阅读说明：本技术 一种3,5-二氯-2-碘苯甲醚的制备工艺 (Preparation process of 3, 5-dichloro-2-iodoanisole ) 是由 汤健志 刘相国 蔡蓉蓉 于 2021-08-09 设计创作，主要内容包括：本发明涉及一种3,5-二氯-2-碘苯甲醚的制备工艺,包含以下步骤：先将3,5-二氯苯酚和有机溶剂依次加入容器中,在低温下加入碱,并搅拌均匀,然后将体系温度恢复室温,搅拌反应定量时间,接着在低温下缓慢加入碘素后逐渐恢复室温,搅拌过夜,然后以酸淬灭反应,并加入乙酸乙酯萃取,接着合并有机层,得到中间产物3,5-二氯-2-碘苯酚,然后将3,5-二氯-2-碘苯酚,碱和有机溶剂依次加入容器中,接着加入甲基化试剂,在氮气保护的条件下,搅拌反应过夜,然后将反应液倒入冰水中,加入有机溶剂萃取,最后合并有机层,得到最终产物3,5-二氯-2-碘苯甲醚；本发明反应条件温和,原料价格低廉,不涉及危险品,投入大批量生产具有很大的优势。(The invention relates to a preparation process of 3, 5-dichloro-2-iodoanisole, which comprises the following steps: sequentially adding 3, 5-dichlorophenol and an organic solvent into a container, adding alkali at a low temperature, uniformly stirring, returning the temperature of the system to room temperature, stirring for reaction for a certain time, slowly adding iodine at a low temperature, gradually returning to the room temperature, stirring overnight, quenching the reaction with acid, adding ethyl acetate for extraction, combining organic layers to obtain an intermediate product 3, 5-dichloro-2-iodophenol, sequentially adding 3, 5-dichloro-2-iodophenol, alkali and the organic solvent into the container, adding a methylating agent, stirring for reaction overnight under the protection of nitrogen, pouring a reaction solution into ice water, adding the organic solvent for extraction, and finally combining the organic layers to obtain a final product 3, 5-dichloro-2-iodoanisole; the method has the advantages of mild reaction conditions, low raw material price, no relation with dangerous goods and great advantages when being put into mass production.)

1. A preparation process of 3, 5-dichloro-2-iodoanisole is characterized by comprising the following steps: comprises the following steps:

s1: sequentially adding 3, 5-dichlorophenol and an organic solvent into a container, and uniformly stirring;

s2: reducing the temperature of the solution obtained in the step S1 to a low temperature, adding alkali, and uniformly stirring;

s3: returning the temperature of the solution obtained in the step S2 to room temperature, and stirring for reaction for 0.1-8 h;

s4: reducing the temperature of the solution obtained in the step S3 to low temperature, slowly adding the iodine, gradually recovering to room temperature, and stirring overnight;

s5: quenching the solution obtained in the step S4 with acid, and adding ethyl acetate for extraction;

s6: combining the organic layers of the extract obtained in the step S5, rinsing with saturated saline, drying with anhydrous magnesium sulfate, and evaporating the solvent to obtain an intermediate product, namely 3, 5-dichloro-2-iodophenol;

s7: sequentially adding the intermediate product 3, 5-dichloro-2-iodophenol obtained in the step S6, alkali and an organic solvent into a container, and uniformly stirring;

s8: adding a methylating agent into the solution obtained in the step S7, and stirring and reacting overnight under the protection of nitrogen;

s9: pouring the solution obtained in the step S8 into ice water, and adding an organic solvent for extraction;

s10: and (4) combining the organic layers of the extract obtained in the step (S9), rinsing with saturated saline, drying with anhydrous magnesium sulfate, and evaporating the solvent to dryness to obtain the final product, namely 3, 5-dichloro-2-iodoanisole.

2. The process for the preparation of 3, 5-dichloro-2-iodoanisole according to claim 1, characterized in that: in the step S1, the concentration of the 3, 5-dichlorophenol is 50-100 g/L.

3. The process for the preparation of 3, 5-dichloro-2-iodoanisole according to claim 1, characterized in that: in step S2, the molar ratio of the alkali to the 3, 5-dichlorophenol is 1:1 to 5: 1.

4. The process for the preparation of 3, 5-dichloro-2-iodoanisole according to claim 1, characterized in that: in step S4, the molar ratio of the iodocin to the 3, 5-dichlorophenol is 0.5:1 to 5: 1.

5. The process for the preparation of 3, 5-dichloro-2-iodoanisole according to claim 1, characterized in that: in step S7, the molar ratio of the alkali to the 3, 5-dichloro-2-iodophenol is 0.5:1 to 5: 1.

6. The process for the preparation of 3, 5-dichloro-2-iodoanisole according to claim 1, characterized in that: in step S8, the molar ratio of the methylating agent to the 3, 5-dichloro-2-iodophenol is 1:1 to 5: 1.

