CN103130717B - Preparation method of 2-benzo diazepine anthrone - Google Patents
Preparation method of 2-benzo diazepine anthrone Download PDFInfo
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- CN103130717B CN103130717B CN201110388230.6A CN201110388230A CN103130717B CN 103130717 B CN103130717 B CN 103130717B CN 201110388230 A CN201110388230 A CN 201110388230A CN 103130717 B CN103130717 B CN 103130717B
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Abstract
The invention discloses a preparation method of 2-benzo diazepine anthrone. The method comprises the following steps: anthranone, dichloromethane and concentrated sulfuric acid are filled in a reaction bulb according to a certain proportion, mechanical stirring is carried out, and sodium azide is slowly filled in the reaction bulb under room temperature to obtain yellow solid; the yellow solid and ammonia water are put in the reaction bulb to heat up to 80 DEG C to 90 DEG C, then zinc powder and copper sulfate are filled in batches, and the solution is stirred for 24 hours to 40 hours. Thin-layer chromatography (TLC) detection is carried out to confirm that no raw materials is left, the solution is cooled to room temperature, the zinc power is filtered out, and the zinc powder is washed for 3 to 4 times by ammonia water of 10%. PH is adjusted to 4 to 5 through acid under the room temperature, the solution is cooled to the temperature lower than 5 DEG C, and is stirred, and suction filtration is carried out, mother solution is extracted through ethyl acetate, organic phase is washed with Na2S solution, Na2SO4 is dried and concentrated, and crude products are obtained through filter cakes and the organic phase; and the crude products and toluene are put into the reaction bulb, and products are obtained after a series of reactions. The purity of the raw materials of the preparation method of the 2-benzo diazepine anthrone is high, and the yield coefficient of the obtained product is quite high.
Description
Technical field
The present invention relates to chemical field, particularly a kind of preparation method of 2-benzo diazepine anthrone.
Background technology
Benzodiazepine is the benzo seven member ring heterocyclic compounds thing that a class has valuable pharmacological activity and physiologically active, is commonly used for the medicine for the treatment of neural system and cardiovascular system diseases.This compounds also has the effects such as antimycotic, bacterium, antiviral and antagonism, obtains huge applications in medical treatment, and respond well, therefore the research of its unique chemical moieties and special physiological activity is obtained always to the extensive concern of people.Result of study finds that mix ester group on tall and erect seven-membered ring different positions and carboxyl of benzo is active group, can effectively increase its bacteriostatic activity.In order to study and find to have the assorted tall and erect compounds of Efficient antibacterial activity.
The synthetic method of current benzodiazepine generally has active methylene group ketone compounds ring-closure reaction under catalyst action with O-Phenylene Diamine and alpha-position obtains.But its productivity ratio is lower, and by product is many.
Summary of the invention
For solving the problems of the technologies described above, another object of the present invention is to the preparation method providing a kind of 2-benzo diazepine anthrone.
The present invention is realized by following technical scheme:
A preparation method for 2-benzo diazepine anthrone, said method comprising the steps of:
(1) in reaction flask, anthrone is added by a certain percentage, methylene dichloride, the vitriol oil, mechanical stirring, room temperature slowly adds sodiumazide, then stirring at room temperature more than 10 hours, after raw material reaction is complete, reaction solution is slowly added in frozen water and stirs, product is viscose glue shape, sour water is poured out, then water washing glues thing 3-4 time, 30%NaOH solution is slowly added in viscous material, reaction is violent, a large amount of gas is had to produce, after stable, be heated to 80-90 DEG C, stir 3-5 hour, TLC detects the completely rear cool to room temperature of raw material reaction, PH=1-5 is adjusted with acid, be cooled to less than 5 DEG C, suction filtration, frozen water washs, oven dry obtains yellow solid,
(2) in reaction flask, by described yellow solid, ammoniacal liquor, then intensification 80-90 DEG C add zinc powder and copper sulfate in batches, stirs 24-40 hour, TLC and detect without raw material, be down to room temperature, elimination zinc powder, and with 10% ammonia scrubbing zinc powder 3-4 time, PH=4-5 is adjusted by sour room temperature, be cooled to less than 5 DEG C, stir, suction filtration, mother liquor is extracted with ethyl acetate, and uses Na
2s solution washing organic phase, Na
2sO
4drying, concentrated, filter cake and organic phase obtain crude product altogether;
(3) in reaction flask, described crude product and toluene, temperature 115 DEG C then fractionation band water in heating up, TLC detects without raw material, and heat leaches insolubles, is down to room temperature, revolves and steams toluene, and crude product EA and PE recrystallization, be prepared into product.
Another aspect of the present invention, adds sodiumazide until raw material reaction is complete in described step (1) in batches.
Another aspect of the present invention, in described step (1), concentrated hydrochloric acid adjusts PH=2-4.
Another aspect of the present invention, in described step (1), yellow solid yield is more than 90%.
Another aspect of the present invention, according to weight content meter, anthrone in described step (1), the ratio of methylene dichloride and the vitriol oil is: 1: 4-1: 6.
Another aspect of the present invention, according to weight content meter, in described step (1), the ratio of sodiumazide and anthrone is: 1: 2-1: 3.
