CN113582818A - Synthetic method of 3-halogen-2-alkylphenol - Google Patents
Synthetic method of 3-halogen-2-alkylphenol Download PDFInfo
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- 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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Abstract
The invention discloses a synthetic method of 3-halogen-2-alkylphenol, belonging to the technical field of organic synthesis. Taking 2, 6-dihalo alkyl benzene as a raw material, nucleophilic substituting with dibenzyl alcohol in the presence of inorganic base, then carrying out Pd/C hydrogenation debenzylation reaction, or carrying out Grignard exchange with metal magnesium in the presence of n-butyl bromide/chlorine, and then introducing air/oxygen to obtain the 3-halogen-2-alkylphenol. The method has the advantages of high regioselectivity, good yield, simple operation process and the like, and the purity of the obtained product can reach more than 99.5 percent.
Description
Technical Field
The invention relates to a synthetic method of 3-halogen-2-alkylphenol, belonging to the field of organic synthesis.
Background
3-halo-2-alkylphenols are important intermediates for medicines, pesticides, dyes and the like, and are widely applied because the aromatic ring functional groups can be used for chemical reactions such as aldehyde, carboxylic acid, cyano and the like derived from alkyl, various substitution reactions derived from halogen and ether derived from phenolic hydroxyl. The document [ Journal of Medicinal Chemistry,2017,60,1417-1431] reports 3-bromo-2-methylphenol as the main raw material for the synthesis of GPR40 agonists for the treatment of diabetes. The chemical formula of the medicine is as follows:
patent WO2017/90002,2017, a2 reports that 3-fluoro-2-methylphenol is useful for the synthesis of a medicament for the prevention or treatment of diseases or disorders associated with abnormal activity of PI3K, such as inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, immunooncology, renal cancer, hepatitis c, hematological malignancies and multiple myeloma. The chemical formula of the medicine is as follows:
the existing synthesis method of the compound mainly adopts 2-methyl-3-haloaniline as a raw material, and 2-methyl-3-halophenol is obtained by diazotization and hydrolysis. The reaction equation is as follows:
patent WO2015/124651,2015, a1, reported that 1 equivalent of 1, 3-dichloro-2-methylbenzene was reacted with 3.0 equivalents of aqueous KOH (85%) in the presence of 10.0 equivalents of methanol to give 3-chloro-2-methylphenol in 86% isolated yield after 20 hours at up to 200 ℃; the reaction equation is as follows:
in the method, potassium chloride is generated after the reaction, so that the reaction kettle is easily subjected to point corrosion in an alkaline high-temperature environment, and the service life of the reaction kettle is shortened.
Therefore, the development of a synthetic method more suitable for industrial production has important research significance.
Disclosure of Invention
In order to overcome the technical defects, the invention discloses a synthetic method of 3-halogen-2-alkylphenol.
Taking 2, 6-dihalo alkyl benzene as a raw material, nucleophilic substituting with dibenzyl alcohol in the presence of inorganic base, then carrying out Pd/C hydrogenation debenzylation reaction, or carrying out Grignard exchange with n-butyl bromide/chlorine and magnesium, and then introducing air/oxygen to obtain the 3-halogen-2-alkyl phenol. The method has the advantages of high regioselectivity, good yield, simple operation process and the like, and the purity of the obtained product can reach more than 99.5 percent.
The invention relates to a synthesis method of 3-halogen-2-alkylphenol, which comprises the following steps:
the method comprises the following steps: mixing the compound A with catalysts of sodium tetrakis (3, 5-bis (trifluoromethyl) phenyl) borate and sulfolane, adding inorganic base, reacting at high temperature, and then adding palladium/carbon for catalytic hydrogenation to obtain 3-halogen-2-alkylphenol B;
the second method comprises the following steps: mixing the compound A, n-butyl bromide/chlorine and magnesium metal in an organic solvent, carrying out Grignard reagent exchange after initiation, then introducing air/oxygen for reaction, and hydrolyzing to obtain the 3-halogen-2-alkylphenol B.
The reaction equation is expressed as follows:
wherein: r is C1-C4 alkyl; x is halogen;
further, in the above technical solution, in the first method, the inorganic base is selected from potassium hydroxide, sodium hydroxide, potassium tert-butoxide or sodium tert-butoxide, and the high temperature is selected from 100-.
Further, in the above technical scheme, in the first method, the molar ratio of the compound a, the inorganic base and the dibenzyl alcohol is 1: 1.05-1.48: 1.01-1.22.
