CN109651094B - Preparation method of p- (2-methoxy) ethylphenol - Google Patents
Preparation method of p- (2-methoxy) ethylphenol Download PDFInfo
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- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/05—Preparation of ethers by addition of compounds to unsaturated compounds
- C07C41/06—Preparation of ethers by addition of compounds to unsaturated compounds by addition of organic compounds only
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- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
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- 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
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
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Abstract
The p-chlorophenol is used as a raw material, the p-chlorophenol protected by phenolic hydroxyl is prepared through etherification reaction, and then the p- (2-methoxyl) ethylphenol is generated through Grignard reaction and chloro-substituted and methoxyl-substituted reaction. The novel preparation method of the p- (2-methoxyl) ethylphenol has the advantages of easily obtained raw materials, mild reaction conditions, high safety coefficient, strong operability, simple process, easy realization of industrialization, high product purity and stable quality, and completely meets the use requirements of the p- (2-methoxyl) ethylphenol as a medical intermediate.
Description
Technical Field
The invention relates to the field of organic synthetic drug chemistry, in particular to a metoprolol intermediate: a novel method for preparing p- (2-methoxy) ethylphenol.
Background
Para- (2-methoxy) ethylphenol is a key intermediate for synthesizing the drug metoprolol. Metoprolol (metoprolol) is an aminopropanol drug, a selective beta 1 receptor blocker, and is the first choice drug for treating hypertension in the world in recent years. It competes with excitatory adrenaline, as well as noradrenaline, and protects the heart at the site of the receptor, inhibits cardiac contractility, avoids hyperexcitability, and prevents nerve impulses. It also ensures the contraction of the smooth muscle of the heart wall itself. And it also has good therapeutic effect on angina pectoris caused by anoxia.
The synthesis of the p- (2-methoxyl) ethylphenol mainly comprises the following steps:
scheme 1:
the method starts from p-nitrotoluene, and synthesizes the p- (2-methoxy) ethylphenol through condensation, methyl etherification, reduction and diazotization hydrolysis, and the method has the problems of low yield, large pollution caused by diazotization hydrolysis and the like.
Scheme 2:
the route takes phenethyl alcohol as a raw material, and the phenethyl alcohol is subjected to methyl etherification, nitration, reduction and diazotization hydrolysis, but the pollution problem also exists, and the cost of the phenethyl alcohol is high.
Scheme 3:
according to the method, p-hydroxyacetophenone is used as a raw material, and steps such as alpha bromination, methoxy substitution, carbonyl reduction and the like are carried out, however, bromine is used in bromination, pollution is large, reduction needs Zn-Hg or metal catalysis, the pollution is large in the former, and the price of the latter is expensive.
Scheme 4:
according to the route, p-methoxyphenethanol is used as a raw material, and the steps of bromination, methoxy substitution and the like are carried out, but the raw material is not easy to obtain, the bromination uses large excess hydrobromic acid, the post-treatment is difficult, the pollution is large, the methoxy substitution also needs large excess sodium methoxide, the yield is low, and the cost is high.
In conclusion, the existing process for synthesizing the p- (2-methoxyl) ethylphenol generally has the problems of low yield, high cost, large pollution, large industrialization difficulty and the like. Therefore, the industrialization needs to be improved to realize the industrialization of p- (2-methoxy) ethylphenol.
The preparation method of the medical intermediate p- (2-methoxyl) ethylphenol provided by the invention has the advantages of simple operation, high chemical reaction yield, less three wastes, low raw material cost and capability of obtaining a high-purity finished product.
