CN109824620B - Preparation method of benzoxazepine seven-membered ring - Google Patents
Preparation method of benzoxazepine seven-membered ring Download PDFInfo
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Abstract
The invention discloses a preparation method of a benzoxazepine seven-membered ring. The preparation method comprises the following steps: in the presence of alkali, the o-fluorobenzamide compound shown as the formula II reacts with the propiolic alcohol compound shown as the formula III to obtain the 1, 4-benzoxazepine shown as the formula I
-5(4H) -one derivatives; in the formulae I and II, R1Is alkyl, cycloalkyl or H, R with 1-6 carbon atoms2The substituent group is a single substituent group on a benzene ring, and is H, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, halogen atom, nitro or fluorinated alkyl with 1-6 carbon atoms; in the formulae I and III, R3Is H or methyl, R4Is H or methyl. The by-product of the reaction of the invention is only potassium fluoride, and the reaction has very high atom utilization rate. Meanwhile, the byproduct potassium chloride can also be obtained by separation, and has certain economic benefit.
Description
Technical Field
The invention relates to a preparation method of a benzooxynitridoheptatomic ring, belonging to the field of organic synthesis methods.
Background
Benzoxazepines
And the derivatives thereof are widely existed in drug molecules due to excellent biological activity and pharmacological activity. Many physiological and pharmacological experiments show that the benzoxaazane contains benzene
The molecules of the backbone can be used as anticonvulsants, antidepressants, central depressant drugs, anti-psychotic neuroleptics, 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
The 5-ketone compound has certain activity of inducing osteoclast formation and bone resorption (Chen, C.; Lee, C.; Chang, D.Eur.J.Med.Chem.,2016,117); certain 7-substituted benzoxazepines
The 5-ketone compound has better anticonvulsive effect and certain neurotoxicity (Deng, X.; Song, M.Med.chem.Res.,2011,20, 996); certain N-substituted benzoxazepines
The compounds can inhibit cellular phosphorylation of a portion of substrates, and have pharmacokinetic activity and certain antitumor activity (Takeuchi, C.S.; Leahy, J.W.J.Med.chem.,2013,56, 2218).
The synthesis method of the benzoxazepine seven-membered ring has attracted much attention because of its excellent physiological activity. Wherein benzooxazas
And derivatives thereof can be synthesized by Schmidt reaction of flavonoid derivatives with Lawesson's reagent (L vai, a.;
t. the method comprises the following steps of; frank, l.; hosztafi, s.heterocycles,1992,34, 1523-; or by the synthetic method of 7-exo-dig intramolecular cyclization of Ugi-propargyl adduct molecules under alkaline conditions (Pandey, s.; Kumar, s.v.; Kant, r.; Chauhan, p.m.s.org.biomol.chem.,2014,12, 5346-; a Smiles rearrangement tandem reaction synthesis method of N-substituted salicylamide and benzene ring derivatives under alkaline conditions (Liu, Y.; Chu, C.; Huang, A.; Zhan, C.; Ma, Y.; Ma, C.; ACS Comb.Sci.2011,13, 547-; one-pot synthesis of palladium-catalyzed N-toluenesulfonylazepine with 2-iodophenol and isocyanate (Ji, F.; Lv, M.; Yi, W.; Caia, C.Adv.Synth. Catl.2013, 355, 3401-3406); palladium-catalyzed intramolecular cyclocarbonylation synthesis of 2- (2-iodophenoxy) aniline derivatives (Lu, S.; Alper, H.J.Am.chem.Soc.2005,127, 14776-14784).
The main disadvantages of the existing reported synthesis methods are that part of the reaction synthesis steps are various and the routes are complex, and part of the reaction uses a very special substrate structure and does not have good applicability; and expensive palladium catalyst is used in part of the reaction, so that the synthesis cost is high. Therefore, the development of a benzoxazepine seven-membered ring compound which is simple in synthesis method, has good substrate applicability, and uses as little noble metal catalyst as possible has been one of the research targets of organic synthesis chemists.
Disclosure of Invention
The invention aims to provide a preparation method of a benzoxazepine seven-membered ring, in particular to 1, 4-benzoxazepine
Preparation of (E) -5(4H) -one derivativesThe preparation method is as follows.