Further, in the above technical scheme, in the first method, the palladium-carbon is 5% Pd/C or 10% Pd/C, the amount is 3-20% of the weight of the compound A, and the hydrogenation pressure is 0.1-0.12 MPa.
Further, in the above technical solution, the organic solvent in the second method is selected from tetrahydrofuran or 2-methyltetrahydrofuran.
Furthermore, in the above technical scheme, a catalytic amount of cobalt tetraphenylporphyrin is added before the air/oxygen reaction in the second method, and the addition amount is 0.01 to 0.03eq of the compound A, so that the oxidation can be accelerated.
Further, in the above technical scheme, the ratio of compound a, magnesium and n-butyl bromide/chloride in method two is 1: 1.00-1.05: 1.01-1.02.
Further, in the above technical scheme, compound a preferably has the following structure:
for one mode of using the method, compound 1 and compound 2 are preferably prepared. For using the method two way, compound 2, compound 3, compound 4 and compound 5 are preferably prepared. Compounds 1-5 correspond to the structures:
advantageous effects of the invention
1) 1, 3-dihalo-2-toluene is used as a raw material, the temperature is prevented from being overhigh during nucleophilic substitution, the reaction time is greatly shortened, and a dibenzyl alcohol reagent is adopted, so that one halogen is subjected to nucleophilic substitution, the other halogen is not easy to react, and disubstituted impurities are reduced.
2) When the halogen is chlorine or bromine, a Grignard reagent exchange mode is skillfully adopted, and the Grignard reagent is synthesized by n-butyl bromide and metal magnesium, and simultaneously, Grignard exchange is carried out with 1, 3-dihalogen-2-toluene; the method avoids the diazo salt/re-hydrolysis mode, reduces the waste water, and meets the development requirement of green chemistry.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
Synthesis of 3-fluoro-2-methylphenol and 3-chloro-2-methylphenol
Example 1
Adding 25.6g (0.2mol,1eq) of 1, 3-difluorotoluene, 0.26g of sodium tetrakis (3, 5-bis (trifluoromethyl) phenyl) borate, 37.6g (0.204mol,1.02eq) of dibenzyl alcohol and 180mL of sulfolane into a reaction bottle under the protection of nitrogen, mixing, heating to 40 ℃, adding 11.76g (0.21mol,1.05eq) of KOH in batches, heating to 120 ℃, stirring for reaction for 3 hours, cooling to room temperature, adding water and acetic acid to adjust the pH value to 6.5-6.8, extracting with 200mL of methyl tert-butyl ether, washing an organic phase with saturated ammonium chloride and water, concentrating the organic phase under reduced pressure, replacing with ethanol, adding 2.6g of 5% Pd/C, hydrogenating for 12 hours at 0.1MPa, filtering Pd/C through kieselguhr, adding 0.12g of thiobisphenol into a filtrate, distilling under reduced pressure to remove ethanol, distilling under high vacuum to obtain 21.1g of 3-fluoro-2-methylphenol with yield of 83.2, and GC content is 99.7%.
Example 2
Under the protection of nitrogen, 32.2g (0.2mol,1eq) of 1, 3-dichlorotoluene, 0.32g of sodium tetrakis (3, 5-bis (trifluoromethyl) phenyl) borate, 37.6g (0.204mol,1.02eq) of dibenzyl alcohol and 180mL of sulfolane are added into a reaction bottle to be mixed, the temperature is raised to 40 ℃, 20.2g (0.21mol,1.05eq) of sodium tert-butoxide is added in batches, the temperature is raised to 100 ℃, stirring reaction is carried out for 3 hours, the temperature is reduced to room temperature, water and acetic acid are added to adjust the pH value to be 6.5-6.8, 200mL of methyl tert-butyl ether are used for extraction, the organic phase is washed by saturated ammonium chloride and water, the organic phase is concentrated under reduced pressure, ethanol is used for replacement, 3.2g of 5% Pd/C is added, 0.1g of Pd/C is added, hydrogenation Mpa is carried out for 12 hours, Pd/C is filtered by diatomite, 0.1g of thiobisphenol is added into the filtrate, the organic phase is concentrated under reduced pressure to remove ethanol, 25.4g of 3-chloro-2-methylphenol is obtained by distillation under high vacuum, the yield was 89.1%, GC 99.5%.
