CN112679420B - Preparation method of 2,5-dibromopyridine - Google Patents
Preparation method of 2,5-dibromopyridine Download PDFInfo
- Publication number
- CN112679420B CN112679420B CN202011572053.2A CN202011572053A CN112679420B CN 112679420 B CN112679420 B CN 112679420B CN 202011572053 A CN202011572053 A CN 202011572053A CN 112679420 B CN112679420 B CN 112679420B
- Authority
- CN
- China
- Prior art keywords
- dibromopyridine
- brominating reagent
- hydroxy
- bromopyridine
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Abstract
The invention discloses a preparation method of 2,5-dibromopyridine, and belongs to the technical field of organic synthesis. 2-hydroxy pyridine is taken as a raw material to react with a brominating reagent to obtain 2-hydroxy-5-bromopyridine; then reacts with brominating reagent under the action of Lewis acid catalyst to obtain 2, 5-dibromopyridine. The method is completed in two steps, the isomer obtained in the first step does not need to be purified, and the product with the purity of more than 99.5% can be obtained in the last step through recrystallization once.
Description
Technical Field
The invention relates to a preparation method of 2,5-dibromopyridine, belonging to the technical field of medicine synthesis.
Background
Pyridine derivatives are widely used in the synthesis of pesticides, medicines and natural products, such as antibiotics, antitumor drugs, antiulcer drugs, antihypertensive drugs and the like. The pyridine ring and the benzene ring are bioisosteres, and the pyridine ring has higher biological activity and smaller toxic and side effects. Pyridine derivatives are a general potential basic unit of nitrogen-containing bioactive molecules. The alkaloid contains a saturated six-membered nitrogen heterocyclic structure, so that an alkaloid skeleton unit can be skillfully constructed through pyridine derivatives, and the method has important significance for synthesizing the nitrogen heterocyclic alkaloid.
2,5-dibromopyridine, english name: 2, 5-Dibronoperidine, CAS 624-28-2, is used as pyridine skeleton intermediate, and bromine at 2-position and 5-position can be subjected to substitution reaction, coupling reaction and other reactions, and is widely used in medicine, pesticide, perfume and other aspects.
Hitherto reported methods for synthesizing 2,5-dibromopyridine [ Synthesis,2015,47,3169-3178], [ Journal of Organic Chemistry,2012,77,6908-6916] and WO2012/162818A1 are by bromination reaction and diazotization reaction, the reaction routes are as follows:
the method has the advantages that the yield of each step is about 85%, but the method has the defects that diazonium salt is unstable and high in activity, is easy to decompose and explode under the condition of heated collision, is unfavorable for safety and environmental protection, and has more waste water in the post-treatment process, thereby being unfavorable for industrial development.
However, in the above synthetic route, diazonium salt generated by diazotization reaction is unstable, and is easy to decompose and explode under the action of light and heat, so that the problem of safe industrial production and the like exists, and therefore, it is necessary to conduct intensive research on the synthetic process of 2,5-dibromopyridine, a better, safe and stable reaction route is provided, and industrial production is met, so as to meet the increasing market demand.
Disclosure of Invention
In order to overcome the technical defects, the invention provides a preparation method of 2, 5-dibromopyridine. 2-hydroxy pyridine is taken as a raw material to react with a brominating reagent to obtain 2-hydroxy-5-bromopyridine; then reacts with brominating reagent under the action of Lewis acid catalyst to obtain 2, 5-dibromopyridine. The method is completed in two steps, the isomer obtained in the first step does not need to be purified, and the product with the purity of more than 99.5% can be obtained in the last step through recrystallization once.
The preparation method of the 2,5-dibromopyridine comprises the following steps: adding 2-hydroxypyridine into an organic solvent, adding a brominating reagent in batches, quenching and filtering to obtain 2-hydroxy-5-bromopyridine; then adding the mixture into an organic solvent, reacting with a brominating reagent in the presence of a Lewis acid catalyst, and recrystallizing the obtained crude product by using a mixed solvent to obtain 2, 5-dibromopyridine; the reaction equation is expressed as follows:
further, in the above technical scheme, the organic solvent is selected from 1, 2-dichloroethane or acetonitrile, and the brominating reagent is selected from NBS and dibromohydantoin; the reaction temperature is between-10 and 25 ℃.
