CN113321575B - 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
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Abstract
The invention provides a high-efficiency method for synthesizing benzyl aryl ether by benzaldehyde compound and phenol compound through one-step reaction, and the method is used for synthesizing 6, 11-dihydro-dibenzo [ b, e ]]The use of an oxazepin-11-one compound; the invention relates to benzyl aryl ether and 6, 11-dihydrodibenzo [ b, e]The oxazepin-11-one compound has chemical structural general formulas 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 ] oxazepin-11-one compound, in particular to a method for synthesizing benzyl aryl ether by a benzaldehyde compound and a phenol compound through one-step reaction, and application of the method in synthesis of the 6, 11-dihydrodibenzo [ b, e ] oxazepin-11-one compound.
Background
6, 11-dihydrodibenzo [ b, e ] oxazepan-11-one compounds and derivatives thereof are a class of substances with important biological activity and are also key intermediates for the synthesis of many drug molecules (Jiang, h.; et al green chem.2019, 21, 5368-5373.). For example, germicides pestalachloride B have significant antifungal activity against various plant pathogens (Li, E.; et al Bioorg. Med. Chem.2008, 16, 7894-7899.), and Doxepin (Chinese name: duoxepin) can be used to treat diseases such as depression (Scoccia, J.; et al tetrahedron 2017, 73, 2913-2922; shah, Y. D.; et al J. Clin. Sleep Med.2020, 16, 743-747; chen, Z.; et al diabetes 2020, 69, 1126-1139.), and Olopatadine (Chinese name: olopatadine) can be used to treat diseases such as seasonal allergic conjunctivitis and rhinitis (Bosch, J.; et al J. Org. Chem. 77, 6340-6344; abelson, M. B.; et al, J. 2012, 2006, 5-45, pharmacol, 1995).
Methods for efficiently preparing such compounds have been developed, and thus are being appreciated by organic chemists, as have a series of efficient synthetic methods (Scoccia, J.; et al tetrahedron 2017, 73, 2913-2922; bosch, J.; et al J. Org. Chem.2012, 77, 6340-6344; farrokh, J.; et al tetrahedron Lett.2015, 56, 5245-5247; jiang, H.; et al Green chem. 2016, 21, 5368-5373.; naporra, F.; et al Pharmm. Res.2016, 113, 610-537.). Among the reported synthetic methods, the synthesis of the key intermediate benzyl aryl ether is often carried out using the Williams ether synthesis method and the substitution reaction of the phenol compound for phthalide (Ueno, K.; et al J.Med. Chem.1976, 19, 941-946; kurokawa, M.; et al chem. Pharm. Bull.1991, 39, 2564-2573.). For example: the method disclosed in Chinese patent CN105418577A takes phthalic dicarboxaldehyde as a raw material, adopts intramolecular kanicorro reaction under the action of strong alkali, and then lactonizes to obtain phthalide, then the phthalide and phenol undergo substitution reaction in an alcohol solution of sodium methoxide to obtain a benzyl aryl ether intermediate, and a large amount of excessive strong alkali and concentrated sulfuric acid are needed in the reaction process; the method disclosed in Chinese patent CN105367538A uses methyl o-halomethylbenzoate as a raw material, and carries out substitution reaction with phenol in an alcohol solution of sodium methoxide to obtain a benzyl aryl ether intermediate, wherein a large amount of excessive sodium methoxide is required to be used for the reaction; the method disclosed in Chinese patent CN105330638A uses o-methyl benzoic acid as a raw material, N-halogenated succinimide is adopted for halogenation, then intramolecular substitution reaction is carried out to obtain phthalide, substitution reaction is carried out with phenol in an alcohol solution of sodium methoxide to obtain a benzyl aryl ether intermediate, the method has more steps, and excessive sodium methoxide strong base is needed to be used. All three methods have the defect of narrow application range of the substrate. In summary, in the current methods for the synthesis of 6, 11-dihydrodibenzo [ b, e ] oxazepin-11-one compounds and derivatives thereof, there is still a lack of efficient and simple methods for the construction of key intermediates for benzyl aryl ethers under mild conditions.
