CN113321575A - Preparation method of benzyl aryl ether and application of benzyl aryl ether in synthesis - Google Patents
Preparation method of benzyl aryl ether and application of benzyl aryl ether in synthesis Download PDFInfo
- Publication number
- CN113321575A CN113321575A CN202110658669.XA CN202110658669A CN113321575A CN 113321575 A CN113321575 A CN 113321575A CN 202110658669 A CN202110658669 A CN 202110658669A CN 113321575 A CN113321575 A CN 113321575A
- Authority
- CN
- China
- Prior art keywords
- compound
- benzyl aryl
- aryl ether
- alkyl
- synthesis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
- C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D313/12—[b,e]-condensed
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a high-efficiency method for synthesizing benzyl aryl ether by one-step reaction of benzaldehyde compound and phenolic compound, and the method is used for synthesizing 6, 11-dihydrodibenzo [ b, e ]]The application of the oxazepin-11-ketone compound; hair brushBenzyl aryl ethers and 6, 11-dihydrodibenzo [ b, e ]]The oxazepin-11-ketone compound has a chemical structural general formula shown in a formula I and a formula II respectively.
Description
Technical Field
The technical scheme of the invention relates to a preparation method of benzyl aryl ether and synthesis of a 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one compound, in particular to a method for synthesizing benzyl aryl ether by one-step reaction of a benzaldehyde compound and a phenol compound, and application of the method in synthesis of the 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one compound.
Background
6, 11-dihydrodibenzo [ b, e ] oxepin-11-one compounds and derivatives thereof are a class of substances with important biological activity and are key intermediates for synthesizing a plurality of drug molecules (Jiang, H.; et al. Green chem.2019, 21, 5368-one 5373.). For example, the fungicide pestalachoride B has significant antifungal activity against different plant pathogenic bacteria (Li, E.; et al. Bioorg. Med. chem.2008, 16, 7894-; 7899.), Doxepin (Chinese name: Doxepin) can be used to treat diseases such as depression (Scoccia, J.; et al. tetrahedron 2017, 73, 2913-; Shah, Y D.; et al. J. Clin. Sleep Med.2020, 16, 743-; Chen, Z.; et al. diabetes 2020, 69, 1126-; et al. J. Clin. Sleep. Med.2020, 16, 743-; Chen, Z.; et al. diabetes. 2020, 1126-; Phaolopatadine (Chinese name: Olopatadine) can treat diseases such as seasonal allergic conjunctivitis and rhinitis (Bosch, J. org. chem. 77, 6340; Abelm. 547J. org. chem. 51.; Eupatorin. 2006, Eupatori, J. multidot. 9.; et al. multidot. 9. multidot. multid.
The development of efficient methods for the preparation of such compounds has received considerable attention from organic chemists, as have a number of effective synthetic methods (Scoccia, J.; et al. tetrahedron 2017, 73, 2913-. Among the reported synthetic methods, Williams' ether synthesis and the substitution reaction of phenols on phthalide are commonly used for the synthesis of benzyl aryl ether as key intermediate (Ueno, K.; et al. J. Med. chem.1976, 19, 941-Bull 946; Kurokawa, M.; et al. chem. Pharm. Bull.1991, 39, 2564-Bull 2573.). For example: the method disclosed in chinese patent CN105418577A uses o-phthalaldehyde as a raw material, and comprises intramolecular cornicylol reaction under the action of strong base, followed by lactonization to obtain phthalide, and then the phthalide and phenol undergo substitution reaction in an alcohol solution of sodium methoxide to obtain a benzyl aryl ether intermediate, wherein a large amount of excess strong base and concentrated sulfuric acid are required in the reaction process; the method disclosed in chinese patent CN105367538A is to use methyl o-halomethylbenzoate as a raw material, and perform substitution reaction with phenol in an alcohol solution of sodium methoxide to obtain a benzyl aryl ether intermediate, where a large amount of excess sodium methoxide is required for the reaction; the method disclosed in chinese patent CN105330638A uses o-methylbenzoic acid as raw material, firstly adopts N-halo succinimide to perform halogenation, then performs intramolecular substitution reaction to obtain phthalide, and then performs substitution reaction with phenol in an alcohol solution of sodium methoxide to obtain a benzyl aryl ether intermediate. The three methods have the defect of narrow substrate application range. In summary, methods for efficiently and easily constructing key intermediates of benzyl aryl ethers under mild conditions are still lacking in the current methods for synthesizing 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one compounds and derivatives thereof.
