CN115286491A - 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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Abstract
The invention discloses a vilant Luo Guanjian intermediate 2- [2- (6-bromohexyloxy) ethoxy methyl]A preparation method of-1,3-dichlorobenzene (formula I), belonging to the field of medicine synthesis. The method uses 2,6-dichlorobenzyl alcohol and dihalogenated alkane as raw materials, and generates a compound (2- [2- (6-bromohexyloxy) ethoxy methyl) in a formula I through twice nucleophilic substitution, sulfoacid 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 product yield and purity, and suitability for industryAnd (5) chemical production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a vilanterol intermediate 2- [2- (6-bromohexyloxy) ethoxy methyl ] -1,3-dichlorobenzene.
Background
Vaticallol is a novel long-acting beta which can be researched and developed by puerarin history 2 Receptor agonists with rapid onset of action, long duration of action, greater tissue affinity and higher beta 2 Receptor selectivity, usually in combination with other drugs. The FDA approved fluticasone/vilanterol (Breo Ellipta) for the long-term maintenance treatment of airflow obstruction in patients with Chronic Obstructive Pulmonary Disease (COPD) in 2013, and is also suitable for the maintenance treatment of asthma in patients with reversible obstructive airway disease above 18 years of age.
Vilanterol, chemically known as (R) -4- (2- ((6- ((2,6-dichlorobenzyl) oxy) -ethoxy) ethyl) amino) -1-hydroxyethyl) -2-hydroxymethylphenol, has the following structural formula:
at present, the synthetic process literature and patents of vilanterol are reported more, but the main synthetic route is the butt joint of the compound I and the compound VII. The mass of the compounds of formula I and VII used in the process has a large influence on the mass of vilanterol. Therefore, the research on the preparation method of (2- [2- (6-bromohexyloxy) ethoxymethyl ] -1,3-dichlorobenzene) has important market value and application value.
The synthesis routes for the compounds of formula I are reported in the literature and patents as follows:
the method takes 2,6-dichlorobenzyl bromide as a raw material, prepares a final intermediate through two-step nucleophilic substitution, has more byproducts, long reaction time and low product purity, and 2- [2- (6-bromoethoxy) ethoxymethyl ] -1,3-dichlorobenzene is oily and has a high boiling point, and a crude product needs column chromatography for purification. In the existing synthetic method, the process intermediate and the product are oily substances, can not be purified by adopting a crystallization method, and must be purified by adopting a column chromatography method, so that the operation is complex, the product purity and the yield are not high, and the method is not suitable for industrial production.
Disclosure of Invention
In order to solve the defects of complicated operation, difficult purification, low product purity, unsuitability for industrial production and the like in the existing preparation technology of the 2- [2- (6-bromohexyloxy) ethoxymethyl ] -1,3-dichlorobenzene, the invention provides a synthetic method of the 2- [2- (6-bromohexyloxy) ethoxymethyl ] -1,3-dichlorobenzene.
The method adopts cheap 2,6-dichlorobenzyl alcohol and dihalogenated alkane as raw materials, obtains the compound shown in the formula I through two nucleophilic substitution and sulfoacid esterification reactions, the compound shown in the formula II is solid and can be refined by a solvent recrystallization method, the refined compound shown in the formula II reacts with bromide of alkali metal to prepare 2- [2- (6-bromohexyloxy) ethoxymethyl ] -1,3-dichlorobenzene, the product purity is up to more than 99%, and complicated purification processes such as column chromatography and the like in documents and patents are avoided.
The preparation method provided by the invention has the advantages of cheap and easily-obtained raw materials, mild reaction conditions, simple operation, high yield and product purity of more than 99%, and is suitable for industrial production.
Specifically, it comprises the following steps:
(1) Dissolving a compound shown in the formula VI and an organic base in an organic solvent, dropwise adding a compound shown in the formula V, stirring at room temperature, concentrating under reduced pressure after the compound shown in the formula VI completely reacts, dissolving a concentrate with ethyl acetate, washing with water to be neutral, drying the ethyl acetate, and concentrating under reduced pressure to obtain a compound shown in the formula IV;
(2) Dissolving 1,6-hexanediol and organic base in an organic solvent, dropwise adding the compound of formula IV, heating to 40-60 ℃, stirring for reaction, concentrating under reduced pressure after the compound of formula IV completely reacts, dissolving the concentrate with ethyl acetate, washing with water, drying the ethyl acetate, and concentrating under reduced pressure to obtain the compound of formula III;
(3) Adding a compound of a formula III, an acid-binding agent and a sulfoacid esterification reagent into an organic solvent for reaction at the temperature of-5-30 ℃, after the compound of the formula III completely reacts, washing the compound of the formula III by using an acid aqueous solution and distilled water in sequence, drying a reaction solution, and then concentrating under reduced pressure to obtain a crude product of the compound of the formula II.