The novel method for synthesizing the benzyl aryl ether by reacting the benzaldehyde compound with a series of phenol compounds under the action of stoichiometric trivalent phosphorus reagent in one step is realized, the benzaldehyde compound particularly comprises a benzaldehyde substrate with aldehyde group, ester group, amide group or cyano group at the ortho position, and the benzyl aryl ether prepared from the substituted benzaldehyde substrate can be conveniently used for synthesizing the 6, 11-dihydro-dibenzo [ b, e ] oxazepin-11-ketone compound. Therefore, the invention provides a novel method for efficiently synthesizing benzyl aryl ether through one-step reaction under mild conditions, and simultaneously provides a novel method for synthesizing 6, 11-dihydrodibenzo [ b, e ] oxazepin-11-one compounds.
Disclosure of Invention
The invention aims to solve the technical problems that: provided are efficient methods for synthesizing benzyl aryl ethers and derivatives thereof; novel methods for synthesizing 6, 11-dihydrodibenzo [ b, e ] oxazepin-11-one compounds are provided.
The invention solves the technical problems by adopting the technical scheme that:
the chemical structural general formula of the benzyl aryl ether is as follows:
wherein: r is R 1 Selected from aldehyde groups, ester groups COOR 4 Cyano, amido CONR 5 R 6 R in the above groups 4 Is C1-C4 alkyl, R 5 ，R 6 Respectively hydrogen or C1-C4 alkyl; r is R 2 Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy; r is R 3 Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, cyano, aldehyde, aryl.
The synthesis method of the benzyl aryl ether comprises the following steps:
wherein: r is R 1 Selected from aldehyde groups, ester groups COOR 4 Cyano, amido CONR 5 R 6 R in the above groups 4 Is C1-C4 alkyl, R 5 ，R 6 Respectively hydrogen or C1-C4 alkyl; r is R 2 Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy; r is R 3 Selected 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 ] oxazepin-11-ketone compound is as follows:
wherein: r is R 2 Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy; r is R 3 Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, cyano, aldehyde, aryl.
The benzyl aryl ether prepared by the invention can be applied to the synthesis of 6, 11-dihydrodibenzo [ b, e ] oxazepin-11-one compounds according to the following synthetic route:
wherein: r is R 1 Selected from aldehyde groups, ester groups COOR 4 Cyano, amido CONR 5 R 6 R in the above groups 4 Is C1-C4 alkyl, R 5 ，R 6 Respectively hydrogen or C1-C4 alkyl; r is R 2 Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy; r is R 3 Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, cyano, aldehyde, aryl.
The method comprises the following steps:
A. preparation of benzyl aryl ether I:
in a 25mL round bottom flask, 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 were successively added, and the resulting reaction mixture was stirred at room temperature for 4 hours. After the reaction is finished, the solvent is removed by rotary evaporation, and the crude product is purified by 200-300 mesh silica gel column chromatography to obtain the benzyl aryl ether target compound. The eluent is petroleum ether with the boiling range of 60-90 ℃ and ethyl acetate, and the volume ratio is 40:1-10:1. The yield of the obtained pure product was calculated and found to be 30 to 97% depending on the target compound. The amount of the target compound I to be produced and the volume of the reaction vessel can be scaled up or down accordingly. The chemical structure and physicochemical parameters of the target compound I are shown in Table 1.
The organic solvent comprises toluene and benzene in hydrocarbon solvents; tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether and 1, 4-dioxane in the ether solvent; dichloromethane, chloroform and 1, 2-dichloroethane in halogenated hydrocarbon solvents.
The benzaldehyde compound comprises a phthalaldehyde compound, a 2-aldehyde benzoate compound, an o-cyano benzaldehyde compound and a 2-aldehyde benzoic acid amide compound.
The phenolic compound includes a substituted phenol.
The trivalent phosphorus reagent comprises phosphine alkane, tri (C1-C6 alkyl) phosphine, triphenylphosphine, tri (C1-C4 alkyl) phosphite, tri (N, N-dimethylamino) phosphoramidite, tri (N, N-diethylamino) phosphoramidite and triphenyl phosphite.