This patent is through benzaldehyde class compound under the effect of stoichiometric trivalent phosphorus reagent, respectively with a series of phenolic compounds reactions, realized under mild condition, through the new method of one-step reaction synthesis benzyl aryl ether, benzaldehyde class compound contains the ortho-position and has the benzaldehyde substrate of aldehyde group, ester group, acylamino or cyano-group very much, benzyl aryl ether by the preparation of this kind of substituted benzaldehyde substrate can conveniently be used for synthesizing 6, 11-dihydrodibenzo [ b, e ] oxapin-11-ketone compound. Therefore, the invention provides a new method for efficiently synthesizing benzyl aryl ether through one-step reaction under mild conditions, and simultaneously provides a new method for synthesizing the 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one compound.
Disclosure of Invention
The technical problems to be solved by the invention are as follows: providing an efficient method for synthesizing benzyl aryl ether and derivatives thereof; provided is a novel method for synthesizing a 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one compound.
The technical scheme adopted by the invention for solving the technical problem is as follows:
the chemical structural general formula of the benzyl aryl ether provided by the invention is as follows:
wherein: r1Selected from aldehyde group, ester group COOR4Cyano, amido CONR5R6In the above radicals R4Is C1-C4 alkyl, R5，R6Hydrogen or C1-C4 alkyl; r2Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy; r3Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, cyano, aldehyde group and aryl.
The synthesis method of benzyl aryl ether comprises the following steps:
wherein: r1Selected from aldehyde group, ester group COOR4Cyano, amido CONR5R6In the above radicals R4Is C1-C4 alkyl, R5，R6Hydrogen or C1-C4 alkyl; r2Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy; r3Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, cyano, aldehyde group and aryl; r is selected from hydrogen, C1-C6 alkyl, phenyl, C1-C4 alkoxy, phenoxy, N-dimethylamino and N, N-diethylamino.
The chemical structural general formula of the 6, 11-dihydrodibenzo [ b, e ] oxepin-11-ketone compound is as follows:
wherein: r2Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy; r3Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, cyano, aldehyde group and aryl.
The benzyl aryl ether prepared by the invention can be applied to synthesizing 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one compounds according to the following synthetic route:
wherein: r1Selected from aldehyde group, ester group COOR4Cyano, amido CONR5R6In the above radicals R4Is C1-C4 alkyl, R5，R6Hydrogen or C1-C4 alkyl; r2Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy; r3Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, cyano, aldehyde group and aryl.
The method comprises the following steps:
A. preparation of benzyl aryl ether I:
a25 mL round-bottomed flask was charged with 5.0mL of an organic solvent, 0.5mmol of a benzaldehyde compound, 0.55mmol of a phenol compound, and 0.55mmol of a trivalent phosphorus reagent in this order, and the resulting reaction mixture was stirred at room temperature for 4 hours. And after the reaction is finished, removing the solvent through rotary evaporation, and purifying the crude product through 200-300-mesh silica gel column chromatography to obtain the benzyl aryl ether target compound. The eluent is petroleum ether and ethyl acetate with a boiling range of 60-90 ℃, and the volume ratio is 40: 1-10: 1. The yield of the obtained pure product is calculated, and is 30-97% according to different target compounds. The amount of the target compound I to be prepared and the volume of the reaction vessel can be enlarged or reduced in a corresponding ratio. The chemical structure and the physicochemical parameters of the target compound I are shown in table 1.
The organic solvent comprises toluene and benzene in a hydrocarbon solvent; tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether and 1, 4-dioxane in an ether solvent; dichloromethane, chloroform, and 1, 2-dichloroethane in halogenated hydrocarbon solvent.
The benzaldehyde compound comprises a phthalic aldehyde compound, a 2-aldehyde benzoate compound, an o-cyano benzaldehyde compound and a 2-aldehyde benzoic acid amide compound.
The phenolic compound comprises a substituted phenol.
The trivalent phosphorus reagent comprises phosphine alkane, tri (C1-C6 alkyl) phosphine, triphenylphosphine, phosphorous acid tri (C1-C4 alkyl) ester, tri (N, N-dimethylamino) phosphoramidite, tri (N, N-diethylamino) phosphoramidite and triphenyl phosphite.
B, preparation of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one Compound II:
according to the functional groups of benzyl aryl ether prepared by the invention, benzyl aryl ether is converted into intermediate carboxylic acid III by adopting an oxidation method and a hydrolysis method respectively.
1. An oxidation method: according to the known literature methods (see Wang, j.; et al, new j. chem.2013, 37, 1700), benzyl aryl ethers bearing an aldehyde function can be converted by oxidation into the corresponding carboxylic acid intermediate III:
wherein: r1Selected from aldehyde groups; r2Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy; r3Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, cyano, aldehyde group and aryl.
