CN113511960A - Synthesis method of 1-chloro-3-methoxy-5-methylbenzene - Google Patents
Synthesis method of 1-chloro-3-methoxy-5-methylbenzene Download PDFInfo
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- CN113511960A CN113511960A CN202110959961.5A CN202110959961A CN113511960A CN 113511960 A CN113511960 A CN 113511960A CN 202110959961 A CN202110959961 A CN 202110959961A CN 113511960 A CN113511960 A CN 113511960A
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- C07—ORGANIC CHEMISTRY
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
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Abstract
The invention belongs to the technical field of synthesis of medicinal compounds, and particularly discloses a synthesis method of 1-chloro-3-methoxy-5-methylbenzene. The synthesis method provided by the invention adopts 1-chloro-3-halogenated toluene as a raw material, and prepares the product 1-chloro-3-methoxy-5-methylbenzene through heating reaction with sodium methoxide. The method has the advantages of cheap and easily obtained raw materials, convenient production and easy purification, and can be developed into an industrial production method.
Description
Technical Field
The invention relates to the technical field of synthesis of medicinal compounds, in particular to a synthesis method of 1-chloro-3-methoxy-5-methylbenzene.
Background
The 1-chloro-3-methoxy-5-methylbenzene compound is a very important medical intermediate and is a key core structure with very high use frequency in drug research and development. At present, the synthesis methods comprise the following two methods:
(1) 1, 3-dichloro-5-methoxybenzene is used as a raw material, and reacts with magnesium metal to form a Grignard reagent, and then reacts with dimethyl sulfate to obtain 1-chloro-3-methoxy-5-methylbenzene, wherein the reaction equation is shown as follows; the method firstly reacts with the magnesium metal to generate the Grignard reagent, the one-step reaction is very dangerous and is not easy to control, once the reaction is out of control, the combustion and explosion are easy to occur, and in addition, a virulent methylating reagent, namely dimethyl sulfate, is also used, so the method has high danger, and is particularly not suitable for industrial large-scale production;
(2) 2, 6-dichloro-4-methoxyaniline is used as a raw material, 1-chloro-3-methoxy-5-methylbenzene is obtained by a diazotization deamination method, and a reaction equation is shown as follows; the reaction is not easy to control because of the diazotization reaction, and the generated diazonium salt has potential explosion risk. In addition, the reaction solvent is hydrochloric acid solution, sodium nitrite is also needed to be used, a large amount of acid solution generated by the reaction causes great environmental pollution and disposal cost, and excessive sodium nitrite generates nitrous acid in the acid solution, so that extremely toxic nitrogen dioxide gas is generated; the method has expensive raw materials and serious pollution, and cannot be used for industrial mass production;
aiming at the problems existing in the existing synthesis of the 1-chloro-3-methoxy-5-methylbenzene, a new synthesis method needs to be developed to replace the existing synthesis process, and the method has important significance for realizing the green and efficient production of the 1-chloro-3-methoxy-5-methylbenzene.
Disclosure of Invention
The invention mainly solves the technical problem of providing a synthesis method of 1-chloro-3-methoxy-5-methylbenzene, and the method has the advantages of cheap and easily obtained raw materials, convenient production, environmental protection and safety.
In order to solve the technical problems, the invention adopts the following technical scheme: a synthetic method of 1-chloro-3-methoxy-5-methylbenzene comprises the following reaction equation:
wherein X is F, Cl or Br;
the synthesis method comprises the following steps: 1-chloro-3-halogenotoluene is used as a raw material, the raw material is mixed with sodium methoxide, and then the mixture is heated to react to prepare the product 1-chloro-3-methoxy-5-methylbenzene.
In a preferred embodiment of the present invention, a solvent is further added when the raw material is mixed with sodium methoxide, and the solvent is one or a mixture of several of methanol, N-dimethylformamide, N-dimethylacetamide and dimethylsulfoxide.
As a preferred embodiment of the present invention, the synthesis method comprises the steps of: dissolving the raw material in the solvent to prepare a raw material solution; adding sodium methoxide solid or sodium methoxide solution into the raw material solution in batches, and then heating for reaction; the sodium methoxide solution is formed by mixing sodium methoxide and the solvent.
In a preferred embodiment of the present invention, the raw material solution is heated to 40 to 60 ℃, and then sodium methoxide solid or sodium methoxide solution is added to the raw material solution in batches, followed by heating reaction.