B.6 Preparation of 11-dihydrodibenzo [ b, e ] oxazepin-11-one Compound II:
the benzyl aryl ether prepared according to the invention is converted to the intermediate carboxylic acid III by oxidation and hydrolysis, respectively, with different functional groups.
1. Oxidation process: benzyl aryl ethers bearing aldehyde functions can be converted by oxidation into the corresponding carboxylic acid intermediate III according to existing literature methods (see Wang, j.; et al new j. Chem.2013, 37, 1700):
wherein: r is R 1 Selected from aldehyde groups; r is R 2 Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy; r is R 3 Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, cyano, aldehyde, aryl.
To a 25mL reaction flask, 1mmol of benzyl aryl ether, 1mmol of sodium t-butoxide and 4mL of tetrahydrofuran were added, and the flask was attached 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 a solvent from a filtrate by rotary evaporation, purifying a crude product by 200-300 mesh silica gel column chromatography, and obtaining a carboxylic acid intermediate III by using petroleum ether with the boiling range of 60-90 ℃ and ethyl acetate as eluent and the volume ratio of 20:1-10:1. The yield of the obtained pure product was calculated and found to be 69 to 97% depending on the target compound.
2. And (3) hydrolysis: benzyl aryl ethers bearing ester, cyano or amide functions can be converted by hydrolysis into the corresponding carboxylic acid intermediate III according to existing literature methods (see Khurana, j.m.; et al monatsh. Chem.2004, 135, 83-87.):
wherein: r is R 1 Selected from ester groups COOR 4 Cyano, amido CONR 5 R 6 R in the above groups 4 Is C1-C4 alkyl, R 5 ，R 6 Respectively hydrogen or C1-C4 alkyl; r is R 2 Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy; r is R 3 Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, cyano, aldehyde, aryl.
1mmol of benzyl aryl ether, 5mmol of potassium hydroxide and 3mL of methanol are added into a 25mL round bottom flask, the mixture is stirred for 1 hour at a temperature of between 30 and 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 solution is filtered, the solvent is removed by rotary evaporation, a crude product is purified by 200 to 300 meshes of silica gel column chromatography, the eluent is petroleum ether with a boiling range of between 60 and 90 ℃ and ethyl acetate, and the volume ratio is 20:1 to 10:1, thus obtaining the carboxylic acid target compound III. The yield of the obtained pure product was calculated and found to be 69 to 97% depending on the target compound.
3. Closing a ring: the benzyl aryl ether prepared according to the invention is used for the synthesis of 6, 11-dihydrodibenzo [ b, e ] oxazepin-11-one compound II by subjecting carboxylic acid intermediate III prepared by the above oxidation and hydrolysis processes to a ring closure reaction according to the reported literature method (see Scoccia, j.; et al tetrahedron 2017, 73, 2913-2922.).
Wherein: r is R 2 Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy; r is R 3 Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, cyano, aldehyde, aryl.
Into a 25mL reaction flask, 1mmol of carboxylic acid compound, 0.6mmol of ferrous chloride, 1mmol of 1, 1-dichloromethyl ether and 10mL of methylene chloride were charged, and the mixture was stirred at room temperature under nitrogen for 3 hours. After the reaction is finished, adding water to quench the reaction, extracting with dichloromethane, washing a water layer with saturated sodium bicarbonate aqueous solution, combining organic layers, drying with anhydrous sodium sulfate, filtering, removing a solvent from filtrate by rotary evaporation, purifying a crude product by 200-300 mesh silica gel column chromatography, and obtaining a target compound II by using petroleum ether with the boiling range of 60-90 ℃ and ethyl acetate as eluent in a volume ratio of 40:1-10:1. The yield of the obtained pure product was calculated and found to be 53 to 75% depending on the target compound.
The amounts of 6, 11-dihydrodibenzo [ b, e ] oxazepin-11-one compound II and carboxylic acid intermediate III prepared and the volume of the reaction vessel may be scaled up or down accordingly. The chemical structures and physicochemical parameters of compounds II and III are shown in Table 2.