A25 mL reaction flask was charged with 1mmol of benzyl aryl ether, 1mmol of sodium tert-butoxide, and 4mL of tetrahydrofuran, and the flask was connected to an air-filled balloon and stirred at room temperature for 1 hour. After the reaction is finished, adding water and dilute hydrochloric acid to quench the reaction, extracting with ethyl acetate, drying an organic layer with anhydrous sodium sulfate, filtering, removing the solvent from the filtrate through rotary evaporation, purifying a crude product through 200-300-mesh silica gel column chromatography, wherein an eluent is petroleum ether with a boiling range of 60-90 ℃ and ethyl acetate, and the volume ratio is 20: 1-10: 1, so as to obtain a carboxylic acid intermediate III. The yield of the obtained pure product is calculated, and is 69-97% according to different target compounds.
2. A hydrolysis method: benzyl aryl ethers bearing ester, cyano or amide functional groups can be converted to the corresponding carboxylic acid intermediates III by hydrolysis according to established literature methods (see Khurana, j.m.; et al, monatsh. chem.2004, 135, 83-87):
wherein: r1Selected from ester groups COOR4Cyano, amido CONR5R6In the above radicals R4Is C1-C4 alkyl, R5，R6Hydrogen or C1-C4 alkyl; r2Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy; r3Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, cyano, aldehyde group and aryl.
Adding 1mmol of benzyl aryl ether, 5mmol of potassium hydroxide and 3mL of methanol into a 25mL round bottom flask, stirring for 1 hour at 30-60 ℃, adding water and dilute hydrochloric acid to quench the reaction after the reaction is finished, extracting with ethyl acetate, drying an organic layer with anhydrous sodium sulfate, filtering, removing the solvent from the filtrate through rotary evaporation, purifying a crude product through 200-300-mesh silica gel column chromatography, wherein an eluent is petroleum ether and ethyl acetate with the boiling range of 60-90 ℃, and the volume ratio is 20: 1-10: 1, so as to obtain the carboxylic acid target compound III. The yield of the obtained pure product is calculated, and is 69-97% according to different target compounds.
3. Closing the ring: the benzyl aryl ethers prepared by the oxidation and hydrolysis methods described above were subjected to ring closure reactions using the reported literature procedures (see Scoccia, J.; et al tetrahedron 2017, 73, 2913-) -2922) to effect the synthesis of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one compounds II:
wherein: r2Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy; r3Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, cyano, aldehyde group and aryl.
A25 mL reaction flask was charged with 1mmol of a carboxylic acid compound, 0.6mmol of ferrous chloride, 1mmol of 1, 1-dichloromethyl ether and 10mL of dichloromethane, and stirred at room temperature for 3 hours under nitrogen. After the reaction is finished, adding water to quench the reaction, extracting with dichloromethane, washing a water layer with a saturated sodium bicarbonate aqueous solution, combining organic layers, drying with anhydrous sodium sulfate, filtering, removing the solvent from the filtrate through rotary evaporation, purifying a crude product through 200-300-mesh silica gel column chromatography, and obtaining a target compound II, wherein an eluant is petroleum ether and ethyl acetate with the boiling range of 60-90 ℃ and the volume ratio of 40: 1-10: 1. The yield of the obtained pure product is calculated, and is 53-75% according to different target compounds.
The amounts of the 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one compound II and the carboxylic acid intermediate III prepared and the volume of the reaction vessel can be enlarged or reduced in corresponding proportion. The chemical structures and the physicochemical parameters of the compounds II and III are shown in Table 2.
The invention has the technical innovation and application that: the preparation method of the benzyl aryl ether I belongs to technical innovation, and the preparation method is applied to synthesis of a 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one compound II, and also belongs to technical innovation.
The present invention is more specifically illustrated by the specific preparation examples of the synthesis of benzyl aryl ether I and 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one compound II. The examples are intended to be illustrative of the invention only and are not intended to be limiting. The specific implementation mode is as follows:
the specific implementation mode is as follows:
example 1.
Synthesis and structure identification of benzyl aryl ether, R in the structural general formula1＝CHO，R2＝H，R3＝H。
In a 25mL round-bottom flask, 5.0mL of methylene chloride, 0.5mmol of o-phthalaldehyde, 0.55mmol of phenol, and 0.55mmol of triethyl phosphite were sequentially added, and the resulting reaction mixture was stirred at room temperature for 4 hours. After the reaction is finished, removing the solvent through rotary evaporation, purifying the crude product through 200-300-mesh silica gel column chromatography, wherein an eluent is a mixed solvent of petroleum ether and ethyl acetate with the boiling range of 60-90 ℃, the volume ratio is 40: l-30: 1, and colorless oily liquid is obtained, and the yield is 84%. The amount of the target compound I and the volume of the reaction vessel can be enlarged or reduced according to the corresponding proportion. The chemical structure and the physicochemical parameters of the target compound I are shown in table 1.