Disclosure of Invention
The invention aims to provide a novel preparation method of p- (2-methoxyl) ethylphenol which is a medicinal intermediate and is suitable for industrial production, simple to operate, relatively low in cost and relatively high in purity. Therefore, the synthetic route adopted by the invention is as follows:
in the invention, p-chlorophenol or p-bromophenol is used as a starting material, and is reacted with isobutene under the catalysis of acid to generate an intermediate I, the intermediate I is formatted and reacts with ethylene oxide to generate an intermediate II, the intermediate II is reacted with thionyl chloride to obtain p-2-chloroethylphenol, and finally methoxy substitution modification is carried out to obtain p- (2-methoxy) ethylphenol
The invention provides a preparation method of an intermediate p- (2-methoxyl) ethylphenol, which comprises the following steps:
1, reacting p-chlorophenol or p-bromophenol with isobutene to protect phenolic hydroxyl, and obtaining p-chlorophenol or p-bromophenol protected by phenolic hydroxyl;
carrying out Grignard reaction on p-chlorophenol or p-bromophenol protected by phenolic hydroxyl and magnesium to obtain a corresponding Grignard reagent, and further reacting with ethylene oxide to obtain p-hydroxyphenylethanol protected by phenolic hydroxyl;
3, carrying out chlorination and deprotection reaction on the p-hydroxyphenylethanol protected by phenolic hydroxyl and thionyl chloride at the temperature of 10-100 ℃ to obtain p-2-chloroethylphenol;
4, p-2-chloroethylphenol with MOH or MOCH3、MHCO3Or M2CO3And (3) performing methoxy substitution on the M which is alkali metal or alkaline earth metal to obtain p- (2-methoxy) ethyl phenol salt, and acidifying to obtain p- (2-methoxy) ethyl phenol.
According to a specific embodiment of the invention, p-chlorophenol or p-bromophenol reacts with isobutylene to protect phenolic hydroxyl group in step 1, so that p-chlorophenol or p-bromophenol protected by phenolic hydroxyl group, preferably p-chlorophenol, is obtained.
According to a specific embodiment of the present invention, the phenolic hydroxyl group-protected p-chlorophenol or p-bromophenol in step 2 is subjected to a Grignard reaction with magnesium to give the corresponding Grignard reagent, and is further reacted with ethylene oxide to give phenolic hydroxyl group-protected p-hydroxyphenylethanol, preferably phenolic hydroxyl group-protected p-chlorophenol.
According to a specific embodiment of the invention, the p-hydroxyphenylethanol protected by phenolic hydroxyl in the step 3 is subjected to chlorination and deprotection reaction with thionyl chloride at-10 to 100 ℃ to obtain p-2-chloroethylphenol, preferably at 45 to 60 ℃.
According to a particular embodiment of the invention, the p-2-chloroethylphenol in step 4 comprises MOH or MOCH in the presence of a base3、MHCO3Or M2CO3Under the action of (A), M is an alkali metal, preferably Na and K, and the alkali is most preferably NaOH or NaOCH3。
According to a specific embodiment of the present invention, there is provided a process for producing p- (2-methoxy) ethylphenol, comprising the steps of:
(1) carrying out methoxy substitution reaction on the p-2-chloroethylphenol under the action of alkali to obtain p- (2-methoxy) ethyl phenolate;
(2) acidifying p- (2-methoxy) ethyl phenate to obtain p- (2-methoxy) ethyl phenol,
the structures of p-2-chloroethylphenol, p- (2-methoxy) ethylphenolate and p- (2-methoxy) ethylphenol are shown below:
where M is an alkali metal or alkaline earth metal, preferably an alkali metal, particularly preferably Na or K.
According to a particular embodiment of the invention, the base used in step (1) is MOH or MOCH3、MHCO3Or MCO3M is an alkali metal or an alkaline earth metal, preferably M is an alkali metal, particularly preferably M is Na or K, and the base is preferably NaOH or NaOCH3。
According to a specific embodiment of the invention, the temperature of the substitution reaction in step (1) is-10 to 100 ℃, preferably 45 to 60 ℃.
According to a particular embodiment of the invention, step (1) is carried out in the presence of a solvent selected from methanol, ethanol, toluene, xylene, dichloroethane, acetonitrile, acetone, tetrahydrofuran or DMF (chinese name, N-dimethylformamide), preferably methanol, DMF.
According to a specific embodiment of the present invention, the acid used for the acidification reaction in step (2) is sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, acetic acid, preferably hydrochloric acid.
According to a specific embodiment of the present invention, the step (2) is carried out at-10 to 60 ℃, preferably at 10 to 30 ℃.