The technical innovation and application of the invention are as follows: the preparation method of the benzyl aryl ether I belongs to technical innovation, and the preparation method is applied to the synthesis of the 6, 11-dihydrodibenzo [ b, e ] oxazepin-11-one compound II, and also belongs to technical innovation.
The synthesis of benzyl aryl ether I and 6, 11-dihydrodibenzo [ b, e ] oxazepin-11-one compound II is more specifically illustrated by the specific preparation examples. The examples are given solely for the purpose of illustration and are not intended to limit the invention. The specific implementation mode is as follows:
the specific embodiment is as follows:
example 1.
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CHO，R 2 ＝H，R 3 ＝H。
In a 25mL round bottom flask, 5.0mL of methylene chloride, 0.5mmol of phthalic aldehyde, 0.55mmol of phenol and 0.55mmol of triethyl phosphite were added in this order, and the resulting reaction mixture was stirred at room temperature for 4 hours. After the reaction is finished, the solvent is removed by rotary evaporation, the crude product is purified by 200-300 mesh silica gel column chromatography, the eluent is petroleum ether and ethyl acetate mixed solvent 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 benzyl aryl ether target compound I prepared and the volume of the reaction vessel can be enlarged or reduced according to corresponding proportion. The chemical structure and physicochemical parameters of the target compound I are shown in Table 1.
Example 2
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CHO，R 2 ＝H，R 3 ＝H。
The synthesis procedure and process parameters were essentially the same as in example 1, except as follows:
the trivalent phosphorus reagent is tris (N, N-dimethylamino) phosphoramidite, and the dosage is 0.55mmol; this gave a colourless oil in 75% yield.
Example 3
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CHO，R 2 ＝H，R 3 ＝4-Me。
The synthesis procedure and process parameters were essentially the same as in example 1, except as follows:
the phenolic compound is 4-methylphenol, and the dosage is 0.55mmol; the yield of the pure white solid product was 97%.
Example 4
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CHO，R 2 ＝H，R 3 ＝4-OMe。
The synthesis procedure and process parameters were essentially the same as in example 1, except as follows:
the phenolic compound is 4-methoxyphenol, and the dosage is 0.55mmol; the yield of the pure white solid product was 87%.
Example 5
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CHO，R 2 ＝H，R 3 ＝4- t Bu。
The synthesis procedure and process parameters were essentially the same as in example 1, except as follows:
the phenolic compound is 4-tertiary butyl phenol, and the dosage is 0.55mmol; the liquid was obtained as a colourless oil in 96% yield.
Example 6
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CHO，R 2 ＝H，R 3 ＝4-Ph。
The synthesis procedure and process parameters were essentially the same as in example 1, except as follows:
the phenolic compound is 4-phenylphenol, and the dosage is 0.55mmol; the yield of the pure white solid product was 92%.
Example 7
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CHO，R 2 ＝H，R 3 ＝4-CH 2 CO 2 Me。
The synthesis procedure and process parameters were essentially the same as in example 1, except as follows:
the phenolic compound is 4-methyl acetate phenol, and the dosage is 0.55mmol; the yield of the pure white solid product was 90%.
Example 8
Synthesis and structural identification of benzyl aryl ether, and structural general formula R 1 ＝CHO，R 2 ＝H，R 3 ＝4-F。
The synthesis procedure and process parameters were essentially the same as in example 1, except as follows:
the phenolic compound is 4-fluorophenol, and the dosage is 0.55mmol; the yield of the pure white solid product was 92%.
Example 9
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CHO，R 2 ＝H，R 3 ＝4-Cl。
The synthesis procedure and process parameters were essentially the same as in example 1, except as follows:
the phenolic compound is 4-chlorophenol, and the dosage is 0.55mmol; the yield of the pure white solid product was 80%.
Example 10
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CHO，R 2 ＝H，R 3 ＝4-Br。
The synthesis procedure and process parameters were essentially the same as in example 1, except as follows:
the phenolic compound is 4-bromophenol, and the dosage is 0.55mmol; the yield of the pure white solid product was 82%.