(4) Refining the crude compound of the formula II by adopting an ether solvent at the temperature of between 0 and 100 ℃ to obtain a white solid, namely a refined compound of the formula II;
(5) Dissolving the refined product of the compound shown in the formula II in an aprotic solvent, adding an alkali metal bromide, reacting at 40-90 ℃, recovering the solvent under reduced pressure after the reaction of the compound shown in 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 shown in the formula I.
Preferably, the compound X of formula V in step (1) of the process of the present invention represents chlorine, bromine or iodine, preferably X is bromine.
Preferably, the organic base in step (1) of the method 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 of the present invention 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 of the present invention is one or two of pyridine, triethylamine and N, N-diisopropylethylamine, and preferably N, N-diisopropylethylamine.
Preferably, the sulfonating reagent in step (3) of the method is one or two of methanesulfonyl chloride, phenylmethanesulfonyl chloride and p-toluenesulfonyl chloride, preferably methanesulfonyl chloride.
Preferably, the ether reagent in step (4) of the method of the present invention is one or two of isopropyl ether, methyl tert-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 of the present invention is 1:1-1, preferably 1:3.
Preferably, the aprotic solvent in step (5) of the method 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 method of the present invention is sodium bromide, lithium bromide, potassium bromide, magnesium bromide, preferably lithium bromide.
Detailed Description
Example 1
Preparation of IV Compound
Tetrahydrofuran (100 ml), 60% sodium hydride (8.8g, 0.22mol) and 2,6-dichlorobenzyl alcohol (35.4g, 0.2mol) are added into a reaction bottle in sequence at room temperature, stirred for 0.5h, added with 1,2-dibromoethane (41.5g, 0.22mol) dropwise and stirred for 3-4h at room temperature; recovering solvent under reduced pressure, adding ethyl acetate (200 ml) into the residue, stirring to dissolve, washing with water to neutral, drying the organic phase with anhydrous sodium sulfate, and recovering ethyl acetate under reduced pressure to obtain oil 50.6g with yield of 89.7%; HPLC purity 98.3%.
Example 2
Preparation of IV Compound
Tetrahydrofuran (100 ml), 60% sodium hydride (8.8g, 0.22mol) and 2,6-dichlorobenzyl alcohol (35.4g, 0.2mol) are added into a reaction bottle in sequence at room temperature, stirred for 0.5h, added with 1,2-diiodoethane (61.8g, 0.22mol) dropwise and stirred for 3-4h at room temperature; recovering solvent under reduced pressure, adding ethyl acetate (200 ml) into the residue, stirring to dissolve, washing with water to neutral, drying the organic phase with anhydrous sodium sulfate, and recovering ethyl acetate under reduced pressure to obtain oil 60.1g with yield 91.3%; HPLC purity 98.6%.
Example 3
Preparation of III Compounds
Adding tert-butanol (50 ml), 1,6-hexanediol (20.6 g, 0.17mol) and potassium tert-butoxide (19.0g, 0.17mol) into a reaction bottle in sequence, stirring at room temperature for 0.5h, dropwise adding an IV compound (41.5g, 0.15mol), and controlling the temperature to be 40-50 ℃ to react for 3-4h; cooling the reaction solution to room temperature, recovering the solvent under reduced pressure, adding ethyl acetate (200 ml) into the residue, stirring and dissolving, washing with water to neutrality, drying the organic phase with anhydrous sodium sulfate, and recovering ethyl acetate under reduced pressure to obtain an oily substance 43.9g with a yield of 91.6%; HPLC purity 96.5%.
Example 4
Preparation of crude II Compound
Adding 80ml of trichloromethane, 38.4g of a III compound (0.12mol) and 15.5g of N, N-diisopropylethylamine (0.12mol) into a reaction bottle in sequence, cooling to 0 to-5 ℃, dropwise adding 14.8g of methylsulfonyl chloride (0.13mol), and controlling the temperature to 0-5 ℃ after dropwise adding to continue reacting for 5-6 h; the organic phase was washed with 2% aqueous lemon solution (30 ml), 2% sodium bicarbonate solution (30 mol) and purified water (30 ml) in this order, dried over anhydrous sodium sulfate, and the solvent was recovered under reduced pressure to give 44.8g of an oil in 93.8% yield.
Example 5
II purification of crude Compound
Adding isopropyl ether (100 ml) and a compound II crude product (20 g) into a reaction bottle, heating to reflux and dissolve, then cooling to 0-10 ℃, continuing stirring for 1h, filtering, washing a filter cake with a small amount of cold isopropyl ether, and drying to obtain a white solid 16.8g, wherein the yield is 84.0%, and the HPLC purity is 99.1%.