Further, in the above technical scheme, the molar ratio of the 2-hydroxypyridine to the brominating reagent is 1:0.60-1.00.
Further, in the above technical scheme, the organic solvent is selected from 1, 2-dichloroethane or acetonitrile, the lewis acid catalyst is selected from tris (pentafluorophenyl) borane or triphenylborane, and the brominating reagent is selected from phosphorus tribromide or phosphorus tribromide. Phosphorus tribromide is preferably used.
Further, in the above technical scheme, the molar ratio of the 2-hydroxy-5-bromopyridine to the catalyst to the brominating reagent is 1:0.05-0.10:1.10-1.30; the reaction is carried out under reflux conditions.
Further, in the above technical scheme, the recrystallization solvent is a mixed solvent of isopropanol and water.
Advantageous effects of the invention
The method is completed in two steps, and in the first step, the bromination reaction of the hydroxy para substituent is carried out, so that the regioselectivity is high and can reach 94/6, and the purification is not needed. In the second step, the product with purity more than 99.5% can be obtained by the reaction with brominating reagent under the catalysis of Lewis acid, the dosage of brominating reagent is almost equivalent, and the recrystallization.
The diazotization reaction with great potential safety hazard is not involved in the route, the operation is easy, the total yield can reach 80%, the wastewater production amount is greatly reduced, and the method is green and environment-friendly and is suitable for industrial production.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples. These examples should be construed as merely illustrative of the present invention and not limiting the scope of the present invention. Various changes and modifications to the present invention may be made by one skilled in the art after reading the description herein, and such equivalent changes and modifications are intended to fall within the scope of the present invention as defined in the appended claims.
Example 1
Into the reaction flask, 50g (0.526 mol) of 2-hydroxypyridine and 250mL of acetonitrile were charged, 93.6g (0.526 mol) of NBS was added in portions at a temperature of-10 to 0℃and after the addition was completed, the temperature was raised to 15 to 25℃and the reaction was carried out for 1 hour. Detecting the reaction completion of the raw materials by sampling HPLC, and the proportion of the product 2-hydroxy-5-bromopyridine to the isomer 2-hydroxy-3-bromopyridineIs 94:6. concentrating the reaction solution at 45 ℃ under reduced pressure, heating the rest materials to 50 ℃ to dissolve the materials, measuring the pH=6.0-7.0, controlling the temperature to 45-50 ℃ and adding 750mL of water, slowly cooling to 20-25 ℃, precipitating the materials, stirring for 3 hours at the temperature, and filtering. The filter cake was rinsed with water and petroleum ether and dried to give 82.6g of 2-hydroxy-5-bromopyridine in 90.3% yield by HPLC:95.6%. 1 HNMR(400MHz,CDCl 3 ):11.73(s,1H),7.70(d,1H),7.56-7.51(m,1H),6.36(d,1H).
Example 2
50g (0.526 mol) of 2-hydroxypyridine and 200ml of 1, 2-dichloroethane are put into a reaction flask, 90g (0.315 mol) of dibromohydantoin is added in portions at a temperature of between-10 and 0 ℃ and then the temperature is raised to between 20 and 25 ℃ after the addition is completed, and the reaction is carried out for 1.5 hours. After the reaction of the raw materials is detected by sampling HPLC, the proportion of the product 2-hydroxy-5-bromopyridine to the isomer 2-hydroxy-3-bromopyridine is 93:7. aqueous sodium bisulphite is added to quench, the layers are separated, the aqueous phase is extracted with 1, 2-dichloroethane, the organic phases are combined, washed with water to ph=6.0-7.0, and the organic phases are dried over anhydrous sodium sulfate to give 435g of 1, 2-dichloroethane solution containing 2-hydroxy-5-bromopyridine, hplc:92.6% and yield 92.0%; and (5) carrying out bromination in the next step.