Example 11
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CHO，R 2 ＝H，R 3 ＝4-CF 3 。
The synthesis procedure and process parameters were essentially the same as in example 1, except as follows:
the phenolic compound is 4-trifluoromethyl phenol, and the dosage is 0.55mmol; the yield of the pure white solid product was 86%.
Example 12
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CHO，R 2 ＝H，R 3 ＝4-CN。
The synthesis procedure and process parameters were essentially the same as in example 1, except as follows:
the phenolic compound is 4-cyanophenol, and the dosage is 0.55mmol; the yield of the pure white solid product was 36%.
Example 13
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CHO，R 2 ＝H，R 3 ＝2-Me。
The synthesis procedure and process parameters were essentially the same as in example 1, except as follows:
the phenolic compound is 2-methylphenol, and the dosage is 0.55mmol; the yield of the pure white solid product was 90%.
Example 14
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CHO，R 2 ＝H，R 3 ＝2-Et。
The synthesis procedure and process parameters were essentially the same as in example 1, except as follows:
the phenolic compound is 2-ethylphenol, and the dosage is 0.55mmol; the pure product was obtained as pale yellow solid in 91% yield.
Example 15
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CHO，R 2 ＝H，R 3 ＝2- i Pr。
The synthesis procedure and process parameters were essentially the same as in example 1, except as follows:
the phenolic compound is 2-isopropyl phenol, and the dosage is 0.55mmol; a pale yellow oily liquid was obtained in 81% yield.
Example 16
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CHO，R 2 ＝H，R 3 ＝2-OMe。
The synthesis procedure and process parameters were essentially the same as in example 1, except as follows:
the phenolic compound is 2-methoxyphenol, and the dosage is 0.55mmol; a pale yellow oily liquid was obtained in 79% yield.
Example 17
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CHO，R 2 ＝H，R 3 ＝2-Cl。
The synthesis procedure and process parameters were essentially the same as in example 1, except as follows:
the phenolic compound is 2-chlorophenol, and the dosage is 0.55mmol; the yield of the pure white solid product was 91%.
Example 18
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CHO，R 2 ＝H，R 3 ＝2-Br。
The synthesis procedure and process parameters were essentially the same as in example 1, except as follows:
the phenolic compound is 2-bromophenol, and the dosage is 0.55mmol; the yield of the pure white solid product was 90%.
Example 19
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CHO，R 2 ＝H，R 3 ＝2-CH 2 CH＝CH 2 。
The synthesis procedure and process parameters were essentially the same as in example 1, except as follows:
the phenolic compound is 2-allylphenol, and the dosage is 0.55mmol; a pale yellow oily liquid was obtained in 75% yield.
Example 20
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CHO，R 2 ＝H，R 3 ＝2-CHO。
The synthesis procedure and process parameters were essentially the same as in example 1, except as follows:
the phenolic compound is salicylaldehyde, and the dosage is 0.55mmol; the yield of the pure white solid product was 35%.
Example 21
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CHO，R 2 ＝H，R 3 ＝3-Me。
The synthesis procedure and process parameters were essentially the same as in example 1, except as follows:
the phenolic compound is 3-methylphenol, and the dosage is 0.55mmol; this gave a colourless oil in 92% yield.
Example 22
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CHO，R 2 ＝H，R 3 ＝3-Br。
The synthesis procedure and process parameters were essentially the same as in example 1, except as follows:
the phenolic compound is 3-bromophenol, and the dosage is 0.55mmol; the yield of the pure white solid product was 90%.
Example 23
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CHO，R 2 ＝H，R 3 ＝3，5-Me 2 。
The synthesis procedure and process parameters were essentially the same as in example 1, except as follows:
the phenolic compound is 3, 5-dimethylphenol, and the dosage is 0.55mmol; the yield of the pure white solid product was 87%.
Example 24
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CHO，R 2 ＝H，R 3 ＝3，4-OCH 2 O-。
The synthesis procedure and process parameters were essentially the same as in example 1, except as follows:
the phenolic compound is sesamol, and the dosage is 0.55mmol; the pure product was obtained as pale yellow solid with a yield of 93%.
