | 2023-09-08 | 天津药业研究院股份有限公司 | Preparation method of vilanaflo |
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