As a preferred embodiment of the invention, the solvent is methanol or dimethyl sulfoxide (DMSO), preferably dimethyl sulfoxide (DMSO).
In a preferred embodiment of the present invention, the reaction temperature of the heating reaction is 70 to 150 ℃, and more preferably 90 to 110 ℃.
As a preferred embodiment of the present invention, in the following general formula, X is Cl,
in a preferred embodiment of the present invention, the molar equivalent ratio of the raw material to the sodium methoxide is 1 (2 to 10).
More preferably, the reaction equivalent ratio of the raw material to the sodium methoxide is 1 (5-9), and more preferably 1 (7-9).
The invention also provides the 1-chloro-3-methoxy-5-methylbenzene prepared by the synthesis method.
The invention provides a novel synthesis method of 1-chloro-3-methoxy-5-methylbenzene, which adopts cheap and easily obtained 1-chloro-3-halogenated methylbenzene as a raw material and sodium methoxide to obtain the 1-chloro-3-methoxy-5-methylbenzene through substitution reaction. The method has the advantages of cheap and easily obtained raw materials, mild reaction conditions, convenient production operation and easy purification, and can be developed into an industrial production method.
Detailed Description
The technical solution of the present invention will be described in detail by examples.
Example 1
This example provides a method for synthesizing 1-chloro-3-methoxy-5-methylbenzene, the reaction equation is:
the synthesis process is as follows:
1, 3-dichloro-5-methylbenzene (starting material) (20g, 124.2mmol) was dissolved in 300 ml of dimethyl sulfoxide, and the temperature was raised to 50 ℃ whereupon sodium methoxide (33.5g, 621mmol) as a solid was added in portions. Then, the reaction mixture was heated to 95 ℃ with stirring, and the reaction was carried out for 15 hours while maintaining the temperature. Pouring the reacted reaction solution into 1000 ml of ice-water mixed solution, extracting with dichloromethane, combining organic phases, washing with saturated saline solution for 3 times, drying the organic phases, spin-drying, and purifying by a column to obtain 13g of the product 1-chloro-3-methoxy-5-methylbenzene with the yield of 67%.
Example 2
This example provides a method for synthesizing 1-chloro-3-methoxy-5-methylbenzene, the reaction equation is:
the synthesis process is as follows:
1, 3-dichloro-5-methylbenzene (starting material) (20g, 124.2mmol) was dissolved in 300 ml of dimethyl sulfoxide (DMSO), and then the temperature was raised to 50 ℃ at which time a solution of sodium methoxide (53.7g, 993.6mmol) in DMSO was added dropwise. After the dropwise addition, the reaction solution was heated to 100 ℃ with stirring, and the reaction was carried out for 12 hours while maintaining the temperature. Then the reaction solution is poured into 1000 ml of ice-water mixed solution, then dichloromethane is used for extraction, organic phases are combined, saturated saline solution is used for washing for 3 times, the organic phases are dried and dried in a spinning mode, then column purification is carried out, and 18g of the product 1-chloro-3-methoxy-5-methylbenzene is obtained, and the yield is 92.3%.
Example 3
This example provides a method for synthesizing 1-chloro-3-methoxy-5-methylbenzene, the reaction equation is:
the synthesis process is as follows:
1, 3-dichloro-5-methylbenzene (starting material) (2Kg, 12.42mol) was dissolved in 30 liters of dimethyl sulfoxide, and then warmed to 50 ℃ whereupon sodium methoxide (5.37Kg, 99.36mol) as a solid was added in portions. After the addition, the reaction solution is heated to 100 ℃ under stirring, and the reaction is carried out for 15 hours under heat preservation. Then the reaction solution is poured into 100 liters of ice-water mixed solution, then dichloromethane is used for extraction, organic phases are combined, saturated saline solution is used for washing for 3 times, the organic phases are dried and dried, and then the reduced pressure distillation is carried out to obtain 1.58Kg of 1-chloro-3-methoxy-5-methylbenzene with the yield of 81.0 percent.
