阅读说明：本技术 一种2-溴-1,4-萘并醌的制备工艺 (Preparation process of 2-bromo-1, 4-naphthoquinone ) 是由 汤健志 刘相国 蔡蓉蓉 于 2021-06-23 设计创作，主要内容包括：本发明涉及一种2-溴-1,4-萘并醌的制备工艺,包含以下步骤：在高温条件下,将含有1-萘酚的冰醋酸溶液缓慢滴加进入含有NBS的冰醋酸溶液中,搅拌后,进行萃取,干燥,脱溶,得到高纯度的2-溴-1,4-萘并醌；本发明能使产品的纯度和收率得到很大的提高,且反应条件温和,投入大批量生产具有很大的优势,重结晶后得到的产品即可直接进行下一步的反应。(The invention relates to a preparation process of 2-bromo-1, 4-naphthoquinone, which comprises the following steps: slowly dripping a glacial acetic acid solution containing 1-naphthol into a glacial acetic acid solution containing NBS under a high-temperature condition, stirring, extracting, drying and desolventizing to obtain high-purity 2-bromo-1, 4-naphthoquinone; the invention can greatly improve the purity and yield of the product, has mild reaction conditions, has great advantages when being put into mass production, and can directly carry out the next reaction on the product obtained after recrystallization.)

1. A preparation process of 2-bromo-1, 4-naphthoquinone is characterized by comprising the following steps: comprises the following steps:

s1: glacial acetic acid, water and NBS are added into a three-neck flask in sequence and stirred uniformly.

S2, dissolving 1-naphthol in glacial acetic acid, and uniformly stirring.

S3, slowly and dropwise adding the solution obtained in the step S2 into the solution obtained in the step S1 within 75 minutes, keeping the reaction temperature at a high temperature, stirring for 30 minutes, and then restoring the reaction temperature to room temperature.

S4, diluting the reaction solution obtained in the step S3 with water, and stirring uniformly.

And S5, extracting the reaction solution obtained in the step S4 by using an extracting agent, combining the extraction solutions, drying the extraction solutions by using a saturated sodium bicarbonate solution and anhydrous magnesium sulfate in sequence, and finally evaporating the solvent to dryness to obtain a white solid.

S6 recrystallization of the white solid obtained in step S5 from an organic solvent yields 2-bromo-1, 4-naphthoquinone of high purity.

2. The process for the preparation of 2-bromo-1, 4-naphthoquinone according to claim 1, wherein: in step S1, the volume ratio of glacial acetic acid to water is 1:2-1: 5.

3. The process for the preparation of 2-bromo-1, 4-naphthoquinone according to claim 1, wherein: in step S1, the concentration of NBS is 47.3-48.3 g/L.

4. The process for the preparation of 2-bromo-1, 4-naphthoquinone according to claim 1, wherein: in step S1, the reaction temperature is controlled to 40-50 ℃ during stirring.

5. The process for the preparation of 2-bromo-1, 4-naphthoquinone according to claim 1, wherein: in step S2, the concentration of the 1-naphthol is 28.5-30.5 g/L.

6. The process for the preparation of 2-bromo-1, 4-naphthoquinone according to claim 1, wherein: in step S3, the elevated temperature is 40-50 ℃.

7. The process for the preparation of 2-bromo-1, 4-naphthoquinone according to claim 1, wherein: in step S4, the volume ratio of the water to the reaction liquid obtained in step S3 is 0.5 to 1.

8. The process for the preparation of 2-bromo-1, 4-naphthoquinone according to claim 1, wherein: in step S5, the extractant is dichloromethane.

9. The process for the preparation of 2-bromo-1, 4-naphthoquinone according to claim 1, wherein: in step S5, the extract needs to be dried by saturated sodium bicarbonate solution several times, and then dried by anhydrous magnesium sulfate.

10. The process for the preparation of 2-bromo-1, 4-naphthoquinone according to claim 1, wherein: in step S6, the organic solvent is 95% ethanol.

Technical Field

The invention relates to the technical field of drug synthesis, in particular to a preparation process of 2-bromo-1, 4-naphthoquinone.

Background

2-bromo-1, 4-naphthoquinone is an important intermediate of bulk drugs, and is frequently found in the synthesis of various new drugs; in the existing synthesis technology, 2-bromo-1, 4-naphthoquinone is mainly obtained by reacting raw materials 1, 4-naphthoquinone with CuBr2 and NBS (N-bromosuccinimide, abbreviated as NBS in the text), and the synthesis route is as follows:

the purity of the product obtained by the method is lower than 80%, and the product with higher purity can be obtained only by a large amount of purification work subsequently, so that the method has certain limitation.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide a preparation process of 2-bromo-1, 4-naphthoquinone.

In order to achieve the purpose, the invention adopts the technical scheme that: a preparation process of 2-bromo-1, 4-naphthoquinone comprises the following steps:

s1: glacial acetic acid, water and NBS are added into a three-neck flask in sequence and stirred uniformly.

S2, dissolving 1-naphthol in glacial acetic acid, and uniformly stirring.

S3, slowly and dropwise adding the solution obtained in the step S2 into the solution obtained in the step S1 within 75 minutes, keeping the reaction temperature at a high temperature, stirring for 30 minutes, and then restoring the reaction temperature to room temperature.

S4, diluting the reaction solution obtained in the step S3 with water, and stirring uniformly.