Example 25
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CO 2 Me，R 2 ＝H，R 3 ＝H。
5.0mL of benzene, 0.5mmol of methyl o-aldehyde benzoate, 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 80-90 ℃. After the reaction is finished, the solvent is removed by rotary evaporation, the crude product is purified by 200-300 mesh silica gel column chromatography, the eluent is petroleum ether and ethyl acetate mixed solvent with the boiling range of 60-90 ℃, the volume ratio is 40:1-30:1, and the benzyl aryl ether target compound is colorless oily liquid, and the yield is 48%.
Example 26
Synthesis and structural identification of benzyl aryl ether, R in structural general formula 1 ＝CN，R 2 ＝H，R 3 ＝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 successively added, and the resulting reaction mixture was stirred at room temperature for 24 hours. After the reaction is finished, the solvent is removed by rotary evaporation, the crude product is purified by 200-300 mesh silica gel column chromatography, the eluent is petroleum ether and ethyl acetate mixed solvent with the boiling range of 60-90 ℃, the volume ratio is 40:1-30:1, and the benzyl aryl ether target compound is 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 structural general formula 2 ＝H，R 3 ＝H。
The synthesis of the target compound is divided into two steps: firstly, preparing a carboxylic acid intermediate III from benzyl aryl ether I through an oxidation method or a hydrolysis method; in the second step, the target compound II is prepared from the carboxylic acid intermediate III through cyclization reaction.
The first step: synthesis of carboxylic acid intermediate III, R in the general structural formula 2 ＝H，R 3 ＝H。
The oxidation method comprises the following steps: in a 25mL reaction flask was charged 1mmol of benzyl aryl ether I (R 1 ＝CHO，R 2 ＝H，R 3 =h), 1mmol of sodium tert-butoxide and 4mL of tetrahydrofuran, a balloon filled with air was attached to the flask mouth and stirred at room temperature for 1 hour. After the reaction is finished, water and dilute hydrochloric acid are added to quench the reaction, ethyl acetate is used for extraction, an organic layer is dried by anhydrous sodium sulfate, filtration and rotary evaporation are carried out on filtrate to remove solvent, a crude product is purified by 200-300 mesh silica gel column chromatography, the eluent is petroleum ether with the boiling range of 60-90 ℃ and ethyl acetate mixed solvent, the volume ratio is 20:1-10:1, and a carboxylic acid intermediate is obtained as 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 accordingly. The chemical structure and physicochemical parameters of carboxylic acid intermediate III are shown in table 2.
The hydrolysis method comprises the following steps: into a 25mL round bottom flask was added 1mmol of benzylAryl ether I (R) 1 ＝CO 2 Me，R 2 ＝H，R 3 =h), 5mmol of potassium hydroxide and 3mL of methanol at 30-60 ℃ for 1 hour, adding water and dilute hydrochloric acid to quench the reaction after the reaction is completed, extracting with ethyl acetate, drying an organic layer with anhydrous sodium sulfate, filtering, removing a solvent by rotary evaporation, purifying a crude product by 200-300 meshes of silica gel column chromatography, wherein the eluent is petroleum ether at 60-90 ℃ in a boiling range and ethyl acetate mixed solvent, the volume ratio is 20:1-10:1, and the carboxylic acid intermediate is white solid with the yield of 97%. The amount of carboxylic acid intermediate produced and the volume of the reaction vessel can be scaled up or down accordingly. The chemical structure and physicochemical parameters of carboxylic acid intermediate III are shown in table 2.
