CN115286491B - Preparation method of 2- [2- (6-bromohexyloxy) ethoxymethyl ] -1, 3-dichlorobenzene - Google Patents
Preparation method of 2- [2- (6-bromohexyloxy) ethoxymethyl ] -1, 3-dichlorobenzene Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
Abstract
The invention discloses a key intermediate 2- [2- (6-bromohexyloxy) ethoxymethyl of vilantro]A preparation method of-1, 3-dichlorobenzene (formula I), belonging to the field of medicine synthesis. The method takes 2, 6-dichlorobenzyl alcohol and dihalide as raw materials, and generates a compound (2- [2- (6-bromohexyloxy) ethoxymethyl) of a formula I through twice nucleophilic substitution, sulfonic acid esterification, refining and bromination]-1, 3-dichlorobenzene). The preparation method provided by the invention has the advantages of cheap and easily obtained raw materials, simple operation, mild reaction conditions, no harsh reaction conditions, high yield and high purity of the obtained product, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a vilanafloc intermediate 2- [2- (6-bromohexyloxy) ethoxymethyl ] -1, 3-dichlorobenzene.
Background
Venlafro is a novel long-acting beta that has been developed with a history of gelan 2 Receptor agonists with fast onset of action, long duration of action, stronger tissue affinity and higher beta 2 Receptor selectivity, typically in combination with other drugs. The FDA approved the use of fluticasone/vilantro (Breo Ellipta) in 2013 for the long-term maintenance therapy of airflow obstruction in patients with Chronic Obstructive Pulmonary Disease (COPD) and also for the maintenance therapy of asthma in patients with reversible obstructive airways disease that are over 18 years of age.
Veland terol, chemical name (R) -4- (2- ((6- ((2, 6-dichlorobenzyl) oxy) -ethoxy) ethyl) amino) -1-hydroxyethyl) -2-hydroxymethylphenol, its structural formula is shown below:
the current synthesis process literature and patent report of vilantro is more, but the main synthesis route is the butt joint of the compound of formula I and the compound of formula VII. The quality of the compounds of formula I and VII used in the process has a greater influence on the quality of the vilantro. Therefore, the research on the preparation method of (2- [2- (6-bromohexyloxy) ethoxymethyl ] -1, 3-dichlorobenzene) has important market value and application value.
The existing literature and patents report the synthetic routes for compounds of formula I as follows:
the route takes 2, 6-dichlorobenzyl dichloride as a raw material, and a final intermediate is prepared through two-step nucleophilic substitution. In the existing synthesis method, the process intermediates and the products are oily substances, cannot be purified by adopting a crystallization method, and are required to be purified by a column chromatography method, so that the operation is complex, the purity and the yield of the products are low, and the method is not suitable for industrial production.
Disclosure of Invention
The invention provides a synthesis method of 2- [2- (6-bromohexyloxy) ethoxymethyl ] -1, 3-dichlorobenzene, which aims to solve the defects of complex operation, difficult purification, low product purity, inapplicability to industrial production and the like in the existing preparation technology of 2- [2- (6-bromohexyloxy) ethoxymethyl ] -1, 3-dichlorobenzene.
The method adopts cheap 2, 6-dichlorobenzyl alcohol and dihalide as raw materials, the compound of the formula I is obtained through twice nucleophilic substitution and sulfoacid esterification, the compound of the formula II is solid, the compound of the formula II after refining can be refined through a solvent recrystallization method, and the 2- [2- (6-bromohexyloxy) ethoxymethyl ] -1, 3-dichlorobenzene is prepared through the reaction of the refined compound of the formula II and alkali metal bromide, the product purity is up to more than 99%, and the purification processes of complicated operations such as column chromatography in documents and patents are avoided.
The preparation method provided by the invention has the advantages of cheap and easily available raw materials, mild reaction conditions, simple operation, higher yield and product purity of more than 99%, and is suitable for industrial production.