And S5, extracting the reaction solution obtained in the step S4 by using an extracting agent, combining the extraction solutions, drying the extraction solutions by using a saturated sodium bicarbonate solution and anhydrous magnesium sulfate in sequence, and finally evaporating the solvent to dryness to obtain a white solid.

S6 recrystallization of the white solid obtained in step S5 from an organic solvent yields 2-bromo-1, 4-naphthoquinone of high purity.

Preferably, in step S1, the ratio of glacial acetic acid to water is 1:2-1:5 by volume.

Preferably, in step S1, the concentration of NBS is 47.3-48.3 g/L.

Preferably, in step S1, the reaction temperature is controlled to 40 to 50 ℃ during stirring.

Preferably, in step S2, the concentration of the 1-naphthol is 28.5-30.5 g/L.

Preferably, in step S3, the high temperature is 40-50 ℃.

Preferably, in step S4, the volume ratio of the water to the reaction liquid obtained in step S3 is 0.5 to 1.

Preferably, in step S5, the extractant is dichloromethane.

Preferably, in step S5, the extract is dried by saturated sodium bicarbonate solution for several times, and then dried by anhydrous magnesium sulfate.

Preferably, in step S6, the organic solvent is 95% ethanol.

Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:

the invention can greatly improve the purity and yield of the product, has mild reaction conditions and has great advantages when being put into mass production; the product obtained after recrystallization can be directly used for the next reaction without silica gel column purification.

Drawings

The technical scheme of the invention is further explained by combining the accompanying drawings as follows:

FIG. 1 is a liquid phase diagram of a conventional 2-bromo-1, 4-naphthoquinone;

FIG. 2 is a nuclear magnetic diagram of 2-bromo-1, 4-naphthoquinone described in example 2 of the present invention;

FIG. 3 is a nuclear magnetic diagram of 2-bromo-1, 4-naphthoquinone described in example 3 of the present invention.

Detailed Description

The invention is described in further detail below with reference to the figures and the embodiments.

Example 1:

the existing synthesis technology comprises the following specific steps: 1, 4-naphthoquinone (5g, 31.61mmol), NBS (11.3g,63.22mmol), CuBr₂(22.6g,101.15mmol) and acetonitrile (600ml) were added in sequence to a three-necked flask, stirred well and heated to reflux; after refluxing for 6 hours, the temperature is reduced to room temperature; the reaction solution was concentrated under reduced pressure to a black solid, and 5% sodium hydrogen sulfite (70ml) was added thereto, followed by stirring for 0.5 hour; the reaction was extracted with ethyl acetate (100ml x 3), combined, dried and the solvent evaporated to dryness to give the product.

The product obtained in example 1 has low yield, the product purity is only about 70%, the purification is difficult, and the liquid phase diagram is shown in figure 1.

The synthetic route of the invention is as follows:

example 2:

glacial acetic acid (500ml), water (1000ml) and NBS (71.2g,0.4mol) are sequentially added into a three-neck flask, stirred uniformly and the reaction temperature is controlled to be 45 ℃ to obtain a reaction solution 1;

dissolving 1-naphthol (14.4g,0.10mol) in glacial acetic acid (100ml) solution, and uniformly stirring to obtain a reaction solution 2;

slowly dropwise adding the reaction liquid 2 into the reaction liquid 1 within 75 minutes, keeping the reaction temperature at 45 ℃, stirring for 30min, and recovering the reaction temperature to room temperature to obtain a reaction liquid 3;

evaporating most of the solvent of the reaction solution 3 to dryness to obtain a black concentrated solution, adding 100ml of water, and uniformly stirring to obtain a reaction solution 4;

extracting the reaction solution 4 with dichloromethane, mixing the extracts, drying with saturated sodium bicarbonate solution (300ml) for four times, drying the extracts with anhydrous magnesium sulfate, and evaporating the solvent to obtain white solid;

the white solid obtained in S5 was recrystallized from 95% ethanol to obtain high purity 2-bromo-1, 4-naphthoquinone.

The product obtained in example 2 has high purity, and the nuclear magnetic diagram is shown in 2, and the product can be directly used in the next step.

Example 3:

glacial acetic acid (500ml), water (1500ml) and NBS (94.6g,0.5mol) are sequentially added into a three-neck flask, stirred uniformly and the reaction temperature is controlled to be 45 ℃ to obtain reaction liquid 1;

dissolving 1-naphthol (14.4g,0.10mol) in glacial acetic acid (100ml) solution, and uniformly stirring to obtain a reaction solution 2;

slowly dropwise adding the reaction liquid 2 into the reaction liquid 1 within 75 minutes, keeping the reaction temperature at 45 ℃, stirring for 30min, and recovering the reaction temperature to room temperature to obtain a reaction liquid 3;

adding 1500ml of water into the reaction solution 3, and uniformly stirring to obtain a reaction solution 4;

extracting the reaction solution 4 with dichloromethane, mixing the extracts, drying with saturated sodium bicarbonate solution (300ml) for four times, drying the extracts with anhydrous magnesium sulfate, and evaporating the solvent to obtain white solid;

the white solid obtained in S5 was recrystallized from 95% ethanol to obtain high purity 2-bromo-1, 4-naphthoquinone.

The product obtained in example 3 has high purity, and the nuclear magnetic diagram is shown in 3, and the product can be directly used in the next step.

The above is only a specific application example of the present invention, and the protection scope of the present invention is not limited in any way. All the technical solutions formed by equivalent transformation or equivalent replacement fall within the protection scope of the present invention.