Example 3
50g (0.287 mol) of 2-hydroxy-5-bromopyridine, 7.3g (0.014 mol) of tris (pentafluorophenyl) borane and 200mL of acetonitrile were charged into the reaction flask under nitrogen protection, 93.2g (0.344 mol) of phosphorus tribromide was added dropwise at room temperature, and the mixture was slowly warmed to reflux after the completion of the dropwise addition, and reacted for 5 hours. Detecting that the raw materials react, concentrating under reduced pressure at 55deg.C until no liquid flows, pouring the residual liquid into 200mL ice water, adding saturated sodium carbonate solution to adjust pH=8.0-9.0, extracting with dichloromethane, concentrating the solvent under reduced pressure, adding 35mL isopropanol for replacement, heating to 50deg.C, adding 100mL water, and slowly cooling to precipitateThe solid was filtered and the filter cake was dried to give 56.3g of 2,5-dibromopyridine in 82.7% yield by HPLC:99.7%. 1 HNMR(400MHz,CDCl 3 )：8.81(d,1H),8.35(d,1H),8.13(d,1H).
Example 4
Under the protection of nitrogen, 435g of the 2-hydroxy-5-bromopyridine/1, 2-dichloroethane-containing solution of example 2 and 11.7g (0.048 mol) of triphenylborane were put into a reaction flask, and 131g (0.484 mol) of phosphorus tribromide was added dropwise, and after the completion of the dropwise addition, the temperature was slowly raised to reflux for 10 hours. After the detection reaction is finished, pouring the residual liquid into 200mL of ice water for quenching, adding 10% sodium hydroxide aqueous solution to adjust the pH value to be 8.0-9.0, washing an organic phase with water, concentrating dichloromethane under reduced pressure, replacing with 55mL of isopropanol, heating to 50 ℃, adding 160mL of water, slowly cooling to precipitate solid, filtering, drying a filter cake to obtain 101.6g of 2,5-dibromopyridine, and obtaining 88.7% yield by HPLC:99.5%.
The foregoing is only a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art, who is within the scope of the present invention, should be covered by the protection scope of the present invention by making equivalents and modifications to the technical solution and the inventive concept thereof.
Claims (3)
1. The preparation method of the 2,5-dibromopyridine is characterized by comprising the following reaction routes:
the method comprises the following steps: adding 2-hydroxypyridine into an organic solvent, adding a brominating reagent in batches, quenching and filtering to obtain 2-hydroxy-5-bromopyridine; then adding the mixture into an organic solvent, reacting with a brominating reagent in the presence of a Lewis acid catalyst, and recrystallizing the obtained crude product by using a mixed solvent to obtain 2, 5-dibromopyridine; the organic solvent is selected from 1, 2-dichloroethane or acetonitrile, the Lewis acid catalyst is selected from tris (pentafluorophenyl) borane or triphenylborane, and the brominating reagent is selected from phosphorus tribromide or phosphorus tribromide oxide; the molar ratio of the 2-hydroxy-5-bromopyridine to the Lewis acid catalyst to the brominating reagent is 1:0.05-0.10:1.10-1.30; the recrystallization adopts a mixed solvent composed of isopropanol and water.
2. The method for preparing 2,5-dibromopyridine according to claim 1, wherein: the brominating reagent is selected from NBS and dibromohydantoin.
3. The method for preparing 2,5-dibromopyridine according to claim 1, wherein: the molar ratio of the 2-hydroxypyridine to the brominating reagent is 1:0.60-1.00.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011572053.2A CN112679420B (en) | 2020-12-27 | 2020-12-27 | Preparation method of 2,5-dibromopyridine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011572053.2A CN112679420B (en) | 2020-12-27 | 2020-12-27 | Preparation method of 2,5-dibromopyridine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112679420A CN112679420A (en) | 2021-04-20 |
| CN112679420B true CN112679420B (en) | 2023-05-12 |
Family
ID=75452120