Example 2
Synthesis and structure identification of benzyl aryl ether, R in the structural general formula1＝CHO，R2＝H，R3＝H。
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the used trivalent phosphorus reagent is tris (N, N-dimethylamino) phosphoramidite, and the dosage is 0.55 mmol; a colorless oily liquid was obtained in a yield of 75%.
Example 3
Synthesis and structure identification of benzyl aryl ether, R in the structural general formula1＝CHO，R2＝H，R3＝4-Me。
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the phenolic compound is 4-methylphenol, and the using amount is 0.55 mmol; the pure white solid was obtained in 97% yield.
Example 4
Synthesis and structure identification of benzyl aryl ether, R in the structural general formula1＝CHO，R2＝H，R3＝4-OMe。
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the phenolic compound is 4-methoxyphenol, and the using amount is 0.55 mmol; the pure white solid was obtained in 87% yield.
Example 5
Synthesis and structure identification of benzyl aryl ether, R in the structural general formula1＝CHO，R2＝H，R3＝4-tBu。
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the used phenolic compound is 4-tert-butylphenol, and the using amount is 0.55 mmol; a colorless oily liquid was obtained in a yield of 96%.
Example 6
Synthesis and structure identification of benzyl aryl ether, R in the structural general formula1＝CHO，R2＝H，R3＝4-Ph。
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the phenolic compound is 4-phenylphenol, and the using amount is 0.55 mmol; the pure white solid was obtained in 92% yield.
Example 7
Synthesis and structure identification of benzyl aryl ether, R in the structural general formula1＝CHO，R2＝H，R3＝4-CH2CO2Me。
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the phenolic compound is 4-methyl acetate phenol, and the using amount is 0.55 mmol; the pure white solid was obtained in a yield of 90%.
Example 8
Synthesis and structure identification of benzyl aryl ether with general structural formula R1＝CHO，R2＝H，R3＝4-F。
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the used phenolic compound is 4-fluorophenol, and the using amount is 0.55 mmol; the pure white solid was obtained in 92% yield.
Example 9
Synthesis and structure identification of benzyl aryl ether, R in the structural general formula1＝CHO，R2＝H，R3＝4-Cl。
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the phenolic compound is 4-chlorophenol, and the dosage is 0.55 mmol; the pure white solid was obtained in 80% yield.
Example 10
Synthesis and structure identification of benzyl aryl ether, R in the structural general formula1＝CHO，R2＝H，R3＝4-Br。
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the used phenolic compound is 4-bromophenol, and the dosage is 0.55 mmol; the pure white solid was obtained in 82% yield.
Example 11
Synthesis and structure identification of benzyl aryl ether, R in the structural general formula1＝CHO，R2＝H，R3＝4-CF3。
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the phenolic compound is 4-trifluoromethyl phenol, and the using amount is 0.55 mmol; the pure white solid was obtained in 86% yield.
Example 12
Synthesis and structure identification of benzyl aryl ether, R in the structural general formula1＝CHO，R2＝H，R3＝4-CN。
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the used phenolic compound is 4-cyanophenol, and the using amount is 0.55 mmol; the pure white solid was obtained in 36% yield.
Example 13
Synthesis and structure identification of benzyl aryl ether, R in the structural general formula1＝CHO，R2＝H，R3＝2-Me。
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the phenolic compound is 2-methylphenol, and the dosage is 0.55 mmol; the pure white solid was obtained in a yield of 90%.
Example 14
Synthesis and structure identification of benzyl aryl ether, R in the structural general formula1＝CHO，R2＝H，R3＝2-Et。
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the phenolic compound is 2-ethylphenol, and the using amount is 0.55 mmol; pure pale yellow solid was obtained in 91% yield.
Example 15
Synthesis and structure identification of benzyl aryl ether, R in the structural general formula1＝CHO，R2＝H，R3＝2-iPr。
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the used phenolic compound is 2-isopropyl phenol, and the using amount is 0.55 mmol; a pale yellow oily liquid was obtained in 81% yield.
Example 16
Synthesis and structure identification of benzyl aryl ether, R in the structural general formula1＝CHO，R2＝H，R3＝2-OMe。
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the phenolic compound is 2-methoxyphenol, and the using amount is 0.55 mmol; a pale yellow oily liquid was obtained in 79% yield.
Example 17
Synthesis and structure identification of benzyl aryl ether, R in the structural general formula1＝CHO，R2＝H，R3＝2-Cl。
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the phenolic compound is 2-chlorophenol, and the dosage is 0.55 mmol; the pure white solid was obtained in 91% yield.
Example 18
Synthesis and structure identification of benzyl aryl ether, R in the structural general formula1＝CHO，R2＝H，R3＝2-Br。
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the used phenolic compound is 2-bromophenol, and the dosage is 0.55 mmol; the pure white solid was obtained in a yield of 90%.
