CN104744271B - A kind of new technology synthesizing Wei Lanteluo - Google Patents
A kind of new technology synthesizing Wei Lanteluo Download PDFInfo
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- CN104744271B CN104744271B CN201310730294.9A CN201310730294A CN104744271B CN 104744271 B CN104744271 B CN 104744271B CN 201310730294 A CN201310730294 A CN 201310730294A CN 104744271 B CN104744271 B CN 104744271B
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Abstract
The invention discloses a kind of new method synthesizing Wei Lanteluo.The invention provides a kind of brand-new Wei Lanteluo synthetic method, the method uses the initiation material being more easy to get, and efficiently avoid the shortcomings such as the harsh reaction condition (such as anhydrous response) of existing technique, expensive reagents, and the method route is shorter simultaneously, yield is higher, has more the market competitiveness.
Description
Technical field
The invention belongs to pharmacy synthesis technology field, be specifically related to the new synthetic method of a kind of Wei Lanteluo (Vilanterol).
Background technology
Chronic obstructive pulmonary disease (Chronic obstructive
Pulmonary disease, COPD) the most limited with air-flow and increase the weight of to be characterized in Progressive symmetric erythrokeratodermia, it has also become cause the fifth-largest cause of disease of death, and actively control symptom, improve the important goal that pulmonary function is the treatment of this disease.At present, the key agents being used for alleviating COPD patient symptom is the Long-effect β_2 reactant excitomotor agent such as formoterol and salmaterol.
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 by GlaxoSmithKline PLC and Theravance two company in mid-May, 2013 approval), every day is used for chronic obstructive pulmonary disease (COPD), including bronchitis and emophysematous long term maintenance therapy 1 time.Wherein Wei Lanteluo (Vilanterol) is a kind of long-acting beta 2 adrenergic receptor agonists (LABA), and in vitro tests shows, its functionally selective is similar to salmaterol.Beta 2 adrenoreceptor excitomotor (including Vilanterol) pharmacological action at least partly stimulates intracellular adenyl cyclase because of it, and this enzyme can promote that adenosine triphosphate (ATP) is converted into cyclic adenosine monophosphate (cAMP).CAMP raises and can relax bronchial smooth muscle and suppress the release of immediate hypersensitivity medium in cell (especially mastocyte).
The mechanism of action high due to Wei Lanteluo (Vilanterol) selectivity and preferably curative effect and less side effect, thus there is good market prospect.
It it is down 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 formoxyl with expensive trimethyl silicane potassium alcoholate, in acetic acid, finally remove propylidene protect and obtain Wei Lanteluo.Employing the reagent such as sodium hydride, trimethyl silicane potassium alcoholate in this technique, reaction needs anhydrous response.And the preparation of starting compound 5 is the most loaded down with trivial details, preparing for raw material with parahydroxyacet-ophenone or the bromo-benzaldehyde of 2-hydroxyl-4-, need could prepare through 7-8 step reaction, not only step is long, and yield is low, wherein need to use bromine, butyl lithium, sodium hydride etc. to be not suitable for the reagent that industrialization is amplified.These all constrain the industry amplification of Wei Lanteluo.It is easy to get it is therefore desirable to find a kind of raw material, operating procedure synthesis technique simple, that easily amplify.
Summary of the invention
It is an object of the invention to invent the new synthetic method of a kind of Wei Lanteluo (Vilanterol).
Specifically, invention provides a kind of new synthetic method of Long-effect β_2 reactant excitomotor agent Wei Lanteluo (Vilanterol).
Synthetic route of the present invention is as follows:
In wherein going up, compound 1 is Wei Lanteluo (Vilanterol), and concrete operation step is as follows:
1) compound 4 reacts with compound 3, obtains compound 2.