Example 4
This example provides a method for synthesizing 1-chloro-3-methoxy-5-methylbenzene, the reaction equation is:
the synthesis process is as follows:
1, 3-dichloro-5-methylbenzene (starting material) (20g, 124.2mmol) was dissolved in 300 ml of methanol, and then the temperature was raised to 40 ℃ whereupon a methanol solution of sodium methoxide (53.7g, 993.6mmol) was added dropwise. After the dropwise addition, the reaction solution was heated to 90 ℃ with stirring, and the reaction was carried out for 15 hours while maintaining the temperature. Then the reaction solution was poured into 1000 ml of ice-water mixed solution, followed by extraction with dichloromethane, and the organic phases were combined, washed 3 times with saturated brine, dried, spun-dried, and then subjected to column chromatography to obtain 8.2g of the product 1-chloro-3-methoxy-5-methylbenzene with a yield of 42.1%.
The nuclear magnetic analysis data of the prepared product 1-chloro-3-methoxy-5-methylbenzene are as follows:1H-NMR(400 MHz,CDCl3)：6.76(s，1H)；6.70(t，1H)；6.59(s，1H)；3.77(s，3H)；2.29(s，3H)。
as can be seen from the above examples, the synthesis method of the present invention can successfully prepare the target product in both gram-level and kilogram-level.
Wherein, the solvent adopted by the reaction system is dimethyl sulfoxide (DMSO) as the best solvent.
In the reaction, the molar ratio of the raw material 1, 3-dichloro-5-methylbenzene to the sodium methoxide is preferably 1 (7-8).
The above description is only an example of the present invention, and is not intended to limit the scope of the present invention, and all equivalent modifications made by the present invention in the specification or other related fields directly or indirectly are included in the scope of the present invention.
Claims (9)
1. A synthetic method of 1-chloro-3-methoxy-5-methylbenzene is characterized in that the reaction equation of the synthetic method is as follows:
wherein X is F, Cl or Br;
the synthesis method comprises the following steps: 1-chloro-3-halogenotoluene is used as a raw material, the raw material is mixed with sodium methoxide, and then the mixture is heated to react to prepare the product 1-chloro-3-methoxy-5-methylbenzene.
2. The synthesis method according to claim 1, wherein a solvent is further added when the raw material is mixed with sodium methoxide, and the solvent is one or more of methanol, N-dimethylformamide, N-dimethylacetamide and dimethylsulfoxide.
3. The method of synthesis according to claim 2, characterized in that it comprises the steps of: dissolving the raw material in the solvent to prepare a raw material solution; adding sodium methoxide solid or sodium methoxide solution into the raw material solution in batches, and then heating for reaction; the sodium methoxide solution is formed by mixing sodium methoxide and the solvent.
4. A synthesis process according to claim 2 or 3, characterized in that the solvent is methanol or dimethyl sulfoxide.
5. The synthesis method according to claim 4, wherein the reaction temperature of the heating reaction is 70-150 ℃, preferably 90-110 ℃.
6. The synthetic method according to any one of claims 1 to 5, wherein X is Cl.
7. The synthesis method according to claim 6, wherein the reaction equivalent ratio of the raw material to the sodium methoxide is 1 (2-10).
8. The synthesis method according to claim 7, wherein the reaction equivalent ratio of the raw material to the sodium methoxide is 1 (5-9).
9. 1-chloro-3-methoxy-5-methylbenzene prepared by the synthesis method of any one of claims 1 to 8.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101501002A (en) * | 2006-08-16 | 2009-08-05 | 弗·哈夫曼-拉罗切有限公司 | Non-nucleoside reverse transcriptase inhibitors |
| CN106518630A (en) * | 2015-09-10 | 2017-03-22 | 江苏扬农化工股份有限公司 | Method for synthesizing 6-chloro-2-methoxytoluene |
| CN113248351A (en) * | 2021-05-26 | 2021-08-13 | 绍兴上虞新银邦生化有限公司 | Preparation method of 6-chloro-2-methoxytoluene and synthetic process of methoxyfenozide |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101501002A (en) * | 2006-08-16 | 2009-08-05 | 弗·哈夫曼-拉罗切有限公司 | Non-nucleoside reverse transcriptase inhibitors |
| CN106518630A (en) * | 2015-09-10 | 2017-03-22 | 江苏扬农化工股份有限公司 | Method for synthesizing 6-chloro-2-methoxytoluene |
| CN113248351A (en) * | 2021-05-26 | 2021-08-13 | 绍兴上虞新银邦生化有限公司 | Preparation method of 6-chloro-2-methoxytoluene and synthetic process of methoxyfenozide |
Non-Patent Citations (1)
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| DAVID J HART等: "A New synthesis of defucogilvocarcin M", 《TETRAHEDRON LETTERS》 * |
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