Example 19
Synthesis and structure identification of benzyl aryl ether, R in the structural general formula1＝CHO，R2＝H，R3＝2-CH2CH＝CH2。
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the phenolic compound is 2-allyl phenol, and the using amount is 0.55 mmol; a pale yellow oily liquid was obtained in 75% yield.
Example 20
Synthesis and structure identification of benzyl aryl ether, R in the structural general formula1＝CHO，R2＝H，R3＝2-CHO。
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the phenolic compound is salicylaldehyde, and the dosage is 0.55 mmol; the pure white solid was obtained in 35% yield.
Example 21
Synthesis and structure identification of benzyl aryl ether, R in the structural general formula1＝CHO，R2＝H，R3＝3-Me。
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the phenolic compound is 3-methylphenol, and the dosage is 0.55 mmol; a colorless oily liquid was obtained in 92% yield.
Example 22
Synthesis and structure identification of benzyl aryl ether, R in the structural general formula1＝CHO，R2＝H，R3＝3-Br。
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the used phenolic compound is 3-bromophenol, and the dosage is 0.55 mmol; the pure white solid was obtained in a yield of 90%.
Example 23
Synthesis and structure identification of benzyl aryl ether, R in the structural general formula1＝CHO，R2＝H，R3＝3，5-Me2。
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the phenolic compound is 3, 5-dimethylphenol, and the using amount is 0.55 mmol; the pure white solid was obtained in 87% yield.
Example 24
Synthesis and structure identification of benzyl aryl ether, R in the structural general formula1＝CHO，R2＝H，R3＝3，4-OCH2O-。
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the used phenolic compound is sesamol, and the dosage is 0.55 mmol; pure pale yellow solid was obtained in 93% yield.
Example 25
Synthesis and structure identification of benzyl aryl ether, R in the structural general formula1＝CO2Me，R2＝H，R3＝H。
5.0mL of benzene, 0.5mmol of methyl anthranilate, 0.55mmol of phenol and 0.55mmol of triethyl phosphite are sequentially added into a 25mL reaction bottle, and the obtained reaction mixture is stirred and refluxed for 24 hours at the temperature of 80-90 ℃. After the reaction is finished, removing the solvent through rotary evaporation, purifying the crude product through 200-300-mesh silica gel column chromatography, wherein an eluent is a mixed solvent of petroleum ether and ethyl acetate with the boiling range of 60-90 ℃, the volume ratio is 40: 1-30: 1, the target compound of the benzyl aryl ether is obtained, the target compound is colorless oily liquid, and the yield is 48%.
Example 26
Synthesis and structure identification of benzyl aryl etherR in the general formula1＝CN，R2＝H，R3＝H。
In a 25mL reaction flask, 5.0mL of methylene chloride, 0.5mmol of o-cyanobenzaldehyde, 0.55mmol of phenol, and 0.55mmol of triethyl phosphite were sequentially added, and the resulting reaction mixture was stirred at room temperature for 24 hours. After the reaction is finished, removing the solvent through rotary evaporation, purifying the crude product through 200-300-mesh silica gel column chromatography, wherein an eluent is a mixed solvent of petroleum ether and ethyl acetate with the boiling range of 60-90 ℃, and the volume ratio is 40: 1-30: 1, so that the target compound of the benzyl aryl ether is obtained and is a white solid, and the yield is 42%.
Example 27
6, 11-dihydrodibenzo [ b, e ]]Synthesis and structural identification of oxazepin-11-one compound II, R in the structural general formula2＝H，R3＝H。
The synthesis of the target compound comprises two steps: preparing a carboxylic acid intermediate III from benzyl aryl ether I by an oxidation method or a hydrolysis method; and in the second step, the target compound II is prepared from the carboxylic acid intermediate III through cyclization reaction.
The first step is as follows: synthesis of carboxylic acid intermediate III, R in the structural formula2＝H，R3＝H。
The oxidation method comprises the following steps: a25 mL reaction flask was charged with 1mmol of benzyl aryl ether I (R)1＝CHO，R2＝H，R3H), 1mmol of sodium tert-butoxide and 4mL of tetrahydrofuran, a balloon filled with air is attached to the neck and stirred at room temperature for 1 hour. After the reaction is finished, adding water and dilute hydrochloric acid to quench the reaction, extracting with ethyl acetate, drying an organic layer with anhydrous sodium sulfate, filtering, removing the solvent from the filtrate through rotary evaporation, purifying a crude product through 200-300-mesh silica gel column chromatography, wherein an eluent is a mixed solvent of petroleum ether and ethyl acetate with a boiling range of 60-90 ℃, and the volume ratio is 20: 1-10: 1, so that a carboxylic acid intermediate is obtained, and is a white solid, and the yield is 74%. The amount of carboxylic acid intermediate produced and the volume of the reaction vessel can be scaled up or down in a corresponding proportion. The chemical structure and the physicochemical parameters of the carboxylic acid intermediate III are shown in Table 2.