Wherein compound 3 can pass through document Tetrahedron:Asymmetry 22
(2011) 1,395 1399 methods provided obtain.Compare compound 5, and compound 3 is more easy to preparation, and cost is lower.The method that compound 4 can pass through Synlett, 2005,12,1948-1950 and provide obtains.Specific to the present invention, the solvent being suitable for this reaction has lower alcohol such as methanol, ethanol, isopropanol etc., chlorohydrocarbon such as dichloromethane, chloroform etc., ether solvent such as oxolane, dioxane etc., arene such as toluene, chlorobenzene etc., consider with reaction rate from economy, prioritizing selection methanol of the present invention.The reducing agent being suitable for this reaction has the combination etc. of boron hydride, lithium aluminium hydride reduction, ammonium formate or the hydrogen such as sodium borohydride, potassium borohydride, sodium cyanoborohydride (potassium), sodium triacetoxyborohydride (potassium) and metallic catalyst such as palladium catalyst, Raney's nickel etc., consider with reaction rate from economy, prioritizing selection sodium borohydride of the present invention.The reaction of this step can be smoothed out between-20 DEG C to solvent reflux temperature, and from the point of view of reaction efficiency and energy consumption, preferred room temperature 25-30 DEG C of the present invention is as reaction temperature.
2) compound 2 deprotects in acid condition and obtains Wei Lanteluo.
Specific to the present invention, the solvent being suitable for this reaction has lower alcohol, water, ether solvent such as oxolane, dioxane, glycol dimethyl ether, glycol monoethyl ether etc., amide solvent such as DMF etc., dimethyl sulfoxide etc. or the mixed solvent of a few kind solvent, consider with reactivity from economy, prioritizing selection water of the present invention.The acid being suitable for this reaction can be organic acid such as acetic acid, propanoic acid, tartaric acid, citric acid etc., or mineral acid example hydrochloric acid, sulphuric acid, phosphoric acid etc., considers with reactivity from economy, prioritizing selection acetic acid of the present invention.Acetic acid ratio in water is between 0-100%, prioritizing selection 2:1 of the present invention.Be suitable for the reaction temperature of this reaction be-20 DEG C between solvent reflux temperature, from the point of view of reaction efficiency and energy consumption, preferred room temperature 25-30 DEG C of the present invention is as reaction temperature.
Contrasting known synthetic method, the synthetic route of the present invention not only raw material is easy to get, and reactions steps is shorter, reaction condition milder, and other reagent are cheap, and yield is higher is more suitable for industrialization amplification.
Specific embodiment
The embodiment of invention now given below, is the description of the invention rather than restriction.
Embodiment 1
(2R) preparation of-hydroxyl-2-(2,2-dimethyl-4H-1,3-benzo diene-6-base)-N-3-[6-[2-[(2,6-Dichlorobenzene base) methoxyl group] ethyoxyl] hexyl]-ethamine
300ml methanol is joined in the there-necked flask of 500ml, 31.9g2-({ 2-[(5-aldehyde radical-hexyloxy)]-ethyoxyl } methyl)-1 it is sequentially added under stirring, 3-dichloro-benzenes and 22.3g (2R)-hydroxyl-2-(2,2-dimethyl-4H-1,3-benzo diene-6-base)-ethamine, about 5h, TLC monitoring reaction is stirred at room temperature complete.Slowly being dividedly in some parts 4.2g sodium borohydride, in controlling, temperature is less than 30 DEG C.Finishing, slowly dropping 5ml shrend is gone out reaction.Stirring will add in 900ml water in reactant liquor, stirring 30min, adding diisopropyl ether to extract 3 times, saturated salt is washed 3 times, and anhydrous sodium sulfate is dried, it is dried concentrating under reduced pressure to do, residue column chromatography purification obtains (2R)-hydroxyl-2-(2,2-dimethyl-4H-1,3-benzo diene-6-base)-N-3-[6-[2-[(2,6-Dichlorobenzene base) methoxyl group] ethyoxyl] hexyl]-ethamine 46.4g, yield 88.3%.
Embodiment 2
4-{ (1R)-2-[(6-{2-[(2,6-Dichlorobenzene base) methoxyl group] ethyoxyl } hexyl) amine]-1-ethoxy } preparation of-2-(methylol) phenol (Wei Lanteluo)
By (2R)-hydroxyl-2-(2,2-dimethyl-4H-1,3-benzo diene-6-base)-N-3-[6-[2-[(2,6-Dichlorobenzene base) methoxyl group] ethyoxyl] hexyl]-ethamine 46.4g adds in 200ml acetic acid, add 100ml water, 7-8h, TLC monitoring reaction is stirred at room temperature complete.Concentrating under reduced pressure, adds 400ml dichloromethane in residue, is adjusted to pH7-8 with saturated sodium bicarbonate, separatory, with saturated salt washing once, anhydrous sodium sulfate is dried organic facies, after concentrating under reduced pressure, residue column chromatography purification obtains 39.5g Wei Lanteluo, yield about 92.1%.