7. The process for the preparation of 3, 5-dichloro-2-iodoanisole according to claim 1, characterized in that: in step S8, the methylating agent is one or more of methyl iodide, dimethyl sulfate and methyl tosylate.

8. The process for the preparation of 3, 5-dichloro-2-iodoanisole according to claim 1, characterized in that: in steps S2 and S7, the alkali is one or more of sodium hydroxide, potassium carbonate, sodium hydride, and cesium carbonate.

9. The process for the preparation of 3, 5-dichloro-2-iodoanisole according to claim 1, characterized in that: in the steps S2 and S4, the low temperature is-40 to 10 ℃.

10. The process for the preparation of 3, 5-dichloro-2-iodoanisole according to claim 1, characterized in that: in steps S1, S7, and S9, the organic solvent is one or more of ethyl acetate, methanol, methyl tert-butyl ether, toluene, dichloromethane, and N, N-dimethylformamide.

Technical Field

The invention relates to the technical field of drug synthesis, in particular to a preparation process of 3, 5-dichloro-2-iodoanisole.

Background

3, 5-dichloro-2-iodoanisole is an important intermediate of raw material medicines, and is frequently generated in the synthesis of a plurality of new medicines; in the existing synthesis technology, 3, 5-dichloro-2-iodoanisole is mainly obtained by reacting raw materials of 3, 5-dichloroanisole with silver tetrafluoroborate and iodogen, and the synthesis route is as follows:

the silver tetrafluoroborate used by the method is a dangerous product, is careless to operate, is easy to cause danger, is expensive and has certain limitation.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide a preparation process of 3, 5-dichloro-2-iodoanisole.

In order to achieve the purpose, the invention adopts the technical scheme that: a preparation process of 3, 5-dichloro-2-iodoanisole comprises the following steps:

s1: sequentially adding 3, 5-dichlorophenol and an organic solvent into a container, and uniformly stirring;

s2: reducing the temperature of the solution obtained in the step S1 to a low temperature, adding alkali, and uniformly stirring;

s3: returning the temperature of the solution obtained in the step S2 to room temperature, and stirring for reaction for 0.1-8 h;

s4: reducing the temperature of the solution obtained in the step S3 to low temperature, slowly adding the iodine, gradually recovering to room temperature, and stirring overnight;

s5: quenching the solution obtained in the step S4 with acid, and adding ethyl acetate for extraction;

s6: combining the organic layers of the extract obtained in the step S5, rinsing with saturated saline, drying with anhydrous magnesium sulfate, and evaporating the solvent to obtain an intermediate product, namely 3, 5-dichloro-2-iodophenol;

s7: sequentially adding the intermediate product 3, 5-dichloro-2-iodophenol obtained in the step S6, alkali and an organic solvent into a container, and uniformly stirring;

s8: adding a methylating agent into the solution obtained in the step S7, and stirring and reacting overnight under the protection of nitrogen;

s9: pouring the solution obtained in the step S8 into ice water, and adding an organic solvent for extraction;

s10: and (4) combining the organic layers of the extract obtained in the step (S9), rinsing with saturated saline, drying with anhydrous magnesium sulfate, and evaporating the solvent to dryness to obtain the final product, namely 3, 5-dichloro-2-iodoanisole.

Preferably, in step S1, the concentration of the 3, 5-dichlorophenol is 50-100 g/L.

Preferably, in step S2, the molar ratio of the base to the 3, 5-dichlorophenol is 1:1 to 5: 1.

Preferably, in step S4, the molar ratio of the iodocin to the 3, 5-dichlorophenol is 0.5:1 to 5: 1.

Preferably, in step S5, the acid is one or more of concentrated sulfuric acid, concentrated hydrochloric acid, diluted hydrochloric acid, and glacial acetic acid.

Preferably, in step S7, the molar ratio of the base to the 3, 5-dichloro-2-iodophenol is 0.5:1 to 5: 1.

Preferably, in step S8, the molar ratio of the methylating agent to the 3, 5-dichloro-2-iodophenol is 1:1 to 5: 1.

Preferably, in step S8, the methylating agent is one or more of methyl iodide, dimethyl sulfate and methyl tosylate.

Preferably, in steps S2 and S7, the alkali is one or more of sodium hydroxide, potassium carbonate, sodium hydride and cesium carbonate.

Preferably, in the steps S2 and S4, the low temperature condition is-40 to 10 ℃.

Preferably, in steps S1, S7 and S9, the organic solvent is one or more selected from ethyl acetate, methanol, methyl tert-butyl ether, toluene, dichloromethane and N, N-dimethylformamide.

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

the method has the advantages of mild reaction conditions, low raw material price, no relation with dangerous goods and great advantages when being put into mass production.