Synthesis of 3-chloro-2-methylphenol, 3-chloro-2-ethylphenol, 3-bromo-2-methylphenol and 3-bromo-2-ethylphenol
Example 3
Under the protection of nitrogen, 3.0g of n-butyl chloride, 5g of magnesium chips (0.21mol,1.05eq) and 20mL of 2-methyltetrahydrofuran are added into a reaction bottle, the temperature is raised to 50 ℃, a plurality of iodine particles are added for initiation, then 300mL of 2-methyltetrahydrofuran solution containing 32.2g (0.2mol,1.0eq) of 1, 3-dichlorotoluene and 17.4g of n-butyl chloride is added dropwise at 55-60 ℃, the temperature is kept for 2 hours after the dropwise addition, and then the temperature is raised and the reflux reaction is carried out for 3 hours. Cooling to-25 ℃, introducing air until the pressure in the kettle is 0.5Mpa, reacting for 10 hours, adding 0.5M dilute hydrochloric acid to adjust the pH value to 3-4, extracting with 200mL ethyl acetate, washing with saturated salt water, adding 0.1g thiobisphenol into the organic phase, concentrating under reduced pressure, evaporating to remove the solvent, distilling under high vacuum to obtain 21.76g of 3-chloro-2-methylphenol, wherein the yield is 76.3 percent, and the GC content is 99.2 percent.
Example 4
Under the protection of nitrogen, 2.2g of 1-bromon-butane, 5g of magnesium chips (0.21mol,1.05eq) and 30mL of 2-methyltetrahydrofuran are added into a reaction bottle, the temperature is raised to 40 ℃, a plurality of iodine particles are added for initiation, then 280mL of 2-methyltetrahydrofuran solution containing 35.0g (0.2mol,1.0eq) of 1, 3-dichloroethylbenzene and 26.8g of 1-bromon-butane is added dropwise at 40-60 ℃, the temperature is kept for 2 hours after the dropwise addition, and then the temperature is raised for reflux reaction for 4 hours. Cooling to-25 ℃, introducing air until the pressure in the kettle is 0.5Mpa, reacting for 10 hours, adjusting the pH value to 3-4 by 0.5M dilute hydrochloric acid, extracting by 200mL ethyl acetate, washing by saturated salt water, adding 0.1g thiobisphenol into the organic phase, concentrating under reduced pressure, evaporating to remove the solvent, distilling under high vacuum to obtain 23.1g of 3-chloro-2-ethylphenol, wherein the yield is 73.8 percent, and the GC content is 99.5 percent.
Example 5
Under the protection of nitrogen, 3.0g of n-butyl chloride, 5g of magnesium chips (0.21mol,1.05eq) and 30mL of tetrahydrofuran are added into a reaction bottle, the temperature is raised to 50 ℃, a plurality of iodine particles are added for initiation, then 330mL of tetrahydrofuran solution containing 50g (0.2mol,1.0eq) of 1, 3-dibromotoluene and 17.4g of n-butyl chloride is added dropwise at 55-60 ℃, the temperature is kept for 2 hours after the dropwise addition, and then the temperature is raised for reflux reaction for 4 hours. Cooling to-25 ℃, introducing air to the kettle until the pressure is 0.5Mpa, reacting for 10 hours, adding 0.5M dilute hydrochloric acid to adjust the pH value to 3-4, extracting with 200mL ethyl acetate, washing with saturated salt water, adding 0.1g thiobisphenol into the organic phase, concentrating under reduced pressure, evaporating to remove the solvent, distilling under high vacuum to obtain 29.5g of 3-bromo-2-methylphenol, wherein the yield is 78.8%, and the GC content is 99.6%.
Example 6
Under the protection of nitrogen, 2.2g of 1-bromon-butane, 5g of magnesium chips (0.21mol,1.05eq) and 30mL of tetrahydrofuran are added into a reaction bottle, the temperature is raised to 40 ℃, a plurality of iodine particles are added for initiation, then 420mL of tetrahydrofuran solution containing 52.8g (0.2mol,1.0eq) of 1, 3-dibromoethylbenzene and 26.8g 1-bromon-butane is added dropwise at 40-60 ℃, the temperature is kept for 2 hours after the dropwise addition, and then the temperature is raised and the reflux reaction is carried out for 4 hours. Cooling to-25 ℃, introducing air until the pressure in the kettle is 0.5Mpa, reacting for 10 hours, adjusting the pH value to 3-4 by 0.5M dilute hydrochloric acid, extracting by 200mL ethyl acetate, washing by saturated salt water, adding 0.1g thiobisphenol into the organic phase, concentrating under reduced pressure, evaporating to remove the solvent, distilling under high vacuum to obtain 28.75g of 3-bromo-2-ethylphenol, the yield is 71.5%, and the GC content is 99.5%.