The invention provides 1, 4-benzoxazepine shown as formula I
A process for the preparation of (4-H) -5-keto derivatives, comprising the steps of:
in the presence of alkali, the o-fluorobenzamide compound shown as the formula II reacts with the propiolic alcohol compound shown as the formula III to obtain the 1, 4-benzoxazepine shown as the formula I
-5(4H) -one derivatives;
in the formulae I and II, R1Is alkyl, cycloalkyl or H, R with 1-6 carbon atoms2The substituent group is a single substituent group on a benzene ring, and is H, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, halogen atom, nitro or fluorinated alkyl with 1-6 carbon atoms;
in the formulae I and III, R3Is H or methyl, R4Is H or methyl;
in the formula I and the formula II, R1Preferably H, methyl, n-propyl, isopropyl, tert-butyl, tert-pentyl, cyclopentyl or cyclohexyl; r2Preferably H, methoxy or chlorine.
In the above preparation method, the alkali may be potassium hydroxide or sodium hydroxide.
In the above preparation method, the molar feeding amount of the propiolic alcohol compound shown in the formula III is 1.0 to 1.5 times of that of the o-fluorobenzamide compound shown in the formula II.
In the preparation method, the molar feeding amount of the alkali is 2.0-4.0 times of that of the o-fluorobenzamide compound shown in the formula II.
In the above production method, the reaction is carried out in a solvent; the solvent is dimethyl sulfoxide, and the water content of the dimethyl sulfoxide is not more than 0.1%.
In the above preparation method, the reaction is carried out in two steps, and the conditions of the first step are as follows: reacting for 6-18 hours at 20-40 ℃, preferably for 12 hours at 30 ℃, and reacting for 6-18 hours at 50-70 ℃, preferably for 12 hours at 50 ℃; the completion of the reaction can be monitored by thin layer chromatography or gas chromatography.
After the reaction is finished, the reaction system can be separated and purified according to a conventional method, and the preferred separation mode is as follows: transferring the stock solution after the reaction into an erlenmeyer flask, flushing a reaction tube by using ethyl acetate during transfer to reduce loss, adding a proper amount of saturated saline solution into the erlenmeyer flask, then transferring the erlenmeyer flask into a separating funnel for extraction for three times, combining organic phases, drying the combined organic phases by using anhydrous magnesium sulfate, and filtering; adding a certain amount of 100-200 meshes of silica gel, and carrying out reduced pressure concentration to remove the solvent to obtain the product-containing silica gel; loading silica gel and petroleum ether with 100-200 meshes into a column, and loading the column by using a dry method; eluting with a petroleum ether/ethyl acetate mixed solvent, wherein the proportion of petroleum ether to ethyl acetate is different according to the polarity of reactants and products, and the volume fraction of ethyl acetate is generally 4-20% by estimating through a result of thin-layer chromatography; the solution containing the reaction product I was collected, concentrated under reduced pressure to remove the solvent and dried under vacuum, weighed and the yield was calculated. For solid products, higher purity can be achieved by recrystallization, which is generally: adding a certain amount of dichloroethane into the sample, heating to completely dissolve the sample, adding a poor solvent n-hexane into the sample, and slowly volatilizing the poor solvent n-hexane to obtain the product single crystal.
The invention provides a method for synthesizing 1, 4-benzoxazepine
-5(4H) -one derivatives having the following characteristics:
(1) is economical. The reaction raw materials o-fluorobenzamide and propiolic alcohol are common chemical raw materials, and the used alkali and solvent are cheap bulk chemical products, and no expensive catalyst is used.
(2) Is universally applicable. The reaction is applicable to a variety of substrates, including a variety of substrates containing alkyl or aryl groups, electron donating groups or electron withdrawing groups, and two different products can be obtained simply by changing the solvent.
(3) Is convenient. The final product can be obtained by only one step, one feeding step and one separation step in the reaction, and the separation process is very simple due to the high chemical selectivity of the reaction.
(4) Green in color. The by-product of the reaction is only potassium fluoride, and the reaction has very high atom utilization rate. Meanwhile, the byproduct potassium chloride can also be obtained by separation, and has certain economic benefit.
Drawings
FIGS. 1 and 2 are a hydrogen nuclear magnetic resonance spectrum and a carbon nuclear magnetic resonance spectrum, respectively, of the objective product obtained in example 1.