And a second step of: preparing a target compound II from a carboxylic acid intermediate III through cyclization reaction, wherein R in the structural general formula 2 ＝H，R 3 ＝H。
In a 25mL reaction flask was charged 1mmol of carboxylic acid intermediate III (R 2 ＝H，R 3 =h), 0.6mmol of ferrous chloride, 1mmol of 1, 1-dichloromethyl ether and 10mL of dichloromethane, and stirred for 3 hours at room temperature under nitrogen. After the reaction is finished, adding water to quench the reaction, extracting with dichloromethane, washing a water layer with saturated sodium bicarbonate aqueous solution, combining organic layers, drying with anhydrous sodium sulfate, filtering, removing a solvent from filtrate by rotary evaporation, purifying a crude product by 200-300 mesh silica gel column chromatography, and obtaining a target compound II as a white solid with the yield of 67 percent, wherein the eluent is petroleum ether with the boiling range of 60-90 ℃ and ethyl acetate mixed solvent with the volume ratio of 40:1-30:1. The amount of the target compound to be produced and the volume of the reaction vessel can be scaled up or down accordingly. The chemical structure and 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 structural general formula 2 ＝H，R 3 ＝2-Me。
The carboxylic acid intermediate synthesis procedure and process parameters were essentially the same as the first oxidation process of example 27, except as set forth below:
benzyl aryl ether I-knot usedR in the general formula 1 ＝CHO，R 2 ＝H，R 3 =2-Me in an amount of 1.0mmol; the carboxylic acid intermediate was obtained as a white solid in 70% yield.
The synthesis of target compound II was essentially the same as in example 27, the second step, carboxylic acid intermediate III (R 2 ＝H，R 3 =2-Me) in an amount of 1.0mmol; the target 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 structural general formula 2 ＝H，R 3 ＝4-OMe。
The carboxylic acid intermediate synthesis procedure and process parameters were essentially the same as the first oxidation process of example 27, except as set forth below:
the structural general formula of the benzyl aryl ether I is R 1 ＝CHO，R 2 ＝H，R 3 =4-OMe, in an amount of 1.0mmol; the carboxylic acid intermediate was obtained as a white solid in 69% yield.
The synthesis of target compound II was essentially the same as in example 27, the second step, carboxylic acid intermediate III (R 2 ＝H，R 3 =4-OMe) in an amount of 1.0mmol; the target 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 structural general formula 2 ＝H，R 3 ＝4-Br。
The carboxylic acid intermediate synthesis procedure and process parameters were essentially the same as the first oxidation process of example 27, except as set forth below:
the structural general formula of the benzyl aryl ether I is R 1 ＝CHO，R 2 ＝H，R 3 =4-Br in an amount of 1.0mmol; the carboxylic acid intermediate was obtained as a white solid in 80% yield.
The synthesis of target compound II was essentially the same as in example 27, the second step, carboxylic acid intermediate III (R 2 ＝H，R 3 =4-Br) was used in an amount of 1.0mmol; the target compound II is obtained as a white solid with a yield of 53%。
TABLE 1 chemical structure and physicochemical parameters of benzyl aryl ether I of the invention
TABLE 2 chemical Structure and physicochemical parameters of Carboxylic acid intermediates III and 6, 11-dihydrodibenzo [ b, e ] oxazepin-11-one II
Claims (3)
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: r is R 1 Selected from aldehyde groups, ester groups COOR 4 Cyano, amido CONR 5 R 6 R in the above groups 4 Is C1-C4 alkyl, R 5 ，R 6 Respectively hydrogen or C1-C4 alkyl; r is R 2 Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy; r is R 3 Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, cyano, aldehyde group; r is selected from C1-C4 alkoxy, phenoxy, N-dimethylamino and N, N-diethylamino; trivalent phosphorus reagent PR 3 Comprises tri (C1-C4 alkyl) phosphite, tri (N, N-dimethylamino) phosphoramidite, and tri (N, N-diethyl)Amino group) phosphoramidites and triphenyl phosphites.
2. The method for preparing benzyl aryl ether according to claim 1, wherein: the organic solvent comprises toluene and benzene in hydrocarbon solvents; tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether and 1, 4-dioxane in the ether solvent; dichloromethane, chloroform and 1, 2-dichloroethane in halogenated hydrocarbon solvents.
3. A preparation method of a 6, 11-dihydrodibenzo [ b, e ] oxazepin-11-one compound shown in a formula II is characterized by comprising the following steps of: the method of claim 1, wherein the compound of formula I is prepared, then the compound of formula I is oxidized or hydrolyzed to form a compound of formula III, and finally the compound of formula III is cyclized to form a compound of formula II:
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