Specifically, it comprises the following steps:
(1) Dissolving a compound of the formula VI and an organic base in an organic solvent, dropwise adding a compound of the formula V, stirring at room temperature, concentrating under reduced pressure after the compound of the formula VI is completely reacted, dissolving the concentrate with ethyl acetate, washing with water to be neutral, drying with ethyl acetate, and concentrating under reduced pressure to obtain a compound of the formula IV;
(2) Dissolving 1, 6-hexanediol and organic alkali in an organic solvent, dropwise adding a compound of the formula IV, heating to 40-60 ℃ and stirring for reaction, concentrating under reduced pressure after the compound of the formula IV is completely reacted, dissolving the concentrate with ethyl acetate, washing with water, drying with ethyl acetate, and concentrating under reduced pressure to obtain a compound of the formula III;
(3) Adding a compound of the formula III, an acid binding agent and a sulfonic acid esterification reagent into an organic solvent for reaction at the temperature of minus 5-30 ℃, washing the compound of the formula III with an aqueous solution of acid and distilled water in sequence after the compound of the formula III is completely reacted, drying the reaction solution, and concentrating under reduced pressure to obtain a crude product of the compound of the formula II.
(4) Refining the crude product of the compound of the formula II at 0-100 ℃ by adopting an ether solvent to obtain a white solid, namely a refined product of the compound of the formula II;
(5) Dissolving the refined product of the compound of the formula II in an aprotic solvent, adding alkali metal bromide for reaction at 40-90 ℃, recovering the solvent under reduced pressure after the reaction of the compound of the formula II is finished, adding an organic solvent into the residue, washing with water, drying the organic phase, and concentrating under reduced pressure to obtain the compound of the formula I.
Preferably, the compound X of formula V in step (1) of the process of the invention represents chlorine, bromine or iodine, preferably X is bromine.
Preferably, the organic base in step (1) of the process of the present invention is one or two of sodium hydride, potassium tert-butoxide and sodium methoxide, preferably sodium hydride.
Preferably, the organic base in step (2) of the method is one or two of sodium hydride, potassium tert-butoxide and sodium methoxide, preferably potassium tert-butoxide.
Preferably, the acid-binding agent in step (3) of the method is one or two of pyridine, triethylamine and N, N-diisopropylethylamine, preferably N, N-diisopropylethylamine.
Preferably, the sulphonic acid esterification reagent in step (3) of the process of the present invention is one or two of methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, preferably methanesulfonyl chloride.
Preferably, the ether reagent in the step (4) of the method is one or two of isopropyl ether, methyl tertiary butyl ether, ethylene glycol monomethyl ether and ethylene glycol dimethyl ether, preferably ethylene glycol dimethyl ether;
further, the mass-to-volume ratio of the crude compound of formula II to the ether solvent in step (4) of the method is 1:1-1:10, preferably 1:3.
Preferably, the aprotic solvent in step (5) of the process of the present invention is one or two of tetrahydrofuran, acetone, ethyl acetate and acetonitrile, preferably acetonitrile;
further, the alkali metal bromide in step (5) of the process of the present invention is sodium bromide, lithium bromide, potassium bromide, magnesium bromide, preferably lithium bromide.
Detailed Description
Example 1
Preparation of IV Compounds
Tetrahydrofuran (100 ml), 60% sodium hydride (8.8 g,0.22 mol) and 2, 6-dichlorobenzyl alcohol (35.4 g,0.2 mol) are sequentially added into a reaction bottle at room temperature, stirred for 0.5h, 1, 2-dibromoethane (41.5 g,0.22 mol) is added dropwise, and stirred for 3-4h at room temperature; recovering the solvent under reduced pressure, adding ethyl acetate (200 ml) to the residue, stirring for dissolution, washing with water to neutrality, drying the organic phase with anhydrous sodium sulfate, recovering ethyl acetate under reduced pressure to obtain 50.6g of oily substance, yield 89.7%; HPLC purity 98.3%.
Example 2
Preparation of IV Compounds
Tetrahydrofuran (100 ml), 60% sodium hydride (8.8 g,0.22 mol) and 2, 6-dichlorobenzyl alcohol (35.4 g,0.2 mol) were sequentially added to the reaction flask at room temperature, stirred for 0.5h, 1, 2-diiodoethane (61.8 g,0.22 mol) was added dropwise, and stirred for 3-4h at room temperature; recovering the solvent under reduced pressure, adding ethyl acetate (200 ml) to the residue, stirring for dissolution, washing with water to neutrality, drying the organic phase with anhydrous sodium sulfate, recovering ethyl acetate under reduced pressure to obtain 60.1g of oily substance, yield 91.3%; HPLC purity 98.6%.