In this example, after completion of grignard exchange, 0.003mol of cobalt tetraphenylporphyrin was added to the reaction system before cooling to-25 ℃ and introducing air, the reaction time was 1.2 hours, the yield was 88.3%, GC: 99.1 percent.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.
Claims (7)
1. A method for synthesizing 3-halogen-2-alkylphenol is characterized by comprising the following steps:
wherein: r is C1-C4 alkyl; x is halogen;
the method comprises the following steps: mixing the compound A with catalysts of sodium tetrakis (3, 5-bis (trifluoromethyl) phenyl) borate and sulfolane, adding inorganic base, reacting at high temperature, and then adding palladium/carbon for catalytic hydrogenation to obtain 3-halogen-2-alkylphenol B;
the second method comprises the following steps: mixing the compound A, n-butyl bromide/chlorine and magnesium metal in an organic solvent, carrying out Grignard reagent exchange after initiation, then introducing air/oxygen for reaction, and hydrolyzing to obtain the 3-halogen-2-alkylphenol B.
2. The method of synthesizing 3-halo-2-alkylphenols according to claim 1, characterized in that: in the first method, the inorganic base is selected from potassium hydroxide, sodium hydroxide, potassium tert-butoxide or sodium tert-butoxide, and the high temperature is selected from 100-120 ℃.
3. The method of synthesizing 3-halo-2-alkylphenols according to claim 1, characterized in that: in the first method, the molar ratio of the compound A, the inorganic base and the dibenzyl alcohol is 1: 1.05-1.48: 1.01-1.22.
4. The method of synthesizing 3-halo-2-alkylphenols according to claim 1, characterized in that: in the first method, the palladium carbon is 5 percent Pd/C or 10 percent Pd/C, the dosage is 3 to 20 percent of the weight of the compound A, and the hydrogenation pressure is 0.1 to 0.12 Mpa.
5. The method of synthesizing 3-halo-2-alkylphenols according to claim 1, characterized in that: in the second method, the organic solvent is selected from tetrahydrofuran or 2-methyltetrahydrofuran.
6. The method of synthesizing 3-halo-2-alkylphenols according to claim 1, characterized in that: in the second method, the ratio of the compound A, magnesium and n-butyl bromide/chloride is 1: 1.00-1.05: 1.01-1.02.
7. The method of synthesizing 3-halo-2-alkylphenols according to claim 1, characterized in that: in the second method, a catalytic amount of tetraphenylporphyrin ferric chloride is added before the reaction of introducing air/oxygen, and the addition amount is 0.01 to 0.03eq of the compound A.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060160786A1 (en) * | 2005-01-20 | 2006-07-20 | Pfizer Inc | Substituted triazole derivatives as oxytocin antagonists |
| US20060276454A1 (en) * | 2005-06-07 | 2006-12-07 | Neurocrine Biosciences, Inc. | Monoamine re-uptake inhibitors and methods relating thereto |
| CN112645801A (en) * | 2020-12-27 | 2021-04-13 | 甘肃瀚聚药业有限公司 | Method for preparing o-fluorophenol by one-pot method |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060160786A1 (en) * | 2005-01-20 | 2006-07-20 | Pfizer Inc | Substituted triazole derivatives as oxytocin antagonists |
| US20060276454A1 (en) * | 2005-06-07 | 2006-12-07 | Neurocrine Biosciences, Inc. | Monoamine re-uptake inhibitors and methods relating thereto |
| CN112645801A (en) * | 2020-12-27 | 2021-04-13 | 甘肃瀚聚药业有限公司 | Method for preparing o-fluorophenol by one-pot method |
Non-Patent Citations (2)
| Title |
|---|
| HE ZHI等: "Continuous-Flow Synthesis of Functionalized Phenols by Aerobic Oxidation of Grignard Reagents", ANGEWANDTE CHEMIE, INTERNATIONAL EDITION (2014), vol. 53, no. 13, pages 3353 - 3357 * |
| HUNTER, SARAH M.等: "Process design methodology for organometallic chemistry in continuous flow systems", TETRAHEDRON (2018), vol. 74, no. 25, pages 3176 - 3182 * |
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