The hydrolysis method comprises the following steps: a25 mL round bottom flask was charged with 1mmol of benzyl aryl ether I (R)1＝CO2Me，R2＝H，R3H), 5mmol of potassium hydroxide and 3mL of methanol are stirred for 1 hour at 30-60 ℃, water and dilute hydrochloric acid are added to quench the reaction after the reaction is finished, ethyl acetate is used for extraction, an organic layer is dried by anhydrous sodium sulfate, the filtration is carried out, the solvent is removed by rotary evaporation of the filtrate, the crude product is purified by 200-300-mesh silica gel column chromatography, the eluent is a mixed solvent of petroleum ether and ethyl acetate with a boiling range of 60-90 ℃, the volume ratio is 20: 1-10: 1, and a carboxylic acid intermediate is obtained and is a white solid, and the yield is 97%. The amount of carboxylic acid intermediate produced and the volume of the reaction vessel can be scaled up or down in a corresponding proportion. The chemical structure and the physicochemical parameters of the carboxylic acid intermediate III are shown in Table 2.
The second step is that: preparing a target compound II by cyclization reaction of a carboxylic acid intermediate III, wherein R in the structural general formula2＝H，R3＝H。
A25 mL reaction flask was charged with 1mmol of carboxylic acid intermediate III (R)2＝H，R3H), 0.6mmol of ferrous chloride, 1mmol of 1, 1-dichloromethyl ether and 10mL of dichloromethane were stirred at room temperature for 3 hours under nitrogen. After the reaction is finished, adding water to quench the reaction, extracting with dichloromethane, washing a water layer with a saturated sodium bicarbonate aqueous solution, combining organic layers, drying with anhydrous sodium sulfate, filtering, removing the solvent from the filtrate through rotary evaporation, purifying a crude product through 200-300-mesh silica gel column chromatography, wherein an eluent is a mixed solvent of petroleum ether and ethyl acetate with the boiling range of 60-90 ℃, and the volume ratio is 40: 1-30: 1, so that a target compound II is obtained and is a white solid, and the yield is 67%. The amount of the target compound to be prepared and the volume of the reaction vessel can be enlarged or reduced in a corresponding ratio. The chemical structure and the physicochemical parameters of the target compound II are shown in Table 2.
Example 28
6, 11-dihydrodibenzo [ b, e ]]Synthesis and structural identification of oxazepin-11-one compound II, R in the structural general formula2＝H，R3＝2-Me。
The carboxylic acid intermediate synthesis steps and process parameters were essentially the same as for the first oxidation procedure of example 27, except as set forth below:
r in the structural general formula of the benzyl aryl ether I1＝CHO，R2＝H，R32-Me in an amount of 1.0 mmol; the carboxylic acid intermediate was obtained as a white solid in 70% yield.
Synthesis of the object Compound II essentially the same as in the second step of example 27, carboxylic acid intermediate III (R)2＝H，R32-Me) in an amount of 1.0 mmol; the expected compound II was obtained as a white solid in 71% yield.
Example 29
6, 11-dihydrodibenzo [ b, e ]]Synthesis and structural identification of oxazepin-11-one compound II, R in the structural general formula2＝H，R3＝4-OMe。
The carboxylic acid intermediate synthesis steps and process parameters were essentially the same as for the first oxidation procedure of example 27, except as set forth below:
r in the structural general formula of the benzyl aryl ether I1＝CHO，R2＝H，R34-OMe in an amount of 1.0 mmol; the carboxylic acid intermediate was obtained as a white solid in 69% yield.
Synthesis of the object Compound II essentially the same as in the second step of example 27, carboxylic acid intermediate III (R)2＝H，R34-OMe) in an amount of 1.0 mmol; the title compound II was obtained as a white solid in 75% yield.
Example 30
6, 11-dihydrodibenzo [ b, e ]]Synthesis and structural identification of oxazepin-11-one compound II, R in the structural general formula2＝H，R3＝4-Br。
The carboxylic acid intermediate synthesis steps and process parameters were essentially the same as for the first oxidation procedure of example 27, except as set forth below:
r in the structural general formula of the benzyl aryl ether I1＝CHO，R2＝H，R34-Br, in an amount of 1.0 mmol; the carboxylic acid intermediate was obtained as a white solid in 80% yield.
Synthesis of the object Compound II essentially the same as in the second step of example 27, carboxylic acid intermediate III (R)2＝H，R34-Br) was used in an amount of 1.0 mmol; the expected compound II was obtained as a white solid in 53% yield.