FIGS. 3 and 4 are a hydrogen nuclear magnetic resonance spectrum and a carbon nuclear magnetic resonance spectrum, respectively, of the objective product obtained in example 2.
FIGS. 5 and 6 are a hydrogen nuclear magnetic resonance spectrum chart and a carbon nuclear magnetic resonance spectrum chart, respectively, of the objective product obtained in example 3.
FIGS. 7 and 8 are a hydrogen nuclear magnetic resonance spectrum chart and a carbon nuclear magnetic resonance spectrum chart, respectively, of the objective product obtained in example 4.
FIGS. 9 and 10 are a hydrogen nuclear magnetic resonance spectrum chart and a carbon nuclear magnetic resonance spectrum chart, respectively, of the objective product obtained in example 5.
FIGS. 11 and 12 are a hydrogen nuclear magnetic resonance spectrum chart and a carbon nuclear magnetic resonance spectrum chart, respectively, of the objective product obtained in example 6.
FIGS. 13 and 14 are a hydrogen nuclear magnetic resonance spectrum chart and a carbon nuclear magnetic resonance spectrum chart, respectively, of the objective product obtained in example 7.
FIGS. 15 and 16 are a hydrogen nuclear magnetic resonance spectrum chart and a carbon nuclear magnetic resonance spectrum chart, respectively, of the objective product obtained in example 8.
FIGS. 17 and 18 are a hydrogen nuclear magnetic resonance spectrum chart and a carbon nuclear magnetic resonance spectrum chart, respectively, of the objective product obtained in example 9.
FIGS. 19 and 20 are a hydrogen nuclear magnetic resonance spectrum chart and a carbon nuclear magnetic resonance spectrum chart, respectively, of the objective product obtained in example 10.
FIGS. 21 and 22 are a hydrogen nuclear magnetic resonance spectrum chart and a carbon nuclear magnetic resonance spectrum chart, respectively, of the objective product obtained in example 11.
Detailed Description
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The o-fluorobenzamide compound represented by the formula II can be prepared by the following method using 2-fluoro-N-N-propylbenzamide (in the formula II, R)1Is n-propyl, R2Is H) as an example to illustrate the preparation method:
0.885g of propylamine (15mmol) and 2.070g of potassium carbonate (15mmol) are weighed in sequence and added into a 100mL round-bottom flask, 25mL of acetonitrile is added into the round-bottom flask, the round-bottom flask is put into an oil bath at 70 ℃ and stirred uniformly, 1.585g of o-fluorobenzoyl chloride (10mmol) is added dropwise by using a rubber head dropper, and the mixture is stirred in the oil bath at 70 ℃ for reaction for 4 hours. Transferring the stock solution after the reaction into a conical flask, flushing a reaction tube by using ethyl acetate during transfer to reduce loss, adding a proper amount of saturated saline solution into the conical flask, transferring the conical flask into a separating funnel for extraction for three times, combining organic phases, drying by anhydrous magnesium sulfate, filtering, adding a certain amount of 100-200 meshes of silica gel, and removing the solvent by concentration under reduced pressure to obtain the product-containing silica gel; loading silica gel and petroleum ether with 100-200 meshes into a column, and loading the column by using a dry method; eluting with petroleum ether/ethyl acetate mixed solvent, wherein the volume fraction of ethyl acetate is 10%; the solution containing the reaction product was collected, concentrated under reduced pressure to remove the solvent and then dried in vacuo to give 1.635g of a pale yellow liquid, the isolated yield of the objective product, 2-fluoro-N-propylbenzamide, being 90%.
Examples 1,
0.0905g of 2-fluoro-N-N-propylbenzamide (0.5mmol), 0.0336g of propiolic alcohol (0.6mmol) and 0.0084g of potassium hydroxide (1.5mmol) were sequentially weighed into a 25mL sealed tube containing a magnetic stirrer, and 4.0mL of anhydrous dimethyl sulfoxide was added. The sealed tube is placed in a magnetic stirring heater at the temperature of 30 ℃ to be stirred and reacted for 12 hours, and then the temperature is increased to 50 ℃ to be continuously stirred and reacted for 12 hours. After the reaction is finished, petroleum ether-ethyl is usedSeparating with ethyl acetate as eluent to obtain light yellow liquid 0.0585g and target product 4-n-propyl-3-methyl-1, 4-benzoxazazepine
The isolated yield of the (4H) -5-one is 54%, i.e., in formula I, R1Is n-propyl, R2Is H, R3And R4Are all H.