Drawings

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

FIG. 1 is a nuclear magnetic diagram of a process for preparing 3, 5-dichloro-2-iodoanisole according to example 1 of the present invention;

FIG. 2 is a nuclear magnetic diagram of the process for preparing 3, 5-dichloro-2-iodoanisole described in example 2 of the present invention;

FIG. 3 is a nuclear magnetic diagram of the process for preparing 3, 5-dichloro-2-iodoanisole 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:

3, 5-dichlorophenol (20g,122.7mmol) and methyl tert-butyl ether (200ml) are added into a three-neck flask and stirred uniformly;

cooling the system to-10 deg.C, adding sodium hydride (5g,208.3mmol) for several times, and stirring;

the temperature of the system is restored to room temperature, and the mixture is stirred and reacts for 30 min;

reducing the temperature of the system to-10 ℃ again, slowly adding the iodine (31.2g,122.9mmol), recovering the system to room temperature after the addition is finished, and stirring for reaction overnight;

adding diluted hydrochloric acid (100ml) to quench the reaction, stirring, and adding ethyl acetate (200ml x 3) to extract;

combining the organic layers, rinsing twice with saturated salt solution, drying once with anhydrous magnesium sulfate, and evaporating the solvent to obtain an intermediate product, namely 3, 5-dichloro-2-iodophenol;

adding the intermediate product 3, 5-dichloro-2-iodophenol (5g,17.3mmol), cesium carbonate (6g,18.4mmol) and DMF (50ml) into a single-mouth reaction bottle, and uniformly stirring;

adding methyl iodide (3g,21.1mmol) under the protection of nitrogen, and stirring for reaction overnight;

stopping stirring, pouring the reaction solution into ice water, and adding ethyl acetate (50ml x 3) for extraction;

and combining organic layers, rinsing with saturated saline, drying with anhydrous magnesium sulfate, and evaporating the solvent to obtain the product 3, 5-dichloro-2-iodoanisole.

The product obtained in this example was 97% pure and 64% yield, as shown in FIG. 1.

Example 2:

adding 3, 5-dichlorophenol (20g,122.7mmol) and methanol (300ml) into a three-neck flask, and uniformly stirring;

the temperature of the system was lowered to-20 deg.C, sodium hydroxide (14.7g,367.5mmol) was added in small portions and stirred well.

Recovering the temperature of the system to room temperature, and stirring for reaction for 2 hours;

then the temperature of the system is reduced to-20 ℃, the iodine element (93.4g,368.0mmol) is slowly added, after the addition is finished, the system is recovered to the room temperature, and the reaction is stirred overnight.

Adding concentrated hydrochloric acid (100ml) to quench the reaction, stirring, and adding ethyl acetate (200ml x 3) to extract;

the organic layers were combined, rinsed twice with saturated brine, dried once over anhydrous magnesium sulfate, and the solvent was evaporated to dryness to give an intermediate 3, 5-dichloro-2-iodophenol.

Adding the intermediate product 3, 5-dichloro-2-iodophenol (5g,17.3mmol), potassium hydroxide (2g,35.6mmol) and ethyl acetate (50ml) into a single-mouth reaction bottle, and uniformly stirring;

adding dimethyl sulfate (4.4g,34.6mmol) under the protection of nitrogen, and stirring for reaction overnight;

stopping stirring, pouring the reaction solution into ice water, and adding dichloromethane (50ml 4) for extraction;

and combining organic layers, rinsing with saturated saline, drying with anhydrous magnesium sulfate, and evaporating the solvent to obtain the product 3, 5-dichloro-2-iodoanisole.

The product obtained in this example was 97% pure and 45% yield, as shown in FIG. 2.

Example 3:

adding 3, 5-dichlorophenol (20g,122.7mmol) and toluene (200ml) into a three-neck flask, and uniformly stirring;

cooling the system to-40 deg.C, adding potassium hydroxide (34.4g,613.2mmol) in small amount for several times, and stirring;

recovering the temperature of the system to room temperature, and stirring for reaction for 5 hours;

the temperature of the system is reduced to-40 ℃ again, the iodogen (31.1g,122.7mmol) is slowly added, and after the addition is finished, the system is recovered to the room temperature and stirred for reaction overnight.

Adding glacial acetic acid (500ml) to quench the reaction, stirring, and adding ethyl acetate (200ml x 3) to extract;

the organic layers were combined, rinsed twice with saturated brine, dried once over anhydrous magnesium sulfate, and the solvent was evaporated to dryness to give an intermediate 3, 5-dichloro-2-iodophenol.

The intermediate 3, 5-dichloro-2-iodophenol (5g,17.3mmol), potassium carbonate (4.8g,34.6mmol) and methanol (50ml) were added to a single-neck reaction flask and stirred well.

Methyl tosylate (8.9g,51.9mmol) was added under nitrogen and the reaction stirred overnight.

Stopping stirring, pouring the reaction solution into ice water, and adding dichloromethane (50ml 4) for extraction;

and combining organic layers, rinsing with saturated saline, drying with anhydrous magnesium sulfate, and evaporating the solvent to obtain the product 3, 5-dichloro-2-iodoanisole.

The product obtained in this example was 95% pure and 64% yield as shown in FIG. 3.

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.