Another aspect of the present invention, according to weight content meter, the zinc in described step (2) and the ratio of copper sulfate are: 20: 1-30: 1.
Another aspect of the present invention, in described step (3), the yield of product is greater than 90%.
Beneficial effect of the present invention is: preparation method's material purity of 2-benzo diazepine anthrone of the present invention is high, and corresponding product yield is high.Acid adjustment after hydrolysis, be transferred to PH ≈ 2-3, guarantee section product is not dissolved in water.Add zinc powder and copper sulfate in batches in preparation feedback of the present invention, add fashionable heat release obvious.And the amount controlling zinc powder and copper sulfate lowers and is conducive to aftertreatment.In preparation feedback of the present invention, concentrated hydrochloric acid adjusts PH=4-5, and product can not be soluble in the aqueous phase.
Embodiment
Below in conjunction with embodiment, the present invention will be further described.
One, total reaction equation:
Two, respectively overview is walked:
The first step:
1, reaction equation:
2, material proportion:
3, operation steps:
270g anthrone is added in 5000ml reaction flask, 500g methylene dichloride, the 2430g vitriol oil, mechanical stirring, room temperature slowly adds 126g sodiumazide, and (palpus more than 12 hours, has hydrazoic acid and nitrogen to produce, tail gas absorption, gas defence), then stirring at room temperature more than 10 hours, continues to add sodiumazide until raw material reaction complete (middle control one) if raw material does not react completely in batches.After raw material reaction is complete, slowly added by reaction solution (attention has a large amount of gas to produce, gas defence) in 5000g frozen water, stir 1 hour, product is viscose glue shape, is poured out by sour water, and then water washing glues thing 3-4 time.Slowly added in viscous material by 30%NaOH solution, reaction is violent, has a large amount of gas to produce, after stable, be heated to 80 degree, stir 3-5 hour, TLC and detect raw material reaction (middle control two) cool to room temperature afterwards completely, PH ≈ 2-3 is adjusted with concentrated hydrochloric acid, be cooled to 5 DEG C, suction filtration, frozen water washs, oven dry obtains 290g yellow solid, yield about 90%.
4, experimental result:
Remarks:
A: product is crude product, because solvability is very poor, do not detect through HPLC, but TLC detects almost inclusion-free point.
B: product is crude product, because solvability is very poor, do not detect through HPLC, but TLC detects almost inclusion-free point.
5, critical control point:
1) this reaction has a large amount of hydrazoic acid to produce, and toxicity is very large, notes tail gas absorption.
2) in, control detects: acid adjustment after hydrolysis, and be transferred to PH ≈ 2-3, if acid was adjusted, product will be partly dissolved, if acid amount not, then has portioned product to be dissolved in water.Mother liquor after suction filtration is extracted with ethyl acetate once, but the amount of product is generally few.
6, control in reaction:
Second step:
1, reaction equation:
2, material proportion:
3, operation steps:
In 3000ml reaction flask, 290B, 1720g ammoniacal liquor, then intensification 80-90 DEG C add 455g Zn and 20 copper sulfate in batches, stirs 24-40 hour.TLC detects without raw material (middle control one), is down to room temperature, elimination zinc powder, and with 10% ammonia scrubbing zinc powder 3-4 time.Adjust PH ≈ 4-5 by concentrated hydrochloric acid room temperature, be cooled to 5 DEG C, stir 1 hour, suction filtration, mother liquor is extracted with ethyl acetate 2 times, uses Na
2s solution washing organic phase, Na
2sO
4drying, concentrated, filter cake and organic phase obtain crude product 190g altogether, yield about 73%.
4, experimental result:
A. reaction carries out three days, and raw material never reacts completely, so this reaction need further optimization.
B. reaction carries out 30 hours, complete reaction, and obtain 190g crude product, solvability is very poor.
5, critical control point:
1. walk product on and under the condition of not exclusively drying, can directly throw the next step (technique needs to be optimized further).
2. add zinc powder and copper sulfate in batches, add fashionable heat release obvious.
3. the amount of zinc powder is now for 8eq. process optimization can reduce consumption, and copper sulfate is now 10%, also can optimize further and be down to 1%.The amount of zinc powder and copper sulfate lowers and is conducive to aftertreatment.
4. concentrated hydrochloric acid adjusts PH=4-5, if during PH=1-2, product will all be soluble in the aqueous phase, because the water soluble crosslinkable of product is large, and more difficult extraction.
3rd step:
1, reaction equation:
2, material proportion:
3, operation steps:
In 3000ml reaction flask, 75g C, 520g toluene, temperature 115 DEG C then fractionation band water in heating up.TLC detects without raw material (middle control one), and heat leaches insolubles, is down to room temperature, revolves and steams toluene, crude product EA and PE recrystallization.Obtain product 62g, yield 90%, HPLC98%.
4, experimental result:
A.1HNMR end product D is determined with MS.
B. material purity is high, and corresponding product yield is high.
C. material purity is low, and corresponding product yield is low.
5, critical control point:
1. namely toluene band water to anhydrous separating react completely.