Claims (19)
1. the synthetic method of Yi Zhong 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 generates Schiff base with compound 3 dehydration, restores and obtains compound 2；Wherein, reduction used
Agent is sodium borohydride；
2) compound 2 deprotects in acid condition and obtains Wei Lanteluo.
Method the most according to claim 1,1) solvent selected from lower alcoholic solvent used in step, chlorinated hydrocarbon solvent, ethers be molten
Agent or aromatic hydrocarbon solvent；Described lower alcohol solvent is selected from methanol, ethanol or isopropanol.
Method the most according to claim 2, described lower alcohol solvent is selected from methanol.
Method the most according to claim 2, described chlorinated hydrocarbon solvent is selected from dichloromethane or chloroform.
Method the most according to claim 2, described ether solvent is selected from oxolane or dioxane.
Method the most according to claim 2, described aromatic hydrocarbon solvent is selected from toluene or chlorobenzene.
Method the most according to claim 1,1) reaction temperature in step be-20 DEG C between solvent reflux temperature.
Method the most according to claim 7,1) reaction temperature in step is room temperature 25-30 DEG C.
Method the most according to claim 1,2) solvent used in step is selected from water, ether solvent, amide solvent, diformazan
Sulfoxide or the mixed solvent of a few kind solvent.
Method the most according to claim 9,2) in step solvent for use selected from water.
11. methods according to claim 9, described ether solvent is selected from oxolane, dioxane, glycol dimethyl ether or ethylene glycol
Monomethyl ether.
12. methods according to claim 9, described amide solvent is selected from DMF.
13. methods according to claim 1,2) acid used in step is selected from organic acid or mineral acid.
14. methods according to claim 13, described organic acid is selected from acetic acid, propanoic acid, tartaric acid or citric acid.
15. methods according to claim 14, described organic acid is selected from acetic acid.
16. methods according to claim 15, described acetic acid is 2:1 with the ratio of water.
17. methods according to claim 13, described mineral acid is selected from hydrochloric acid, sulphuric acid or phosphoric acid.
18. methods according to claim 1,2) reaction temperature in step be-20 DEG C between solvent reflux temperature.
19. methods according to claim 18,2) reaction temperature in step is room temperature 25-30 DEG C.
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| WO2017138588A1 (en) | 2016-02-10 | 2017-08-17 | 住友化学株式会社 | Method for producing 1-methylpyrrolidin-3-ol |
| CN109574860B (en) * | 2019-01-22 | 2021-07-27 | 安徽德信佳生物医药有限公司 | Method for preparing vilanterol |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4992474A (en) * | 1983-04-18 | 1991-02-12 | Glaxo Group Ltd. | Phenethanolamine derivatives |
| CN1585633A (en) * | 2001-09-14 | 2005-02-23 | 葛兰素集团有限公司 | Phenethanolamine derivatives for treatment of respiratory diseases |
| CN103096897A (en) * | 2010-07-16 | 2013-05-08 | 希普拉有限公司 | Pharmaceutical compositions comprising R (+) budesonide and one or more bronchodilators |
-
2013
- 2013-12-26 CN CN201310730294.9A patent/CN104744271B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4992474A (en) * | 1983-04-18 | 1991-02-12 | Glaxo Group Ltd. | Phenethanolamine derivatives |
| CN1585633A (en) * | 2001-09-14 | 2005-02-23 | 葛兰素集团有限公司 | Phenethanolamine derivatives for treatment of respiratory diseases |
| CN103096897A (en) * | 2010-07-16 | 2013-05-08 | 希普拉有限公司 | Pharmaceutical compositions comprising R (+) budesonide and one or more bronchodilators |
Non-Patent Citations (1)
| Title |
|---|
| 糠酸氟替卡松、三氟甲磺酸维兰特罗及其联合制剂治疗慢性阻塞性肺疾病研究进展;梁丽等;《世界临床药物》;20110731;第32卷(第07期);第392-394页 * |
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