FIG. 1 and FIG. 2 show the NMR spectrum and the carbon spectrum of the product obtained in this example, respectively, and it can be seen that the compound has a correct structure.
Examples 2,
0.0695g of 2-fluorobenzamide (0.5mmol), 0.0336g of propiolic alcohol (0.6mmol) and 0.0084g of potassium hydroxide (1.5mmol) are weighed in sequence into a 25mL sealed tube containing a magnetic stirrer, and 4.0mL of anhydrous dimethyl sulfoxide is added. The sealed tube is placed in a magnetic stirring heater at the temperature of 30 ℃ to be stirred and reacted for 12 hours, and then the temperature is increased to 50 ℃ to be continuously stirred and reacted for 12 hours. After the reaction is finished, petroleum ether-ethyl acetate is used as eluent for column separation to obtain light yellow liquid 0.0269g and a target product 3-methyl-1, 4-benzoxazazepine
The isolated yield of the (4H) -5-ketone was 31%.
FIG. 3 and FIG. 4 are the NMR spectrum and the carbon spectrum of the product obtained in this example, respectively, and it can be seen that the compound has a correct structure.
Examples 3,
0.0765g of 2-fluoro-N-methylbenzamide (0.5mmol), 0.0336g of propiolic alcohol (0.6mmol) and 0.0084g of potassium hydroxide (1.5mmol) were sequentially weighed into a 25mL sealed tube containing a magnetic stirrer, and 4.0mL of anhydrous dimethyl sulfoxide was added. The sealed tube is placed in a magnetic stirring heater at the temperature of 30 ℃ to be stirred and reacted for 12 hours, and then the temperature is increased to 50 ℃ to be continuously stirred and reacted for 12 hours. After the reaction is finished, petroleum ether-ethyl acetate is used as eluent for column separation to obtain 0.0541g of light yellow liquid and the target product 4-methyl-3-methyl-1, 4-benzoxazepine
The isolated yield of the (4H) -5-one is 57%, i.e., in formula I, R1Is methyl, R2Is H, R3And R4Are all H.
FIGS. 5 and 6 show the NMR spectrum and the carbon spectrum of the product obtained in this example, respectively, and it can be seen that the compound has a correct structure.
Examples 4,
0.1045g of 2-fluoro-N-tert-pentylbenzamide (0.5mmol), 0.0336g of propiolic alcohol (0.6mmol) and 0.0084g of potassium hydroxide (1.5mmol) were sequentially weighed into a 25mL sealed tube containing a magnetic stirrer, and 4.0mL of anhydrous dimethyl sulfoxide was added. The sealed tube is placed in a magnetic stirring heater at the temperature of 30 ℃ to be stirred and reacted for 12 hours, and then the temperature is increased to 50 ℃ to be continuously stirred and reacted for 12 hours. After the reaction is finished, petroleum ether-ethyl acetate is used as eluent for column separation to obtain 0.0621g of light yellow solid and the target product 4-tert-amyl-3-methyl-1, 4-benzoxaza
The isolated yield of the (4H) -5-one is 51%, i.e., in formula I, R1Is tert-amyl, R2Is H, R3And R4Are all H.
FIGS. 7 and 8 show the NMR spectrum and the carbon spectrum of the product obtained in this example, respectively, and it can be seen that the compound has a correct structure.
Examples 5,
0.0905g of 2-fluoro-N-isopropylbenzamide (0.5mmol), 0.0336g of propiolic alcohol (0.6mmol) and 0.0084g of potassium hydroxide (1.5mmol) were weighed in this order into a 25mL sealed tube containing a magnetic stirrer, and 4.0mL of anhydrous dimethyl sulfoxide was added. The sealed tube is placed in a magnetic stirring heater at the temperature of 30 ℃ to be stirred and reacted for 12 hours, and then the temperature is increased to 50 ℃ to be continuously stirred and reacted for 12 hours. After the reaction is finished, petroleum ether-ethyl acetate is used as eluent for column separation to obtain 0.0647g of light yellow liquid and the target product 4-isopropyl-3-methyl-1, 4-benzoxazepine
The isolated yield of the (4H) -5-one is 60%, i.e., in formula I, R1Is isopropyl, R2Is H, R3And R4Are all H.
FIG. 9 and FIG. 10 show the NMR spectrum and the carbon spectrum of the product obtained in this example, respectively, and it can be seen that the compound has a correct structure.
Examples 6,
0.1035g of 2-fluoro-N-cyclopentylbenzamide (0.5mmol), 0.0336g of propiolic alcohol (0.6mmol) and 0.0084g of potassium hydroxide (1.5mmol) were sequentially weighed into a 25mL sealed tube containing a magnetic stirrer, and 4.0mL of anhydrous dimethyl sulfoxide was added. The sealed tube is placed in a magnetic stirring heater at the temperature of 30 ℃ to be stirred and reacted for 12 hours, and then the temperature is increased to 50 ℃ to be continuously stirred and reacted for 12 hours. After the reaction is finished, petroleum ether-ethyl acetate is used as eluent for column separation to obtain light yellow liquid 0.0781g and a target product 4-cyclopentyl-3-methyl-1, 4-benzoxazepine
The isolated yield of the (4H) -5-one is 64%, i.e., in formula I, R1Is cyclopentyl, R2Is H, R3And R4Are all H.
FIGS. 11 and 12 show the NMR spectrum and the carbon spectrum of the product obtained in this example, respectively, and it can be seen that the compound has a correct structure.
Example 7,
0.1105g of 2-fluoro-N-cyclohexylbenzamide (0.5mmol), 0.0336g of propiolic alcohol (0.6mmol) and 0.0084g of potassium hydroxide (1.5mmol) were sequentially weighed into a 25mL sealed tube containing a magnetic stirrer, and 4.0mL of anhydrous dimethyl sulfoxide was added. The sealed tube is placed in a magnetic stirring heater at the temperature of 30 ℃ to be stirred and reacted for 12 hours, and then the temperature is increased to 50 ℃ to be continuously stirred and reacted for 12 hours. After the reaction is finished, petroleum ether-ethyl acetate is used as eluent for column separation to obtain 0.0894g of light yellow solid and the target product 4-cyclohexyl-3-methyl-1, 4-benzoxazepine
The isolated yield of the (4H) -5-one is 70%, i.e., in formula I, R1Is cyclohexyl, R2Is H, R3And R4Are all H.
FIGS. 13 and 14 show the NMR spectrum and the carbon spectrum of the product obtained in this example, respectively, and it can be seen that the compound has a correct structure.
Example 8,
0.0975g of 2-fluoro-N-tert-butylbenzamide (0.5mmol), 0.0336g of propiolic alcohol (0.6mmol) and 0.0084g of potassium hydroxide (1.5mmol) were sequentially weighed into a 25mL sealed tube containing a magnetic stirrer, and 4.0mL of anhydrous dimethyl sulfoxide was added. The sealed tube is placed in a magnetic stirring heater at the temperature of 30 ℃ to be stirred and reacted for 12 hours, and then the temperature is increased to 50 ℃ to be continuously stirred and reacted for 12 hours. After the reaction is finished, petroleum ether-ethyl acetate is used as eluent for column separation to obtain light yellow liquid 0.0682g and a target product 4-tert-butyl-3-methyl-1, 4-benzoxazazepine
The isolated yield of the (4H) -5-one is 59%, i.e., in formula I, R1Is tert-butyl, R2Is H, R3And R4Are all H.
FIG. 15 and FIG. 16 are the NMR hydrogen spectrum and the carbon spectrum, respectively, of the product obtained in this example, and it can be seen that the compound has a correct structure.
Examples 9,
0.1055g of 2-fluoro-4-methoxy-N-N-propylbenzamide (0.5mmol), 0.0336g of propargyl alcohol (0.6mmol) and 0.0084g of potassium hydroxide (1.5mmol) were sequentially weighed into a 25mL sealed tube containing a magnetic stirrer, and 4.0mL of anhydrous dimethyl sulfoxide was added. The sealed tube is placed in a magnetic stirring heater at the temperature of 30 ℃ to be stirred and reacted for 12 hours, and then the temperature is increased to 50 ℃ to be continuously stirred and reacted for 12 hours. After the reaction is finished, petroleum ether-ethyl acetate is used as eluent for column separation to obtain light yellow liquid 0.0841g and a target product 8-methoxy-4-propyl-3-methyl-1, 4-benzoxazazepine
The isolated yield of the (4H) -5-one is 68%, i.e., in formula I, R1Is methoxy, R2Is H, R3And R4Are all H.
FIG. 17 and FIG. 18 show the NMR spectrum and the carbon spectrum of the product obtained in this example, respectively, and it can be seen that the compound has a correct structure.
Examples 10,
0.0975g of 2-fluoro-3-methyl-N-N-propylbenzamide (0.5mmol), 0.0336g of propiolic alcohol (0.6mmol) and 0.0084g of potassium hydroxide (1.5mmol) were sequentially weighed into a 25mL sealed tube containing a magnetic stirrer, and 4.0mL of anhydrous dimethyl sulfoxide was added. The sealed tube is placed in a magnetic stirring heater at the temperature of 30 ℃ to be stirred and reacted for 12 hours, and then the temperature is increased to 50 ℃ to be continuously stirred and reacted for 12 hours. After the reaction is finished, petroleum ether-ethyl acetate is used as eluent for column separation to obtain light yellow liquid 0.0523g and a target product 4-propyl-3, 9-dimethyl-1, 4-benzoxazepine
The isolated yield of the (4H) -5-one is 45%, i.e., in formula I, R1Is methyl, R2Is H, R3And R4Are all H.
FIGS. 19 and 20 show the NMR spectrum and the carbon spectrum of the product obtained in this example, respectively, and it can be seen that the compound has a correct structure.
Examples 11,
0.1078g of 4-chloro-2-fluoro-N-N-propylbenzamide (0.5mmol), 0.0336g of propiolic alcohol (0.6mmol) and 0.0084g of potassium hydroxide (1.5mmol) were weighed in this order into a 25mL sealed tube containing a magnetic stirrer, and 4.0mL of anhydrous dimethyl sulfoxide was added. The sealed tube is placed in a magnetic stirring heater at the temperature of 30 ℃ to be stirred and reacted for 12 hours, and then the temperature is increased to 50 ℃ to be continuously stirred and reacted for 12 hours. After the reaction is finished, petroleum ether-ethyl acetate is used as eluent for column separation to obtain 0.0223g of light yellow liquid and the target product 8-chloro-4-propyl-3-methyl-1, 4-benzoxaza
The isolated yield of the (4H) -5-one is 18%, i.e., in formula I, R1Is n-propyl, R2Is chlorine, R3And R4Are all H.
FIGS. 21 and 22 show the NMR spectrum and the carbon spectrum of the product obtained in this example, respectively, and it can be seen that the compound has a correct structure.
Comparative examples 1,
0.0905g of 2-fluoro-N-N-propylbenzamide (0.5mmol), 0.0336g of propiolic alcohol (0.6mmol) and 0.0084g of potassium hydroxide (1.5mmol) were weighed in this order into a 25mL sealed tube containing a magnetic stirrer, and 4.0mL of dimethyl sulfoxide (undried, water content: about 0.3%) was added. The sealed tube is placed in a magnetic stirring heater at the temperature of 30 ℃ to be stirred and reacted for 12 hours, and then the temperature is increased to 50 ℃ to be continuously stirred and reacted for 12 hours. After the reaction is finished, petroleum ether-ethyl acetate is used as eluent for column separation to obtain light yellow liquid 0.0531g and target product 4-propyl-3-methyl-1, 4-benzoxazazepine
The isolated yield of the (4H) -5-ketone was 49%.
Comparative examples 2,
0.0905g of 2-fluoro-N-N-propylbenzamide (0.5mmol), 0.0336g of propiolic alcohol (0.6mmol) and 0.0084g of potassium hydroxide (1.5mmol) were sequentially weighed into a 25mL sealed tube containing a magnetic stirrer, and 4.0mL of dimethyl sulfoxide was added. The sealed tube is placed in a magnetic stirring heater at the temperature of 30 ℃ to be stirred and reacted for 12 hours, and then the temperature is increased to 70 ℃ to be continuously stirred and reacted for 12 hours. After the reaction is finished, petroleum ether-ethyl acetate is used as eluent for column separation to obtain light yellow liquid 0.0444g and the target product 4-propyl-3-methyl-1, 4-benzoxazazepine
The isolated yield of the (4H) -5-ketone was 41%.
Comparative examples 3,
0.0905g of 2-fluoro-N-N-propylbenzamide (0.5mmol), 0.0336g of propiolic alcohol (0.6mmol) and 0.0060g of sodium hydroxide (1.5mmol) were sequentially weighed out into a 25mL sealed tube containing a magnetic stirrer, and 4.0mL of dimethyl sulfoxide was added. The sealed tube is placed in a magnetic stirring heater at the temperature of 30 ℃ to be stirred and reacted for 12 hours, and then the temperature is increased to 50 ℃ to be continuously stirred and reacted for 12 hours. After the reaction is finished, petroleum ether-ethyl acetate is used as eluent for column separation to obtain light yellow liquid 0.0357g and a target product 4-propyl-3-methyl-1, 4-benzoxazepine
The isolated yield of the (4H) -5-ketone was 33%.
Comparative examples 4,
0.0905g of 2-fluoro-N-N-propylbenzamide (0.5mmol), 0.0336g of propiolic alcohol (0.6mmol) and 0.0084g of potassium hydroxide (1.5mmol) were sequentially weighed into a 25mL sealed tube containing a magnetic stirrer, and 4.0mL of dimethyl sulfoxide was added. The tube was sealed and the reaction was stirred at 30 ℃ for 12 hours. After the reaction is finished, petroleum ether-ethyl acetate is used as eluent for column separation to obtain 0.0487g of light yellow liquid and the target product 4-propyl-3-methyl-1, 4-benzoxaazane
The isolated yield of-5 (4H) -ketone was 45%; this gave 0.0130g of a pale yellow liquid and an isolated yield of the desired product 5-propyl-2, 5-dihydro-6H-1, 5-benzoxazepin-6-one of 12%.
Comparative examples 5,
0.0905g of 2-fluoro-N-N-propylbenzamide (0.5mmol), 0.0336g of propiolic alcohol (0.6mmol) and 0.0084g of potassium hydroxide (1.5mmol) were sequentially weighed into a 25mL sealed tube containing a magnetic stirrer, and 4.0mL of dimethyl sulfoxide was added. The tube was sealed and the reaction was stirred at 50 ℃ for 12 hours. After the reaction is finished, petroleum ether-ethyl acetate is used as eluent for column separation to obtain 0.0563g of light yellow liquid and the target product 4-propyl-3-methyl-1, 4-benzoxaazaneThe isolated yield of-5 (4H) -ketone was 52%; this gave 0.0076g of a pale yellow liquid, and the isolated yield of the desired product, 5-propyl-2, 5-dihydro-6H-1, 5-benzoxazepin-6-one, was 7%.
Claims (1)
1. 1, 4-benzoxazepines of the formula I
A process for the preparation of (4-H) -5-keto derivatives, comprising the steps of:
in the presence of a base, reacting an o-fluorobenzamide compound represented by the formula II with a compound represented by the formula IReacting the propiolic alcohol compound shown as the formula II to obtain the 1, 4-benzoxazepine shown as the formula I
-5(4H) -one derivatives;
the alkali is potassium hydroxide;
the molar feeding amount of the propiolic alcohol compound shown in the formula III is 1.0-1.5 times of that of the o-fluorobenzamide compound shown in the formula II;
the molar feeding amount of the alkali is 2.0-4.0 times of that of the o-fluorobenzamide compound shown in the formula II;
the reaction is carried out in a solvent; the solvent is dimethyl sulfoxide, and the water content of the dimethyl sulfoxide is not more than 0.1%;
the reaction is carried out in two steps, the conditions of the first step are as follows: reacting for 6-18 hours at the temperature of 20-40 ℃, and reacting for 6-18 hours at the temperature of 50-70 ℃ in the second step;
in the formulae I and II, R1Is alkyl, cycloalkyl or H, R with 1-6 carbon atoms2The substituent group is a single substituent group on a benzene ring, and is H, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, halogen atom, nitro or fluorinated alkyl with 1-6 carbon atoms;
in the formulae I and III, R3Is H or methyl, R4Is H or methyl.
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