6, control in reaction:
| Sampling spot | Sample treatment | Testing conditions | Detection method | Middle control standard |
| Middle control 1 | Take a morsel reaction solution | TLC | PE∶EA＝3∶1 | Without raw material |
Should be appreciated that and above describe for the present invention to be as set forth in the claims only example and illustrative, not to be limited it.Content of the present invention disclosed by this paper, other embodiment of the present invention is apparent for a person skilled in the art.It should be noted that this specification sheets and embodiment only should be seen as example, actual range of the present invention and spirit should be determined by claim.
Claims (2)
1. a preparation method for 2-benzo diazepine anthrone, is characterized in that: said method comprising the steps of:
(1) in reaction flask, anthrone is added by a certain percentage, methylene dichloride, the vitriol oil, mechanical stirring, room temperature slowly adds sodiumazide, then stirring at room temperature more than 10 hours, after raw material reaction is complete, reaction solution is slowly added in frozen water and stirs, product is viscose glue shape, sour water is poured out, then water washing glues thing 3-4 time, 30%NaOH solution is slowly added in viscous material, reaction is violent, a large amount of gas is had to produce, after stable, be heated to 80-90 DEG C, stir 3-5 hour, TLC detects the completely rear cool to room temperature of raw material reaction, PH=1-5 is adjusted with acid, be cooled to less than 5 DEG C, suction filtration, frozen water washs, oven dry obtains yellow solid,
(2) in reaction flask, by described yellow solid, ammoniacal liquor, then intensification 80-90 DEG C add zinc powder and copper sulfate in batches, stirs 24-40 hour, TLC and detect without raw material, be down to room temperature, elimination zinc powder, and with 10% ammonia scrubbing zinc powder 3-4 time, PH=4-5 is adjusted by sour room temperature, be cooled to less than 5 DEG C, stir, suction filtration, mother liquor is extracted with ethyl acetate, and uses Na
2s solution washing has
Machine phase, Na
2sO
4drying, concentrated, filter cake and organic phase obtain crude product altogether;
(3) in reaction flask, described crude product and toluene, temperature 115 DEG C then fractionation band water in heating up, TLC detects without raw material, and heat filters insolubles, is down to room temperature, revolves and steams toluene, and crude product ethyl acetate and sherwood oil recrystallization, be prepared into product;
Wherein, add sodiumazide until raw material reaction is complete in described step (1) in batches;
According to weight content meter, anthrone in described step (1), the ratio of methylene dichloride and the vitriol oil is: 1: 4-1: 6;
According to weight content meter, in described step (1), the ratio of sodiumazide and anthrone is: 1: 2-1: 3;
According to weight content meter, the zinc in described step (2) and the ratio of copper sulfate are: 20: 1-30: 1.
2. the preparation method of a kind of 2-benzo diazepine anthrone as claimed in claim 1, is characterized in that: in described step (1), concentrated hydrochloric acid adjusts PH=2-4.
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| CN105646486B (en) * | 2016-03-01 | 2017-10-13 | 苏州艾缇克药物化学有限公司 | A kind of synthetic method of 5 azaindole |
| CN106543082B (en) * | 2016-10-31 | 2020-03-31 | 河南省化工研究所有限责任公司 | Preparation method of 5, 11-dihydro-6H-dibenzo [ b, e ] azepine-6 ketone |
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| US4058561A (en) * | 1975-02-12 | 1977-11-15 | Bayer Aktiengesellschaft | 2-Chloromethylphenylcarbamic acid fluoride |
| CN101304999A (en) * | 2005-08-29 | 2008-11-12 | 欧加农股份有限公司 | Non-steroidal compounds useful as glucocorticoid receptor modulators |
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| CN102153513A (en) * | 2011-02-28 | 2011-08-17 | 中国农业大学 | Hydrocarbon-oxygen imino group dibenzo caprolactam derivative, as well as preparation method of the derivative and application of the derivative in serving as bactericide |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100486320B1 (en) * | 2002-07-06 | 2005-04-29 | 일동제약주식회사 | Preparation method of 5,11-dihydro-6H-dibenz[b,e]azepin-6-one |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4058561A (en) * | 1975-02-12 | 1977-11-15 | Bayer Aktiengesellschaft | 2-Chloromethylphenylcarbamic acid fluoride |
| CN101304999A (en) * | 2005-08-29 | 2008-11-12 | 欧加农股份有限公司 | Non-steroidal compounds useful as glucocorticoid receptor modulators |
| CN101348411A (en) * | 2007-07-20 | 2009-01-21 | 河南大学 | Preparation of 2-alkyl anthracene derivative |
| CN102153513A (en) * | 2011-02-28 | 2011-08-17 | 中国农业大学 | Hydrocarbon-oxygen imino group dibenzo caprolactam derivative, as well as preparation method of the derivative and application of the derivative in serving as bactericide |
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| Mario Bigioni,等.Set-up of a new series of HDAC inhibitors: the 5,11-dihydrodibenzo[b,e]azepin-6-ones as privileged structures.《Bioorganic & * |
| Medicinal Chemistry Letters》.2012,第22卷第5360–5362页. * |
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