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011572053.2A Active CN112679420B (en) | 2020-12-27 | 2020-12-27 | Preparation method of 2,5-dibromopyridine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112679420B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113461603A (en) * | 2021-07-01 | 2021-10-01 | 南京超逸生物科技有限公司 | Synthetic method of medicine raw material 2, 5-dibromopyridine |
| CN113402451A (en) * | 2021-07-04 | 2021-09-17 | 南京超逸生物科技有限公司 | Preparation method of 2, 5-dibromopyridine |
| CN113773291B (en) * | 2021-10-09 | 2023-04-25 | 上海昕凯医药科技有限公司 | Improved synthesis method of glass color factor of cosmetic active ingredient |
| CN114591225B (en) * | 2022-03-02 | 2024-02-06 | 河南阿尔法医药科技有限公司 | Method for large-scale production of 2, 6-dibromo-4-methylpyridine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105061301A (en) * | 2015-09-07 | 2015-11-18 | 陈吉美 | Synthesis method of 2,5-dibromopyridine |
| WO2018231627A1 (en) * | 2017-06-12 | 2018-12-20 | Viamet Pharmaceuticals (NC), Inc. | 2,5-dibromopyridine and processes of preparation |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0707704D0 (en) * | 2007-04-20 | 2007-05-30 | Glaxo Group Ltd | Compounds |
-
2020
- 2020-12-27 CN CN202011572053.2A patent/CN112679420B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105061301A (en) * | 2015-09-07 | 2015-11-18 | 陈吉美 | Synthesis method of 2,5-dibromopyridine |
| WO2018231627A1 (en) * | 2017-06-12 | 2018-12-20 | Viamet Pharmaceuticals (NC), Inc. | 2,5-dibromopyridine and processes of preparation |
Non-Patent Citations (3)
| Title |
|---|
| C. Scott Shultz 等.Practical Synthesis of a Potent Bradykinin B1 Antagonist via Enantioselective Hydrogenation of a PyridylN-Acyl Enamide.《J. Org. Chem.》.2009,第74卷4547-4553. * |
| Mercedes Santos 等.Mild Regioselective Halogenation of Activated Pyridines with NBromosuccinimide.《Synthesis 》.2001,第14卷2176页table，2177页制备方法. * |
| 刘鹰翔.《药物合成反应》.中国中医药出版社,2017,(第第1版版),66-75. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112679420A (en) | 2021-04-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112679420B (en) | Preparation method of 2,5-dibromopyridine | |
| CN104610250B (en) | 1,2,3-thiadiazole-5-formamidine compound containing three N-heterocycles and synthesis | |
| CN102898361B (en) | Method for preparing 2-chlorine-3-amino-4-picoline | |
| CN112174989B (en) | Preparation method of clenbuterol | |
| JP7038263B2 (en) | Method for Producing Morpholine Quinazoline Compound and its Intermediate | |
| CN114315823B (en) | Intermediate of berberine hydrochloride and analogues thereof and preparation method thereof | |
| CN108373468B (en) | Preparation method of N-2-pyridine-5-pyrimidine methylamine | |
| CN103980188B (en) | The synthetic method of a kind of pyrrole Lun Panai and the synthetic method of intermediate and intermediate thereof | |
| CN103772189B (en) | Synthesis method of diethylstilbestrol compound methyl pigeon pea ketonic acid A | |
| CN111116493B (en) | Method for preparing Apabetalone, intermediate and preparation method of intermediate | |
| CN110256451B (en) | Synthetic method of benzofuro [2,3-b ] quinoline derivative | |
| CN103804187B (en) | Synthesis method of diethylstilbestrol compound pigeon pea ketonic acid A | |
| RU2630700C2 (en) | METHODS FOR OBTAINING 5-[2-[7-(TRIFLUOROMETHYL)-5-[4-(TRIFLUOROMETHYL)PHENYL]PYRAZOLO[1,5-a]PYRIMIDINE-3-YL]ETHINYL]-2-PYRIDINAMINE | |
| CN106243022A (en) | A kind of preparation method of nevirapine intermediate | |
| CN112457243B (en) | Synthesis method of 7-bromo-5-methoxyquinoline | |
| CN110563721A (en) | Preparation method of azasetron hydrochloride | |
| CN113979928B (en) | Preparation method of 2-chloro-5-nitropyridine | |
| CN110423224B (en) | Synthesis method of 2-aminopyrimidine type antiplatelet compound | |
| CN114349690B (en) | Synthesis method of doravirine intermediate | |
| CN109879815B (en) | 2-bromo-6-aldehyde pyridine and preparation method thereof | |
| CN109422681A (en) | A kind of preparation method of Pitavastatin Calcium intermediate | |
| CN113582953B (en) | Preparation method of key intermediate of amiodarone hydrochloride | |
| CN113816912B (en) | Preparation method of phenazine | |
| KR102327657B1 (en) | Novel azulene compounds and its preparation method | |
| CN110054626B (en) | Preparation method of pyridopyrimidine derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |