CN109824620A - The preparation method of benzo oxygen azepine heptatomic ring - Google Patents
The preparation method of benzo oxygen azepine heptatomic ring Download PDFInfo
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Abstract
The invention discloses a kind of preparation methods of benzo oxygen azepine heptatomic ring.The preparation method includes the following steps: in the presence of a base, and the amine compounds of neighbour's fluorobenzoyl shown in Formula II are reacted with propine alcoholic compound shown in formula III to get to Isosorbide-5-Nitrae shown in Formulas I-benzo oxygen azepine- 5 (4H) -one derivatives；In Formulas I and Formula II, R1Alkyl, naphthenic base or the H for being 1~6 for carbon atom number, R2It is H, the alkyl that the carbon atom number for alkoxy, halogen atom, nitro or the fluoro that the alkyl that carbon atom number is 1~6, carbon atom number are 1~6 is 1~6 for the monosubstituted base on phenyl ring；In Formulas I and formula III, R3For H or methyl, R4For H or methyl.The by-product that the present invention reacts only has potassium fluoride, and reaction has very high atom utilization.Side product chlorinated potassium can also be by isolated, with certain economic benefit simultaneously.
Description
Technical field
The present invention relates to a kind of preparation methods of benzo oxygen azepine heptatomic ring, belong to methodology of organic synthesis field.
Background technique
Benzo oxygen azepineAnd its derivative is because it there is brilliant bioactivity and pharmacological activity to be widely present in drug
In molecule.Many physiology, pharmacological evaluation show the azepine of oxygen containing benzoThe molecule of skeleton can be used as anticonvulsant drug, antidepression
Drug, central depressants, anti-ataraxy drug, and as non-nucleoside HIV-1-1 reverse transcriptase inhibitor (Pandey, S.；
Kumar,S.V.；Kant,R.；Chauhan,P.M.S.Org.Biomol.Chem.,2014,12,5346).Certain 1,4- benzos
Oxygen azepine- 5- ketone compound has activity (Chen, the C. of certain induction osteoclast formation and bone resorption；Lee,C.；
Chang,D.Eur.J.Med.Chem.,2016,117)；Certain 7 substitutions benzo oxygen azepines- 5- ketone compound has preferable
Anticonvulsant action and certain neurotoxicity (Deng, X.；Song,M.Med.Chem.Res.,2011,20,996)；It is certain
N- replaces benzo oxygen azepineCompound can inhibit the cells phosphorylation of part substrate, at the same have pharmacodynamic activity and
Certain anti-tumor activity (Takeuchi, C.S.；Leahy,J.W.J.Med.Chem.,2013,56,2218).
Since benzo oxygen azepine heptatomic ring has good physiological activity, synthetic method is widely noticed.Wherein benzo oxygen
AzepineAnd its derivative can be carried out by Flavoneoid derivative and Lawesson reagent Schmidt react synthesis (L é vai,
A.；T.；Frank,L.；Hosztafi,S.Heterocycles,1992,34,1523-1538)；Or by alkali
Ugi- propargyl addition product molecule 7-exo-dig intramolecular cyclization reaction synthetic method (Pandey, S. under the conditions of property；Kumar,
S.V.；Kant,R.；Chauhan,P.M.S.Org.Biomol.Chem.,2014,12,5346-5350)；N- takes under alkaline condition
Ortho-hydroxybenzamide and phenyl ring derivative carry out Smiles and reset tandem reaction synthetic method (Liu, Y.；Chu,C.；Huang,A.；
Zhan,C.；Ma,Y.；Ma,C.；ACS Comb.Sci.2011,13,547-553)；The N- tosyl azacyclo- of palladium chtalyst
One-pot synthesis method (Ji, the F. of propane and 2- iodophenol and isocyanates；Lv,M.；Yi,W.；Caia,
C.Adv.Synth.Catal.2013,355,3401-3406)；Point of 2- (2- iodo phenoxy group) anil of palladium chtalyst
Sub- inner ring carbonylation synthetic method (Lu, S.；Alper,H.J.Am.Chem.Soc.2005,127,14776-14784).
The major defect of the existing synthetic method reported is that part reaction synthesis step is various and route is complicated, and part is anti-
Very special substrate structure should have been used, and has not had good applicability；Part reaction has used palladium costly to urge
Agent, synthesis cost are high.Therefore, simple synthetic method is developed, there is preferable substrate applicability, while your gold do not used as far as possible
The benzo oxygen azepine compounds with 7-member cycle of metal catalyst becomes one of the goal in research of synthetic organic chemists.
Summary of the invention
The object of the present invention is to provide a kind of preparation methods of benzo oxygen azepine heptatomic ring, specially Isosorbide-5-Nitrae-benzo oxygen azepineThe preparation method of -5 (4H) -one derivatives.
1,4- benzo oxygen azepine shown in Formulas I provided by the present inventionThe preparation method of -5 (4H) -one derivatives, including such as
Lower step:
In the presence of a base, propine alcoholic compound shown in the amine compounds of neighbour's fluorobenzoyl shown in Formula II and formula III into
Row reaction is to get to Isosorbide-5-Nitrae shown in Formulas I-benzo oxygen azepine- 5 (4H) -one derivatives；
In Formulas I and Formula II, R1Alkyl, naphthenic base or the H for being 1~6 for carbon atom number, R2For the monosubstituted base on phenyl ring, it is
H, the carbon atom number of alkoxy, halogen atom, nitro or fluoro that carbon atom number is 1~6 alkyl, carbon atom number are 1~6 is 1
~6 alkyl；
In Formulas I and formula III, R3For H or methyl, R4For H or methyl；
Specifically, in Formulas I and Formula II, R1Preferably H, methyl, n-propyl, isopropyl, tert-butyl, tertiary pentyl, cyclopenta
Or cyclohexyl；R2Preferably H, methoxyl group or chlorine.
In above-mentioned preparation method, the alkali can be potassium hydroxide or sodium hydroxide.
In above-mentioned preparation method, the dosage that mole feeds intake of propine alcoholic compound shown in formula III is neighbour's fluorobenzene shown in Formula II
1.0~1.5 times of benzamide compound.
In above-mentioned preparation method, the dosage that mole feeds intake of the alkali is neighbour's fluorobenzoyl amine compounds shown in Formula II
2.0~4.0 times.
In above-mentioned preparation method, the reaction carries out in a solvent；The solvent is dimethyl sulfoxide, and the diformazan
The water content of base sulfoxide is no more than 0.1%.
In above-mentioned preparation method, the reaction is carried out in two steps, and the condition of the first step is: under conditions of 20~40 DEG C
Reaction 6~18 hours, preferably reacts 12 hours under conditions of 30 DEG C, and the condition of second step is anti-under conditions of 50~70 DEG C
It answers 6~18 hours, is preferably reacted 12 hours under conditions of 50 DEG C；Whether reaction finishes can be by thin-layer chromatography or gas phase color
Spectrum is monitored.
After completion of the reaction, reaction system can conventionally be carried out to separating-purifying, preferred separate mode are as follows: will
Stoste after reaction is transferred in conical flask, shifts Shi Keyong ethyl acetate rinse reaction tube, to reduce loss, to conical flask
It is middle that appropriate saturated salt solution is added, it is then transferred in separatory funnel and extracts three times, merge organic phase, it is dry through anhydrous magnesium sulfate
It is dry, filtering；The silica gel of a certain amount of 100~200 mesh is added, removing solvent is concentrated under reduced pressure and obtains the silica gel containing product；Using 100~
The silica gel and petroleum ether of 200 mesh fill column, use dry method upper prop；It is eluted with petrol ether/ethyl acetate mixed solvent, petroleum ether
With the ratio visual response object of ethyl acetate and the polarity of product and it is different, need to be estimated by the result of thin-layer chromatography, second
The volume fraction of acetoacetic ester is generally 4~20%；The solution comprising reaction product I is collected, vacuum after removing solvent is concentrated under reduced pressure
It is dry, it weighs and calculates yield.For solid product, higher purity can be obtained by way of recrystallization, general weight
The mode of crystallization is: a certain amount of dichloroethanes being added in the sample, heating is so that sample is completely dissolved, then is added thereto not
After good solvent n-hexane, it is allowed slowly to volatilize, the monocrystalline of product can be obtained.
Synthesis 1,4- benzo oxygen azepine provided by the invention- 5 (4H) -one derivatives, have the following characteristics that
(1) economical.Reaction raw materials neighbour fluorobenzamide and propilolic alcohol are common industrial chemicals, used alkali and solvent
Even more cheap large chemical products, while the catalyst of any valuableness is not used.
(2) pervasive.Reaction is to a variety of substrates, including various contains alkyl or aryl, the bottom of donor residues or electron-withdrawing group
Object is applicable in, and can be obtained by two different products only by replacement solvent.
(3) convenient.Reaction only needs a step, primary feed intake that final product can be obtained with first separation step, due to reaction
With very high chemo-selective, separation process is also very simple.
(4) green.The by-product of reaction only has potassium fluoride, and reaction has very high atom utilization.By-product simultaneously
Potassium chloride can also be by isolated, with certain economic benefit.
Detailed description of the invention
Fig. 1 and Fig. 2 is respectively the hydrogen nuclear magnetic resonance spectrogram and nuclear magnetic resonance of carbon spectrogram of 1 gained target product of embodiment.
Fig. 3 and Fig. 4 is respectively the hydrogen nuclear magnetic resonance spectrogram and nuclear magnetic resonance of carbon spectrogram of 2 gained target product of embodiment.
Fig. 5 and Fig. 6 is respectively the hydrogen nuclear magnetic resonance spectrogram and nuclear magnetic resonance of carbon spectrogram of 3 gained target product of embodiment.
Fig. 7 and Fig. 8 is respectively the hydrogen nuclear magnetic resonance spectrogram and nuclear magnetic resonance of carbon spectrogram of 4 gained target product of embodiment.
Fig. 9 and Figure 10 is respectively the hydrogen nuclear magnetic resonance spectrogram and nuclear magnetic resonance of carbon spectrogram of 5 gained target product of embodiment.
Figure 11 and Figure 12 is respectively the hydrogen nuclear magnetic resonance spectrogram and nuclear magnetic resonance of carbon spectrogram of 6 gained target product of embodiment.
Figure 13 and Figure 14 is respectively the hydrogen nuclear magnetic resonance spectrogram and nuclear magnetic resonance of carbon spectrogram of 7 gained target product of embodiment.
Figure 15 and Figure 16 is respectively the hydrogen nuclear magnetic resonance spectrogram and nuclear magnetic resonance of carbon spectrogram of 8 gained target product of embodiment.
Figure 17 and Figure 18 is respectively the hydrogen nuclear magnetic resonance spectrogram and nuclear magnetic resonance of carbon spectrogram of 9 gained target product of embodiment.
Figure 19 and Figure 20 is respectively the hydrogen nuclear magnetic resonance spectrogram and nuclear magnetic resonance of carbon spectrogram of 10 gained target product of embodiment.
Figure 21 and Figure 22 is respectively the hydrogen nuclear magnetic resonance spectrogram and nuclear magnetic resonance of carbon spectrogram of 11 gained target product of embodiment.
Specific embodiment
Experimental method used in following embodiments is conventional method unless otherwise specified.
The materials, reagents and the like used in the following examples is commercially available unless otherwise specified.
The amine compounds of neighbour's fluorobenzoyl shown in Formula II can be prepared by the following method, below with the fluoro- N- n-propyl of 2-
Benzamide (in Formula II, R1For n-propyl, R2To illustrate preparation method for H):
Successively weigh 0.885g propylamine (15mmol), 2.070g potassium carbonate (15mmol) be added 100mL round-bottomed flask in, then
25mL acetonitrile is added to round-bottomed flask, is put into 70 DEG C of oil bath and stirs evenly, then total 1.585g is added dropwise with rubber head dropper
O-fluoro-benzoyl chloride (10mmol) is stirred to react 4 hours in 70 DEG C of oil bath.Stoste after reaction is transferred to conical flask
In, Shi Keyong ethyl acetate rinse reaction tube is shifted, to reduce loss, appropriate saturated salt solution is added into conical flask, then
It is transferred in separatory funnel and extracts three times, merge organic phase, dried, filtered through anhydrous magnesium sulfate, be added a certain amount of 100~200
Purpose silica gel is concentrated under reduced pressure removing solvent and obtains the silica gel containing product；Column is filled using the silica gel and petroleum ether of 100~200 mesh, is made
With dry method upper prop；It is eluted with petrol ether/ethyl acetate mixed solvent, the volume fraction of ethyl acetate is 10%；Collect packet
Solution containing reaction product is concentrated under reduced pressure after removing solvent and is dried in vacuo, obtains light yellow liquid 1.635g, target product 2-
The separation yield of fluoro- N- n-propylbenzene formamide is 90%.
Embodiment 1,
Successively weigh the fluoro- N- n-propylbenzene formamide (0.5mmol) of 0.0905g 2-, 0.0336g propilolic alcohol
4.0mL anhydrous two is added in the 25mL tube sealing containing magnetic stirrer in (0.6mmol), 0.0084g potassium hydroxide (1.5mmol)
Methyl sulfoxide.Tube sealing is placed on after being stirred to react 12 hours in 30 DEG C of magnetic agitation heaters, is warming up to 50 DEG C and continues stirring instead
It answers 12 hours.It uses petroleum ether-ethyl acetate to carry out post separation as eluant, eluent after reaction, obtains light yellow liquid
0.0585g, target product 4- n-propyl -3- methyl-1,4- benzo oxygen azepineThe separation yield of -5 (4H) -one is 54%, that is,
In Formulas I, R1For n-propyl, R2For H, R3And R4It is H.
Fig. 1 and Fig. 2 is respectively the nuclear magnetic resonance spectroscopy and carbon spectrum that the embodiment prepares products obtained therefrom, as seen from the figure, the change
It is correct to close object structure.
Embodiment 2,
Successively weigh 0.0695g 2- fluorobenzamide (0.5mmol), 0.0336g propilolic alcohol (0.6mmol), 0.0084g
4.0mL anhydrous dimethyl sulphoxide is added in the 25mL tube sealing containing magnetic stirrer in potassium hydroxide (1.5mmol).Tube sealing is put
After being stirred to react 12 hours in 30 DEG C of magnetic agitation heaters, it is warming up to 50 DEG C and continues to be stirred to react 12 hours.Reaction terminates
It uses petroleum ether-ethyl acetate to carry out post separation as eluant, eluent afterwards, obtains light yellow liquid 0.0269g, target product 3- methyl-
1,4- benzo oxygen azepineThe separation yield of -5 (4H) -one is 31%.
Fig. 3 and Fig. 4 is respectively the nuclear magnetic resonance spectroscopy and carbon spectrum that the embodiment prepares products obtained therefrom, as seen from the figure, the change
It is correct to close object structure.
Embodiment 3,
Successively weigh the fluoro- N-methyl-benzamide of 0.0765g 2- (0.5mmol), 0.0336g propilolic alcohol (0.6mmol),
4.0mL anhydrous dimethyl sulphoxide is added in the 25mL tube sealing containing magnetic stirrer in 0.0084g potassium hydroxide (1.5mmol).It will
Tube sealing is placed on be stirred to react 12 hours in 30 DEG C of magnetic agitation heaters after, be warming up to 50 DEG C and continue to be stirred to react 12 hours.Instead
It uses petroleum ether-ethyl acetate to carry out post separation as eluant, eluent after answering, obtains light yellow liquid 0.0541g, target product
4- methyl -3- methyl-1,4- benzo oxygen azepineThe separation yield of -5 (4H) -one is 57%, that is, in Formulas I, R1For methyl, R2
For H, R3And R4It is H.
Fig. 5 and Fig. 6 is respectively the nuclear magnetic resonance spectroscopy and carbon spectrum that the embodiment prepares products obtained therefrom, as seen from the figure, the change
It is correct to close object structure.
Embodiment 4,
Successively weigh the fluoro- N- tert-amyl benzene formamide (0.5mmol) of 0.1045g 2-, 0.0336g propilolic alcohol
4.0mL anhydrous two is added in the 25mL tube sealing containing magnetic stirrer in (0.6mmol), 0.0084g potassium hydroxide (1.5mmol)
Methyl sulfoxide.Tube sealing is placed on after being stirred to react 12 hours in 30 DEG C of magnetic agitation heaters, is warming up to 50 DEG C and continues stirring instead
It answers 12 hours.It uses petroleum ether-ethyl acetate to carry out post separation as eluant, eluent after reaction, obtains light yellow solid
0.0621g, target product 4- tertiary pentyl -3- methyl-1,4- benzo oxygen azepineThe separation yield of -5 (4H) -one is 51%, that is,
In Formulas I, R1For tertiary pentyl, R2For H, R3And R4It is H.
Fig. 7 and Fig. 8 is respectively the nuclear magnetic resonance spectroscopy and carbon spectrum that the embodiment prepares products obtained therefrom, as seen from the figure, the change
It is correct to close object structure.
Embodiment 5,
Successively weigh the fluoro- N- isopropylbenzamide (0.5mmol) of 0.0905g 2-, 0.0336g propilolic alcohol
4.0mL anhydrous two is added in the 25mL tube sealing containing magnetic stirrer in (0.6mmol), 0.0084g potassium hydroxide (1.5mmol)
Methyl sulfoxide.Tube sealing is placed on after being stirred to react 12 hours in 30 DEG C of magnetic agitation heaters, is warming up to 50 DEG C and continues stirring instead
It answers 12 hours.It uses petroleum ether-ethyl acetate to carry out post separation as eluant, eluent after reaction, obtains light yellow liquid
0.0647g, target product 4- isopropyl -3- methyl-1,4- benzo oxygen azepineThe separation yield of -5 (4H) -one is 60%, that is,
In Formulas I, R1For isopropyl, R2For H, R3And R4It is H.
Fig. 9 and Figure 10 is respectively the nuclear magnetic resonance spectroscopy and carbon spectrum that the embodiment prepares products obtained therefrom, as seen from the figure, the change
It is correct to close object structure.
Embodiment 6,
Successively weigh the fluoro- N- cyclopenta benzamide (0.5mmol) of 0.1035g2-, 0.0336g propilolic alcohol (0.6mmol),
4.0mL anhydrous dimethyl sulphoxide is added in the 25mL tube sealing containing magnetic stirrer in 0.0084g potassium hydroxide (1.5mmol).It will
Tube sealing is placed on be stirred to react 12 hours in 30 DEG C of magnetic agitation heaters after, be warming up to 50 DEG C and continue to be stirred to react 12 hours.Instead
It uses petroleum ether-ethyl acetate to carry out post separation as eluant, eluent after answering, obtains light yellow liquid 0.0781g, target product
4- cyclopenta -3- methyl-1,4- benzo oxygen azepineThe separation yield of -5 (4H) -one is 64%, that is, in Formulas I, R1For ring penta
Base, R2For H, R3And R4It is H.
Figure 11 and Figure 12 is respectively the nuclear magnetic resonance spectroscopy and carbon spectrum that the embodiment prepares products obtained therefrom, as seen from the figure, this
Compound structure is correct.
Embodiment 7,
Successively weigh the fluoro- N- cyclohexylbenzoyl amine (0.5mmol) of 0.1105g2-, 0.0336g propilolic alcohol (0.6mmol),
4.0mL anhydrous dimethyl sulphoxide is added in the 25mL tube sealing containing magnetic stirrer in 0.0084g potassium hydroxide (1.5mmol).It will
Tube sealing is placed on be stirred to react 12 hours in 30 DEG C of magnetic agitation heaters after, be warming up to 50 DEG C and continue to be stirred to react 12 hours.Instead
It uses petroleum ether-ethyl acetate to carry out post separation as eluant, eluent after answering, obtains light yellow solid 0.0894g, target product
4- cyclohexyl -3- methyl-1,4- benzo oxygen azepineThe separation yield of -5 (4H) -one is 70%, that is, in Formulas I, R1For hexamethylene
Base, R2For H, R3And R4It is H.
Figure 13 and Figure 14 is respectively the nuclear magnetic resonance spectroscopy and carbon spectrum that the embodiment prepares products obtained therefrom, as seen from the figure, this
Compound structure is correct.
Embodiment 8,
Successively weigh the fluoro- N- t-butylbenzamide (0.5mmol) of 0.0975g2-, 0.0336g propilolic alcohol (0.6mmol),
4.0mL anhydrous dimethyl sulphoxide is added in the 25mL tube sealing containing magnetic stirrer in 0.0084g potassium hydroxide (1.5mmol).It will
Tube sealing is placed on be stirred to react 12 hours in 30 DEG C of magnetic agitation heaters after, be warming up to 50 DEG C and continue to be stirred to react 12 hours.Instead
It uses petroleum ether-ethyl acetate to carry out post separation as eluant, eluent after answering, obtains light yellow liquid 0.0682g, target product
4- tert-butyl -3- methyl-1,4- benzo oxygen azepineThe separation yield of -5 (4H) -one is 59%, that is, in Formulas I, R1For tertiary fourth
Base, R2For H, R3And R4It is H.
Figure 15 and Figure 16 is respectively the nuclear magnetic resonance spectroscopy and carbon spectrum that the embodiment prepares products obtained therefrom, as seen from the figure, this
Compound structure is correct.
Embodiment 9,
Successively weigh the fluoro- 4- methoxyl group-N- n-propylbenzene formamide (0.5mmol) of 0.1055g 2-, 0.0336g propilolic alcohol
4.0mL anhydrous two is added in the 25mL tube sealing containing magnetic stirrer in (0.6mmol), 0.0084g potassium hydroxide (1.5mmol)
Methyl sulfoxide.Tube sealing is placed on after being stirred to react 12 hours in 30 DEG C of magnetic agitation heaters, is warming up to 50 DEG C and continues stirring instead
It answers 12 hours.It uses petroleum ether-ethyl acetate to carry out post separation as eluant, eluent after reaction, obtains light yellow liquid
0.0841g, target product 8- methoxyl group -4- propyl -3- methyl-1,4- benzo oxygen azepineThe separation yield of -5 (4H) -one is
68%, that is, in Formulas I, R1For methoxyl group, R2For H, R3And R4It is H.
Figure 17 and Figure 18 is respectively the nuclear magnetic resonance spectroscopy and carbon spectrum that the embodiment prepares products obtained therefrom, as seen from the figure, this
Compound structure is correct.
Embodiment 10,
Successively weigh the fluoro- 3- methyl-N-n-propyl benzamide (0.5mmol) of 0.0975g2-, 0.0336g propilolic alcohol
4.0mL anhydrous two is added in the 25mL tube sealing containing magnetic stirrer in (0.6mmol), 0.0084g potassium hydroxide (1.5mmol)
Methyl sulfoxide.Tube sealing is placed on after being stirred to react 12 hours in 30 DEG C of magnetic agitation heaters, is warming up to 50 DEG C and continues stirring instead
It answers 12 hours.It uses petroleum ether-ethyl acetate to carry out post separation as eluant, eluent after reaction, obtains light yellow liquid
0.0523g, target product 4- propyl -3,9- dimethyl-Isosorbide-5-Nitrae-benzo oxygen azepineThe separation yield of -5 (4H) -one is 45%,
That is, in Formulas I, R1For methyl, R2For H, R3And R4It is H.
Figure 19 and Figure 20 is respectively the nuclear magnetic resonance spectroscopy and carbon spectrum that the embodiment prepares products obtained therefrom, as seen from the figure, this
Compound structure is correct.
Embodiment 11,
Successively weigh the fluoro- N- n-propylbenzene formamide (0.5mmol) of the chloro- 2- of 0.1078g 4-, 0.0336g propilolic alcohol
4.0mL anhydrous two is added in the 25mL tube sealing containing magnetic stirrer in (0.6mmol), 0.0084g potassium hydroxide (1.5mmol)
Methyl sulfoxide.Tube sealing is placed on after being stirred to react 12 hours in 30 DEG C of magnetic agitation heaters, is warming up to 50 DEG C and continues stirring instead
It answers 12 hours.It uses petroleum ether-ethyl acetate to carry out post separation as eluant, eluent after reaction, obtains light yellow liquid
The chloro- 4- propyl -3- methyl-1 of 0.0223g, target product 8-, 4- benzo oxygen azepineThe separation yield of -5 (4H) -one is 18%,
That is, in Formulas I, R1For n-propyl, R2For chlorine, R3And R4It is H.
Figure 21 and Figure 22 is respectively the nuclear magnetic resonance spectroscopy and carbon spectrum that the embodiment prepares products obtained therefrom, as seen from the figure, this
Compound structure is correct.
Comparative example 1,
Successively weigh the fluoro- N- n-propylbenzene formamide (0.5mmol) of 0.0905g2-, 0.0336g propilolic alcohol (0.6mmol),
It is (not dry that 4.0mL dimethyl sulfoxide is added in the 25mL tube sealing containing magnetic stirrer in 0.0084g potassium hydroxide (1.5mmol)
Dry, water content is about 0.3%).Tube sealing is placed on after being stirred to react 12 hours in 30 DEG C of magnetic agitation heaters, is warming up to 50 DEG C
Continue to be stirred to react 12 hours.It uses petroleum ether-ethyl acetate to carry out post separation as eluant, eluent after reaction, obtains light yellow
Liquid 0.0531g, target product 4- propyl -3- methyl-1,4- benzo oxygen azepineThe separation yield of -5 (4H) -one is 49%.
Comparative example 2,
Successively weigh the fluoro- N- n-propylbenzene formamide (0.5mmol) of 0.0905g 2-, 0.0336g propilolic alcohol
4.0mL dimethyl is added in the 25mL tube sealing containing magnetic stirrer in (0.6mmol), 0.0084g potassium hydroxide (1.5mmol)
Sulfoxide.Tube sealing is placed on after being stirred to react 12 hours in 30 DEG C of magnetic agitation heaters, is warming up to 70 DEG C and continues to be stirred to react 12
Hour.It uses petroleum ether-ethyl acetate to carry out post separation as eluant, eluent after reaction, obtains light yellow liquid 0.0444g, mesh
Mark product 4- propyl -3- methyl-1,4- benzo oxygen azepineThe separation yield of -5 (4H) -one is 41%.
Comparative example 3,
Successively weigh the fluoro- N- n-propylbenzene formamide (0.5mmol) of 0.0905g2-, 0.0336g propilolic alcohol (0.6mmol),
4.0mL dimethyl sulfoxide is added in the 25mL tube sealing containing magnetic stirrer in 0.0060g sodium hydroxide (1.5mmol).By tube sealing
It is placed on after being stirred to react 12 hours in 30 DEG C of magnetic agitation heaters, is warming up to 50 DEG C and continues to be stirred to react 12 hours.Reaction knot
Shu Houyong petroleum ether-ethyl acetate carries out post separation as eluant, eluent, obtains light yellow liquid 0.0357g, target product 4- third
Base -3- methyl-1,4- benzo oxygen azepineThe separation yield of -5 (4H) -one is 33%.
Comparative example 4,
Successively weigh the fluoro- N- n-propylbenzene formamide (0.5mmol) of 0.0905g 2-, 0.0336g propilolic alcohol
4.0mL dimethyl is added in the 25mL tube sealing containing magnetic stirrer in (0.6mmol), 0.0084g potassium hydroxide (1.5mmol)
Sulfoxide.Tube sealing is placed on 30 DEG C to be stirred to react 12 hours.Petroleum ether-ethyl acetate is used to carry out column as eluant, eluent after reaction
Separation, obtains light yellow liquid 0.0487g, target product 4- propyl -3- methyl-1,4- benzo oxygen azepine- 5 (4H) -one
Separating yield is 45%；Obtain light yellow liquid 0.0130g, target product 5- propyl -2,5- dihydro -6H-1,5- benzo oxygen nitrogen
The separation yield of heterocycle octatetraene -6- ketone is 12%.
Comparative example 5,
Successively weigh the fluoro- N- n-propylbenzene formamide (0.5mmol) of 0.0905g2-, 0.0336g propilolic alcohol (0.6mmol),
4.0mL dimethyl sulfoxide is added in the 25mL tube sealing containing magnetic stirrer in 0.0084g potassium hydroxide (1.5mmol).By tube sealing
50 DEG C are placed on to be stirred to react 12 hours.It uses petroleum ether-ethyl acetate to carry out post separation as eluant, eluent after reaction, obtains shallow
Yellow liquid 0.0563g, target product 4- propyl -3- methyl-1,4- benzo oxygen azepineThe separation yield of -5 (4H) -one is
52%；Obtain light yellow liquid 0.0076g, target product 5- propyl -2,5- dihydro -6H-1,5- benzo oxaza octatetraene -
The separation yield of 6- ketone is 7%.
Claims (6)
1. the oxygen azepine of 1,4- benzo shown in Formulas IThe preparation method of -5 (4H) -one derivatives, includes the following steps:
In the presence of a base, the amine compounds of neighbour's fluorobenzoyl shown in Formula II carry out anti-with propine alcoholic compound shown in formula III
It should be to get to Isosorbide-5-Nitrae shown in Formulas I-benzo oxygen azepine- 5 (4H) -one derivatives；
In Formulas I and Formula II, R1Alkyl, naphthenic base or the H for being 1~6 for carbon atom number, R2It is H, carbon for the monosubstituted base on phenyl ring
The carbon atom number of alkoxy, halogen atom, nitro or fluoro that alkyl that atomicity is 1~6, carbon atom number are 1~6 is 1~6
Alkyl；
In Formulas I and formula III, R3For H or methyl, R4For H or methyl.
2. preparation method according to claim 1, it is characterised in that: the alkali is potassium hydroxide or sodium hydroxide.
3. preparation method according to claim 1 or 2, it is characterised in that: mole throwing of propine alcoholic compound shown in formula III
Expect that dosage is 1.0~1.5 times of neighbour's fluorobenzoyl amine compounds shown in Formula II.
4. preparation method according to any one of claim 1-3, it is characterised in that: the dosage that mole feeds intake of the alkali is
2.0~4.0 times of the amine compounds of neighbour's fluorobenzoyl shown in Formula II.
5. preparation method described in any one of -4 according to claim 1, it is characterised in that: the reaction carries out in a solvent；
The solvent is dimethyl sulfoxide, and the water content of the dimethyl sulfoxide is no more than 0.1%.
6. preparation method according to any one of claims 1-5, it is characterised in that: the reaction is carried out in two steps, the
The condition of one step is: reacting 6~18 hours under conditions of 20~40 DEG C, the condition of second step is under conditions of 50~70 DEG C
Reaction 6~18 hours.
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| FERDINANDO FIORINO ET AL.: "Synthesis of benzamide derivatives and their evaluation as antiprion agents", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| VON VERONICA SCHERRER ET AL.: "62. Basenkatalysierte Cyclisierungen von 2-(2-Propinyl)oxybenzamiden", 《HELVETICA CHIMICA ACTA》 * |
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