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Preparation method of benzoxazepine seven-membered ring

A technology of benzoxazepine and o-fluorobenzamide is applied in the preparation of benzoxazepine seven-membered rings and in the field of organic synthesis, and can solve the problems of complex routes, numerous synthesis steps, and no applicability, and achieves the The effect of simple separation process and high chemoselectivity

Active Publication Date: 2020-10-16
TSINGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The main shortcoming of the existing reported synthetic method is that some reaction synthesis steps are numerous and the route is complicated, and some reactions have used very special substrate structure, do not have very good applicability; Part reactions have used comparatively expensive palladium catalyst, expensive to synthesize

Method used

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  • Preparation method of benzoxazepine seven-membered ring
  • Preparation method of benzoxazepine seven-membered ring
  • Preparation method of benzoxazepine seven-membered ring

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Sequentially weigh 0.0905g 2-fluoro-N-n-propylbenzamide (0.5mmol), 0.0336g propynol (0.6mmol), 0.0084g potassium hydroxide (1.5mmol) in a 25mL sealed tube containing a magnetic stir bar , add 4.0 mL of anhydrous dimethyl sulfoxide. The sealed tube was placed in a magnetic stirring heater at 30°C for 12 hours of stirring reaction, and then the temperature was raised to 50°C to continue the stirring reaction for 12 hours. After the reaction, use petroleum ether-ethyl acetate as the eluent for column separation to obtain 0.0585 g of light yellow liquid, the target product 4-n-propyl-3-methyl-1,4-benzoxazepine The isolated yield of -5(4H)-ketone was 54%, that is, in formula I, R 1 is n-propyl, R 2 for H, R 3 and R 4 Both are H.

[0040] figure 1 and figure 2 The proton nuclear magnetic resonance spectrum and carbon spectrum of the product prepared in this embodiment are respectively, as can be seen from the figure, the structure of the compound is correct.

Embodiment 2

[0042] Weigh successively 0.0695g 2-fluorobenzamide (0.5mmol), 0.0336g propynol (0.6mmol), 0.0084g potassium hydroxide (1.5mmol) into a 25mL sealed tube containing a magnetic stirrer, add 4.0mL without water dimethyl sulfoxide. The sealed tube was placed in a magnetic stirring heater at 30°C for 12 hours of stirring reaction, and then the temperature was raised to 50°C to continue the stirring reaction for 12 hours. After the reaction, use petroleum ether-ethyl acetate as the eluent for column separation to obtain 0.0269 g of light yellow liquid, the target product 3-methyl-1,4-benzoxazepine -5(4H)-one in 31% isolated yield.

[0043] image 3 and Figure 4 The proton nuclear magnetic resonance spectrum and carbon spectrum of the product prepared in this embodiment are respectively, as can be seen from the figure, the structure of the compound is correct.

Embodiment 3

[0045] Sequentially weigh 0.0765g 2-fluoro-N-methylbenzamide (0.5mmol), 0.0336g propynyl alcohol (0.6mmol), 0.0084g potassium hydroxide (1.5mmol) in a 25mL sealed tube containing a magnetic stirring bar , add 4.0 mL of anhydrous dimethyl sulfoxide. The sealed tube was placed in a magnetic stirring heater at 30°C for 12 hours of stirring reaction, and then the temperature was raised to 50°C to continue the stirring reaction for 12 hours. After the reaction, use petroleum ether-ethyl acetate as the eluent for column separation to obtain 0.0541 g of light yellow liquid, the target product 4-methyl-3-methyl-1,4-benzoxazepine The isolated yield of -5(4H)-ketone was 57%, that is, in formula I, R 1 is methyl, R 2 for H, R 3 and R 4 Both are H.

[0046] Figure 5 and Figure 6 The proton nuclear magnetic resonance spectrum and carbon spectrum of the product prepared in this embodiment are respectively, as can be seen from the figure, the structure of the compound is correct. ...

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Abstract

The invention discloses a preparation method of a benzoxaza seven-membered ring.The preparation method comprises the following steps of: in the presence of alkali, an o-fluorobenzamide compound shownin a formula II is reacted with a propynol compound shown in a formula III to obtain a 1,4-benzoxaza-5(4H)-keto derivativescompound shown in a formula I; in the formula I and formula II, R1 is alkyl with 1-6 carbon atoms, cycloalkyl or H, R2 is monosubstituent on a benzene ring, and is H, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, halogen atom, nitro or fluoro alkyl with 1-6 carbonatoms; and in the formula I and formula III, R3 is H or methyl, and R4 is H or methyl. Potassium fluoride is the only by-product of the reaction of the preparation method of thebenzoxaza seven-membered ring, and the reaction has very high atom utilization rate. And meanwhile, the by-product potassium chloride can also be obtained through separation, thereby having certain economic benefit.

Description

technical field [0001] The invention relates to a preparation method of a benzoxazepine seven-membered ring, which belongs to the field of organic synthesis methods. Background technique [0002] Benzoxazepines And its derivatives widely exist in drug molecules because of their excellent biological activity and pharmacological activity. Many physiological and pharmacological experiments have shown that benzoxazepine The molecules of the backbone can act as anticonvulsants, antidepressants, central depressants, antipsychotics, and as non-nucleoside HIV-1 reverse transcriptase inhibitors (Pandey, S.; Kumar, S.V.; Kant, R.; Chauhan , P.M.S.Org.Biomol.Chem., 2014, 12, 5346). certain 1,4-benzoxazepines -5-Kone compounds have certain activities of inducing osteoclastogenesis and bone resorption (Chen, C.; Lee, C.; Chang, D. Eur. J. Med. Chem., 2016, 117); some 7 Substituted benzoxazepines -5-Kone compounds have good anticonvulsant effect and certain neurotoxicity (Deng, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D267/14
Inventor 华瑞茂陈骞
Owner TSINGHUA UNIV