Example 3
Preparation of the III Compounds
Tert-butanol (50 ml), 1, 6-hexanediol (20.6 g,0.17 mol) and potassium tert-butoxide (19.0 g,0.17 mol) are sequentially added into a reaction flask, stirred at room temperature for 0.5h, and IV compound (41.5 g,0.15 mol) is added dropwise for reaction at 40-50 ℃ for 3-4h; the reaction solution was cooled to room temperature, the solvent was recovered under reduced pressure, ethyl acetate (200 ml) was added to the residue and dissolved under stirring, the mixture was washed with water to neutrality, and the organic phase was dried over anhydrous sodium sulfate, and then ethyl acetate was recovered under reduced pressure to give 43.9g of an oil, yield 91.6%; HPLC purity 96.5%.
Example 4
Preparation of crude Compound II
Chloroform (80 ml), III compound (38.4 g,0.12 mol) and N, N-diisopropylethylamine (15.5 g,0.12 mol) are added into a reaction bottle in sequence, the temperature is reduced to 0 to-5 ℃, methylsulfonyl chloride (14.8 g,0.13 mol) is added dropwise, and the temperature is controlled to 0 to 5 ℃ after the dropwise addition, and the reaction is continued for 5 to 6 hours; the organic phase was dried over anhydrous sodium sulfate, washed with 2% aqueous citric acid (30 ml), 2% sodium hydrogencarbonate (30 mol) and purified water (30 ml) in this order, and the solvent was recovered under reduced pressure to give 44.8g of an oil with a yield of 93.8%.
Example 5
Refining crude compounds II
Isopropyl ether (100 ml) and crude compound II (20 g) were added to a reaction flask, heated to reflux to dissolve, then cooled to 0-10 ℃, stirred for 1h, filtered, the filter cake washed with a small amount of cold isopropyl ether, dried to give 16.8g of white solid with a yield of 84.0% and an HPLC purity of 99.1%.
Example 6
Refining crude compounds II
Adding ethylene glycol dimethyl ether (60 ml) and crude product of II compound (20 g) into a reaction bottle, heating to reflux and dissolve, cooling to 0-10 ℃, continuously stirring for 1h, filtering, washing a filter cake with a small amount of cold ethylene glycol dimethyl ether, and drying to obtain white solid with the yield of 18.4g and the HPLC purity of 99.1%.
Example 7
Refining crude compounds II
Adding ethylene glycol dimethyl ether (100 ml) and crude product of II compound (20 g) into a reaction bottle, heating to reflux and dissolve, cooling to 0-10 ℃, continuously stirring for 1h, filtering, washing a filter cake with a small amount of cold ethylene glycol dimethyl ether, and drying to obtain 17.7g of white solid with the yield of 88.5% and the HPLC purity of 99.3%.
Example 8
Preparation of 2- [2- (6-bromohexyloxy) ethoxymethyl ] -1, 3-dichlorobenzene
Acetonitrile (80 ml), a refined product of the II compound (16.0 g,0.04 mol) and lithium bromide (5.2 g,0.06 mol) were sequentially added into a reaction flask, and the mixture was heated and refluxed for 5 hours; the reaction mixture was cooled to room temperature, acetonitrile was recovered under reduced pressure, isopropyl ether (60 ml) was added to the residue, the organic phase was washed three times with purified water, and after drying the organic phase over anhydrous sodium sulfate, the solvent was recovered under reduced pressure to obtain 15.1g of a colorless oil, yield 98.3%, and HPLC purity 99.0%.