According to a specific embodiment of the present invention, p-2-chloroethylphenol is synthesized by:
p-chlorophenol or p-bromophenol is taken as a raw material, and is catalyzed by isobutene to generate an intermediate I;
the intermediate I is subjected to Grignard reaction and reacts with ethylene oxide to generate an intermediate II;
and (3) carrying out chlorination and deprotection reaction on the intermediate II and thionyl chloride to obtain p-2-chloroethylphenol, wherein X is selected from Cl or Br.
According to a specific embodiment of the invention, the intermediate II is subjected to chlorination and deprotection reaction with thionyl chloride at 10-100 ℃ to obtain p-2-chloroethylphenol.
According to a particular embodiment of the invention, intermediate I is subjected to a grignard reaction with magnesium to obtain a grignard reagent and further reacted with ethylene oxide to obtain intermediate II.
According to a particular embodiment of the invention, X is Cl.
Compared with the prior art, the invention has the technical advancement that:
1) compared with the prior synthesis method, the method avoids the purification of intermediates (such as reduced pressure distillation and other methods) through the telescoping reaction, and greatly improves the convenience of operation.
2) Avoids the dangerous and polluting processes such as nitration, diazotization hydrolysis and the like, is environment-friendly and has less three wastes.
3) P-chlorophenol or p-bromophenol is used as a raw material, the tert-butyl protected p-hydroxyphenol is obtained at a high yield, compared with methyl protection, the tert-butyl has better deprotection performance, demethylation conditions are harsher (methyl cannot be successfully removed under the action of thionyl chloride at 50-60 ℃), the yield is lower, the tert-butyl deprotection reaction conditions are mild (50-60 ℃), and the yield is higher (close to 100%).
4) Compared with bromination, chlorination reaction is easier in the third step, yield (about 95%) is higher than that of bromination, large excess hydrobromic acid is not needed, and the advantages of environmental protection and cost are obvious.
5) In the introduction of methoxy groups, use is made of bases, e.g. MOH or MOCH3Or MCO3Under the action of the (A), the target compound is obtained, and the use of dimethyl sulfate with higher toxicity is effectively avoided.
The method provided by the invention has the advantages of higher yield, low cost and less pollution, thereby being particularly suitable for industrial production.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the scope of the present invention in any way.
Example 1:
115g of p-chlorophenol, 260g of toluene and 3g of concentrated sulfuric acid are added into a 1L four-neck flask, the mixture is uniformly stirred, 120g of isobutene is slowly introduced at the internal temperature of lower than-10 ℃, the introduction is completed within 4h, the temperature is kept at-10 ℃ to 0 ℃ for 12h, 120g of 30% NaOH is added for quenching, 60g of 30% NaOH is washed once again, 60g of water is washed once, the toluene is removed, and the intermediate I-Cl (150g, the purity is 99.2%, and the yield is 90%) is obtained after concentration.
Example 2:
150g of p-bromophenol, 350g of toluene and 5g of concentrated sulfuric acid are added into a 1L four-neck flask, the mixture is uniformly stirred, 130g of isobutene is slowly introduced at the internal temperature of lower than minus 10 ℃, the mixture is completely introduced for 4h, the temperature is kept at minus 10 ℃ to 0 ℃ for 12h, 120g of 30% NaOH is added for quenching, 60g of 30% NaOH is washed again and 60g of water is washed once to remove the toluene, and the product is concentrated to obtain an intermediate I-Br (161g, the purity is 98.3%, and the yield is 81%).
Example 3:
A1L four-neck flask was charged with 23g of magnesium turnings, 150g of THF, N2Protecting, heating at 65 ℃, dissolving 150g of intermediate I-Cl obtained in example 1 in 150g of THF, slowly adding the THF, reacting for 16h at 72 ℃, cooling the reaction solution to 0-10 ℃, slowly dropwise adding 43g of ethylene oxide, keeping the temperature for 2-3 h at 10 ℃, dropwise adding 300g of 30% sulfuric acid solution, extracting 150g of toluene, washing an organic phase with 100g of water once, drying, recovering toluene and THF to obtain 150g of intermediate II crude product with purity of 91% and yield of 88%. The crude product can be directly subjected to the next reaction or purified by reduced pressure distillation to obtain 120g of pure product with the purity of 99%.