Example 6
II purification of crude Compound
Adding ethylene glycol dimethyl ether (60 ml) and a compound II crude product (20 g) into a reaction bottle, heating to reflux and dissolve, then cooling to 0-10 ℃, continuing stirring for 1h, filtering, washing a filter cake with a small amount of cold ethylene glycol dimethyl ether, and drying to obtain 18.4g of white solid, wherein the yield is 92.0%, and the HPLC purity is 99.1%.
Example 7
II purification of crude Compound
Adding ethylene glycol dimethyl ether (100 ml) and a compound II crude product (20 g) into a reaction bottle, heating to reflux and dissolve, then cooling to 0-10 ℃, continuing 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, wherein the yield is 88.5%, and the HPLC purity is 99.3%.
Example 8
Preparation of 2- [2- (6-bromohexyloxy) ethoxymethyl ] -1,3-dichlorobenzene
Acetonitrile (80 ml), a refined product of a compound II (16.0 g, 0.04mol) and lithium bromide (5.2 g, 0.06mol) are added into a reaction bottle in sequence, and heating reflux reaction is carried out for 5 hours; the reaction solution 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 with purified water three times, and after the organic phase was dried over anhydrous sodium sulfate, the solvent was recovered under reduced pressure to give 15.1g of a colorless oily substance, yield 98.3%, and HPLC purity 99.0%.
Claims (7)
1. A method for synthesizing a vilanterol intermediate from 2,6-dichlorobenzyl alcohol, comprising the steps of:
(1) Dissolving a compound shown in the formula VI and an organic base in an organic solvent, dropwise adding a compound shown in the formula V, stirring at room temperature, carrying out reduced pressure concentration after the compound shown in the formula VI completely reacts, dissolving a concentrate with ethyl acetate, washing with water to be neutral, drying the ethyl acetate, and carrying out reduced pressure concentration to obtain a compound shown in the formula IV;
(2) Dissolving 1,6-hexanediol and organic base in an organic solvent, dropwise adding an organic solution of a compound of formula IV, heating to 40-60 ℃, stirring for reaction, concentrating under reduced pressure after the compound of formula IV completely reacts, dissolving a 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 a formula III, an acid-binding agent and a sulfoacid esterification reagent into an organic solvent for reaction at the temperature of-5-30 ℃, after the compound of the formula III completely reacts, sequentially washing the compound with an acid aqueous solution, an alkali aqueous solution and distilled water, drying an organic phase, and then concentrating under reduced pressure to obtain a crude product of the compound of the formula II;
(4) Refining the crude compound of the formula II by adopting an ether solvent at the temperature of between 0 and 100 ℃ to obtain a white solid, namely a refined compound of the formula II;
(5) Dissolving the refined product of the compound shown in the formula II in an aprotic solvent, adding an alkali metal bromide, reacting at 40-90 ℃, recovering the solvent under reduced pressure after the reaction of the compound shown in 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 shown in the formula I;
the reaction route is as follows:
2. the method of claim 1, wherein: the compound X in the formula V in the step (1) represents chlorine, bromine and iodine, and preferably X is bromine; the organic base is one or two of sodium hydride, potassium tert-butoxide and sodium methoxide, preferably sodium hydride.
3. The method of claim 1, wherein: the organic base in the step (2) is one or two of sodium hydride, potassium tert-butoxide and sodium methoxide, and potassium tert-butoxide is preferred.
4. The method of claim 1, wherein: the acid binding agent in the step (3) is one or two of piperidine, pyridine, triethylamine and N, N-diisopropylethylamine, and preferably the N, N-diisopropylethylamine.
5. The method of claim 1, wherein: the sulfoesterification reagent in the step (3) is one or two of methanesulfonyl chloride, phenylmethanesulfonyl chloride and p-toluenesulfonyl chloride, preferably methanesulfonyl chloride.
6. The method of claim 1, wherein: the ether reagent in the step (4) is one or two of isopropyl ether, methyl tert-butyl ether, ethylene glycol monomethyl ether and ethylene glycol dimethyl ether, preferably ethylene glycol dimethyl ether; the mass-to-volume ratio of the crude compound of formula II to the ether solvent is 1:1-1, preferably 1:3.
7. The method of claim 1, wherein: the aprotic solvent in the step (5) is one or two of dioxane, tetrahydrofuran, acetone, ethyl acetate and acetonitrile, preferably acetonitrile; the alkali metal bromide is sodium bromide, lithium bromide, potassium bromide, magnesium bromide, preferably lithium bromide.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116283512A (en) * | 2023-02-24 | 2023-06-23 | 博诺康源(北京)药业科技有限公司 | Method for synthesizing vilanabro and salts thereof |
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| 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 |
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| 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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| 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 |
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| CN116283512A (en) * | 2023-02-24 | 2023-06-23 | 博诺康源(北京)药业科技有限公司 | Method for synthesizing vilanabro and salts thereof |
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