Claims (3)
1. A method for synthesizing a vilanarol intermediate from 2, 6-dichlorobenzyl alcohol, comprising the steps of:
(1) Dissolving a compound shown in a formula VI and alkali in an organic solvent, dropwise adding a compound shown in a formula V, stirring at room temperature, concentrating under reduced pressure after the compound shown in the formula VI reacts completely, dissolving the concentrate with ethyl acetate, washing with water to be neutral, drying with ethyl acetate, and concentrating under reduced pressure to obtain a compound shown in a formula IV;
(2) Dissolving 1, 6-hexanediol and alkali in an organic solvent, dropwise adding an organic solution of a compound of formula IV, heating to 40-60 ℃ and stirring for reaction, concentrating under reduced pressure after the compound of formula IV is completely reacted, dissolving the concentrate with ethyl acetate, washing with water, drying with ethyl acetate, and concentrating under reduced pressure to obtain a compound of formula III;
(3) Adding a compound of the formula III, an acid binding agent and a sulfonic acid esterification reagent into an organic solvent for reaction at the temperature of minus 5-30 ℃, washing the compound of the formula III with an aqueous acid solution, an aqueous alkali solution and distilled water in sequence after the compound of the formula III is completely reacted, drying an organic phase, and concentrating under reduced pressure to obtain a crude product of the compound of the formula II;
(4) Refining the crude product of the compound of the formula II at 0-100 ℃ by adopting an ether solvent to obtain a white solid, namely a refined product of the compound of the formula II;
(5) Dissolving the refined product of the compound of the formula II in an aprotic solvent, adding alkali metal bromide, reacting at 40-90 ℃, recovering the solvent under reduced pressure after the reaction of the compound of the formula II is finished, adding an organic solvent into the residue, washing with water, drying the organic phase, and concentrating under reduced pressure to obtain the compound of the formula I;
the reaction route is as follows:
the compound of formula V in step (1) is selected from 1, 2-dibromoethane; the organic solvent is selected from tetrahydrofuran;
the organic solvent in step (2) is selected from t-butanol;
the organic solvent in the step (3) is selected from chloroform; the sulfoacid esterifying reagent is selected from methylsulfonyl chloride;
the ether solvent in the step (4) is selected from ethylene glycol dimethyl ether; the mass volume ratio of the crude product of the compound of the formula II to the ethylene glycol dimethyl ether is 1:3;
the alkali in the step (1) or the step (2) is selected from one or two of sodium hydride, potassium tert-butoxide and sodium methoxide.
2. The method according to claim 1, characterized in that: the acid binding agent in the step (3) is one or two selected from triethylamine, N-diisopropylethylamine, piperidine and pyridine.
3. The method according to claim 1, characterized in that: the aprotic solvent in the step (5) is selected from one or two of dioxane, tetrahydrofuran, acetone, ethyl acetate and acetonitrile; the alkali metal bromide is selected from sodium bromide, lithium bromide and potassium bromide.
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| CN202211059267.9A CN115286491B (en) | 2022-08-31 | 2022-08-31 | Preparation method of 2- [2- (6-bromohexyloxy) ethoxymethyl ] -1, 3-dichlorobenzene |
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Citations (7)
| 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 |
| CN103923058A (en) * | 2014-05-06 | 2014-07-16 | 上海鼎雅药物化学科技有限公司 | Method for synthesizing vilanterol intermediate and salt thereof |
| CN107188865A (en) * | 2016-03-14 | 2017-09-22 | 益方生物科技（上海）有限公司 | Benzoxazine compound and its production and use |
| CN109896934A (en) * | 2019-03-08 | 2019-06-18 | 山东省药学科学院 | A kind of preparation method of high-purity 2- benzyloxy bromoethane |
| CN111018678A (en) * | 2019-12-10 | 2020-04-17 | 山东省药学科学院 | Preparation method of high-purity 3-phenoxy bromopropane |
| WO2021033198A1 (en) * | 2019-08-16 | 2021-02-25 | Melody Healthcare Pvt. Ltd | An improved process for preparation of vilanterol or a pharmaceutically acceptable salt thereof |
| WO2021155006A1 (en) * | 2020-01-31 | 2021-08-05 | Les Laboratoires Servier Sas | Inhibitors of cyclin-dependent kinases and uses thereof |
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- 2022-08-31 CN CN202211059267.9A patent/CN115286491B/en active Active
Patent Citations (7)
| 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 |
| CN103923058A (en) * | 2014-05-06 | 2014-07-16 | 上海鼎雅药物化学科技有限公司 | Method for synthesizing vilanterol intermediate and salt thereof |
| CN107188865A (en) * | 2016-03-14 | 2017-09-22 | 益方生物科技（上海）有限公司 | Benzoxazine compound and its production and use |
| CN109896934A (en) * | 2019-03-08 | 2019-06-18 | 山东省药学科学院 | A kind of preparation method of high-purity 2- benzyloxy bromoethane |
| WO2021033198A1 (en) * | 2019-08-16 | 2021-02-25 | Melody Healthcare Pvt. Ltd | An improved process for preparation of vilanterol or a pharmaceutically acceptable salt thereof |
| CN111018678A (en) * | 2019-12-10 | 2020-04-17 | 山东省药学科学院 | Preparation method of high-purity 3-phenoxy bromopropane |
| WO2021155006A1 (en) * | 2020-01-31 | 2021-08-05 | Les Laboratoires Servier Sas | Inhibitors of cyclin-dependent kinases and uses thereof |
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