Example 4:
A1L four-neck flask was charged with 23g of magnesium turnings, 150g of THF, N2Protecting, heating at 65 ℃, dissolving 185g of intermediate I-Br in 200g of THF, slowly adding the THF into the reaction solution, keeping the temperature at 72 ℃ for reaction for 6h, cooling the reaction solution to 0-10 ℃, slowly dropwise adding 43g of ethylene oxide, keeping the temperature at 10 ℃ for 2-3 h after the addition is finished, dropwise adding 300g of 30% sulfuric acid solution, extracting 150g of toluene, washing an organic phase with 100g of water once, drying, recovering toluene and THF, and obtaining 140g of intermediate II crude product with purity of 88% and yield of 78%. The crude product can be directly used for the next reaction or purified by reduced pressure distillation to obtain 105g of pure product with the purity of 99 percent.
Example 5:
150g of the crude intermediate II from example 3, 200g of toluene and 15g of DMF were added to a 1L four-necked flask, the temperature was raised to 55-60 ℃ and 104g of SOCl was slowly added dropwise2The solution color deepens in the dripping process, after the dripping is finished, the solution is kept at 60 ℃ for 2h, the solution is cooled to 10-30 ℃, 100g of 10 percent NaOH solution is slowly dripped to quench the reaction, after the solution is stirred for half an hour, the solution is separated, the organic phase is concentrated to obtain 119g of p-2-chloroethylphenol, the purity is 90.5 percent, the yield is 96 percent, and the crude product can be directly subjected to the next reaction.
Example 6:
A1L four-necked flask was charged with 150g of intermediate II (99% purity) of example 3, 200g of toluene and 15g of DMF, heated to 55 to 60 ℃ and slowly dropped with 104g of SOCl2The solution color deepens in the dropping process, after the adding is finished, the temperature is kept at 60 ℃ for 2h, the solution is cooled to 10 to 30 ℃, 100g of 10 percent NaOH solution is slowly dropped to quench the reaction, the solution is separated after being stirred for half an hour, the organic phase is concentrated and passes through a column layer114g of product (98.5% purity) were isolated in 95% yield.
Example 7:
98g of NaOH and 300g of methanol are added into a 1L four-neck flask, heating and dissolving are carried out at 50 ℃, 119g of p-2-chloroethylphenol crude product obtained in example 5 is dissolved in 50g of methanol, slowly dropwise added into reaction liquid for 1h, kept at 50 ℃ and stirred for 6h, cooled to room temperature, dropwise added with hydrochloric acid, adjusted to pH value of 5-6, added with 100g of toluene for extraction, separated, concentrated in an organic phase, and then purified by reduced pressure distillation to obtain 94g of pure product with purity of 99.7% and yield of 90%.
Example 8:
130g of NaOCH are added into a 1L four-mouth flask3300g of methanol is heated and dissolved at 50 ℃, 119g of the crude p-2-chloroethylphenol obtained in example 5 is dissolved in 50g of methanol, slowly and dropwise added into the reaction solution, the solution is added for 1h, the solution is kept at 50 ℃ and stirred for 6h, cooled to room temperature, dropwise added with hydrochloric acid, the pH value is adjusted to 5-6, 100g of toluene is added for extraction, liquid separation is carried out, the organic phase is concentrated, and the crude product is purified by reduced pressure distillation to obtain 98g of pure product with the purity of 99.4 percent and the yield of 92 percent.