TABLE 1 chemical Structure and physicochemical parameters of benzyl aryl ethers I according to the invention
TABLE 2 chemical structures and physicochemical parameters of the carboxylic acid intermediates III and 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one II
Claims (6)
1. A preparation method of benzyl aryl ether shown in formula I is characterized in that the benzyl aryl ether is synthesized according to the following method:
wherein: r1Selected from aldehyde group, ester group COOR4Cyano, amido CONR5R6In the above radicals R4Is C1-C4 alkyl, R5，R6Hydrogen or C1-C4 alkyl; r2Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy; r3Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, cyano, aldehyde group and aryl; r is selected from hydrogen, C1-C6 alkyl, phenyl, C1-C4 alkoxy, phenoxy, N-dimethylamino and N, N-diethylamino.
2. The process for the preparation of benzyl aryl ethers according to claim 1, characterized in that: the organic solvent comprises toluene and benzene in a hydrocarbon solvent; tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether and 1, 4-dioxane in an ether solvent; dichloromethane, chloroform, and 1, 2-dichloroethane in halogenated hydrocarbon solvent.
3. The process for the preparation of benzyl aryl ethers according to claim 1, characterized in that: the benzaldehyde compound comprises a phthalic aldehyde compound, a 2-aldehyde benzoate compound, an o-cyano benzaldehyde compound and a 2-aldehyde benzoic acid amide compound.
4. The process for the preparation of benzyl aryl ethers according to claim 1, characterized in that: the phenolic compounds include mono-substituted phenols and poly-substituted phenols.
5. The process for the preparation of benzyl aryl ethers according to claim 1, characterized in that: the trivalent phosphorus reagent comprises phosphine alkane, tri (C1-C6 alkyl) phosphine, triphenylphosphine, phosphorous acid tri (C1-C4 alkyl) ester, tri (N, N-dimethylamino) phosphoramidite, tri (N, N-diethylamino) phosphoramidite and triphenyl phosphite.
6. A method for preparing a 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one compound represented by formula II, which comprises the following steps: preparing a compound of formula I by a process according to claim 1, followed by oxidation or hydrolysis of the compound of formula I to give a compound of formula III, and finally ring closure of the compound of formula III to give a compound of formula II:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110658669.XA CN113321575B (en) | 2021-06-15 | 2021-06-15 | Preparation method of benzyl aryl ether and application of benzyl aryl ether in synthesis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110658669.XA CN113321575B (en) | 2021-06-15 | 2021-06-15 | Preparation method of benzyl aryl ether and application of benzyl aryl ether in synthesis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113321575A true CN113321575A (en) | 2021-08-31 |
| CN113321575B CN113321575B (en) | 2023-05-26 |
Family
ID=77421322
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110658669.XA Active CN113321575B (en) | 2021-06-15 | 2021-06-15 | Preparation method of benzyl aryl ether and application of benzyl aryl ether in synthesis |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113321575B (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105418577A (en) * | 2015-11-26 | 2016-03-23 | 苏州黄河制药有限公司 | Method for synthesizing doxepin hydrochloride from o-phthalaldehyde |
| CN106365966A (en) * | 2015-07-24 | 2017-02-01 | 上海医药集团股份有限公司 | Preparation method of benzyl aryl ether |
| CN109195602A (en) * | 2016-08-03 | 2019-01-11 | 亚星国际公司 | Symmetrical or hemihedrism compound as immunomodulator |
| CN112645821A (en) * | 2021-01-22 | 2021-04-13 | 苏州大学 | Method for synthesizing aryl benzyl ether compound |
| CN112694375A (en) * | 2021-01-22 | 2021-04-23 | 苏州大学 | Application of iron (III) complex containing 1, 3-di-tert-butylimidazole cation in synthesis of aryl benzyl ether compounds |
| CN112876352A (en) * | 2021-01-15 | 2021-06-01 | 南京艾美斐生物医药科技有限公司 | GPR120 protein receptor inhibitor and preparation and application thereof |
-
2021
- 2021-06-15 CN CN202110658669.XA patent/CN113321575B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106365966A (en) * | 2015-07-24 | 2017-02-01 | 上海医药集团股份有限公司 | Preparation method of benzyl aryl ether |
| CN105418577A (en) * | 2015-11-26 | 2016-03-23 | 苏州黄河制药有限公司 | Method for synthesizing doxepin hydrochloride from o-phthalaldehyde |