Example 9:
130g of NaOCH are added into a 1L four-mouth flask3300g of DMF, heating to 50 ℃ to dissolve, dissolving 119g of the crude p-2-chloroethylphenol obtained in example 5 in 50g of DMF, slowly dropwise adding the solution into the reaction solution for 1h, keeping the temperature at 50 ℃ and stirring for 6h, cooling to room temperature, dropwise adding hydrochloric acid, adjusting the pH to 5-6, adding 100g of toluene for extraction, separating the solution, concentrating the organic phase, and then carrying out reduced pressure distillation and purification on the crude product to obtain 90g of pure product with the purity of 98.2 percent and the yield of 90 percent88％。
The above detailed description is specific to one possible embodiment of the present invention, and the embodiment is not intended to limit the scope of the present invention, and all equivalent implementations or modifications without departing from the scope of the present invention should be included in the technical scope of the present invention.
Claims (8)
1. A preparation method of p- (2-methoxyl) ethylphenol is characterized by comprising the following steps:
(1) carrying out methoxy substitution reaction on p-2-chloroethylphenol under the action of alkali to obtain p- (2-methoxy) ethyl phenolate, wherein the alkali is MOH or MOCH3M is an alkali metal, the temperature of the substitution reaction is 45-60 ℃, and the step (1) is carried out in the presence of a solvent, wherein the solvent is selected from methanol or DMF;
(2) carrying out acidification reaction on the p- (2-methoxy) ethyl phenol salt to obtain p- (2-methoxy) ethyl phenol,
the structures of p-2-chloroethylphenol, p- (2-methoxy) ethylphenolate and p- (2-methoxy) ethylphenol are shown below:
the p-2-chloroethylphenol is synthesized by the following method:
p-chlorophenol or p-bromophenol is taken as a raw material, and is catalyzed by isobutene to generate an intermediate I;
carrying out Grignard reaction on the intermediate I and magnesium to obtain a Grignard reagent, and further reacting with ethylene oxide to obtain an intermediate II;
and (3) carrying out chlorination and deprotection reaction on the intermediate II and thionyl chloride at the temperature of 45-60 ℃ to obtain the p-2-chloroethylphenol, wherein X is Cl or Br.
2. The method of claim 1, wherein M is Na or K.
3. The method according to claim 1, wherein the base in step (1) is NaOH or NaOCH3。
4. The method according to claim 1, wherein the acid used for the acidification in step (2) is at least one of sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, and acetic acid.
5. The method according to claim 4, wherein the acid used for the acidification in step (2) is at least one of hydrochloric acid and dilute sulfuric acid.
6. The process according to claim 1, wherein step (2) is carried out at a temperature of-10 to 60 ℃.
7. The process according to claim 1, wherein step (2) is carried out at 10-30 ℃.
8. The process according to claim 1, characterized in that X is Cl.
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| CN111116328A (en) * | 2019-12-27 | 2020-05-08 | 江西美晶科技有限公司 | Preparation method of metoprolol intermediate |
| CN115286783B (en) * | 2021-12-29 | 2023-10-17 | 常熟耐素生物材料科技有限公司 | Preparation method of m-pentadecenyl phenol polyether |
| CN114702372B (en) * | 2022-03-25 | 2022-12-16 | 台州市前进化工有限公司 | Method for preparing 4- (2-methoxyl) ethylphenol |
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| CN1800128A (en) * | 2006-01-18 | 2006-07-12 | 上海应用技术学院 | Para-(2-methoxyl) ethylphenol synthesis method |
| CN107382683A (en) * | 2017-07-18 | 2017-11-24 | 荆门医药工业技术研究院 | A kind of synthetic method for preparing Metoprolol intermediate |
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| JPH0699352B2 (en) * | 1988-12-13 | 1994-12-07 | 北興化学工業株式会社 | Method for synthesizing p- or m- [2- (methoxy) ethyl] phenol |
| JPH0669982B2 (en) * | 1988-12-23 | 1994-09-07 | 北興化学工業株式会社 | 2- (p- or m-tert-butoxyphenyl) ethyl methyl ether and its synthesis method |
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| CN1800128A (en) * | 2006-01-18 | 2006-07-12 | 上海应用技术学院 | Para-(2-methoxyl) ethylphenol synthesis method |
| CN107382683A (en) * | 2017-07-18 | 2017-11-24 | 荆门医药工业技术研究院 | A kind of synthetic method for preparing Metoprolol intermediate |
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