| CN109195602A (en) * | 2016-08-03 | 2019-01-11 | 亚星国际公司 | Symmetrical or hemihedrism compound as immunomodulator |
| CN112876352A (en) * | 2021-01-15 | 2021-06-01 | 南京艾美斐生物医药科技有限公司 | GPR120 protein receptor inhibitor and preparation and application thereof |
| CN112645821A (en) * | 2021-01-22 | 2021-04-13 | 苏州大学 | Method for synthesizing aryl benzyl ether compound |
| CN112694375A (en) * | 2021-01-22 | 2021-04-23 | 苏州大学 | Application of iron (III) complex containing 1, 3-di-tert-butylimidazole cation in synthesis of aryl benzyl ether compounds |
Non-Patent Citations (5)
| Title |
|---|
| DAISUKE ANDO 等: "Metabolism of the Strobilurin Fungicide Mandestrobin in Wheat", 《JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY》 * |
| HIROAKI MATSUOKA 等: "Metal-free catalytic reduction of aldehydes, ketones,aldimines, and ketimines", 《CHINESE CHEMICAL LETTERS》 * |
| JIMENA SCOCCIA 等: "Iron(II) promoted direct synthesis of dibenzo[b,e]oxepin-11(6H)-one derivatives with biological activity. A short synthesis of doxepin", 《TETRAHEDRON》 * |
| LI, HAO-TIAN 等: "Synthesis and evaluation of novel α-aminoamides with substituted benzene scaffold for the treatment of neuropathic pain", 《CHINESE CHEMICAL LETTERS》 * |
| WANG, TIANLONG 等: "Production of γ-Valerolactone from One-Pot Transformation of Biomass-Derived Carbohydrates Over Chitosan-Supported Ruthenium Catalyst Combined with Zeolite ZSM-5", 《EUROPEAN JOURNAL OF ORGANIC CHEMISTRY》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113321575B (en) | 2023-05-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Takahata et al. | Asymmetric synthesis of 1-deoxynojirimycin and its congeners from a common chiral building block | |
| Wu et al. | Simple and inexpensive threonine-based organocatalysts for the highly diastereo-and enantioselective direct large-scale syn-aldol and anti-Mannich reactions of α-hydroxyacetone | |
| Sunden et al. | Direct enantioselective synthesis of bicyclic Diels–Alder products | |
| Yokomatsu et al. | Stereocontrolled synthesis of hydroxymethylene phosphonate analogues of phosphorylated tyrosine and their conversion to monofluoromethylene phosphonate analogues | |
| Riley et al. | Improved synthesis of 2-methyl-6-methylene-2, 7-octadien-4-ol, a pheromone of Ips paraconfusus, and an alternative synthesis of the intermediate, 2-bromomethyl-1, 3-butadiene | |
| CN114591344B (en) | Synthesis method of chiral spiro tetrahydrofuran-pyrazolone compound | |
| CN106349130B (en) | A kind of synthetic method of new Florfenicol | |
| CN114369011A (en) | Green novel method for preparing 2-diarylmethyl substituted-1-naphthol compound | |
| Tummatorn et al. | Convenient synthetic route to a dehydrorotenoid via selective intramolecular aldol condensation of 1, 2-diaryl diketone | |
| CN111285759B (en) | Synthetic method of chalcone derivative | |
| Basu et al. | Polymer supported synthesis of a natural product-inspired oxepane library | |
| CN113321575B (en) | Preparation method of benzyl aryl ether and application of benzyl aryl ether in synthesis | |
| EP2225200B1 (en) | Convergent synthesis of renin inhibitors and intermediates useful therein | |
| CN102344431A (en) | Method for preparing nebivolol hydrochloride | |
| CN107674016B (en) | Preparation method of telaprevir intermediate and intermediate thereof | |
| Chen et al. | Chiral N-phosphonyl imine chemistry: asymmetric additions of malonate-derived enolates to chiral N-phosphonyl imines for the synthesis of β-aminomalonates | |
| CN112979523B (en) | Preparation method of chiral 1, 4-diphenyl-2-hydroxy-1, 4-dibutyl ketone compound | |
| Le et al. | Novel synthesis of the natural protoberberine alkaloids: Oxypalmatine and oxypseudopalmatine | |
| CN110903177A (en) | Method for preparing levo muscone | |
| CN100432044C (en) | New process for preparing levo-albuterol | |
| CN115286556B (en) | Preparation method of ester compound containing indolone or isoquinoline-1, 3-dione structure | |
| Gu et al. | Organocatalytic direct asymmetric Mannich reactions of hydroxyacetone by (2S, 5S)‐pyrrolidine‐2, 5‐dicarboxylic acid | |
| CN109833908A (en) | A kind of chirality high price iodine catalyst and its preparation method and application | |
| Albrecht et al. | Enantio-and Diastereoselective Synthesis of β, γ, γ, δ-Tetrasubstituted α-Methylene-δ-lactones | |
| CN115650824B (en) | Chiral diol and preparation method thereof, prepared catalyst and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |