10/5/2020 CN101423496 Chemical synthesis method of 10-methoxyl-5H-dibenz[b,f]azapine

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1. CN101423496-CHEMICAL SYNTHESIS METHOD OF

10-METHOXYL-5H-DIBENZ[B,F]AZAPINE
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[ZH]

Chemical synthesis method of 10-methoxy-5H-

dibenzo[b,f]azepine

Technical field
The present invention relates to the technical field of 10-methoxy-5H-dibenzo[b,f]azepine, and more
specifically, to the technical field of 10-methoxy-5H-dibenzo[b,f]azepine The technical field of chemical
synthesis, in particular, refers to a chemical synthesis method of 10-methoxy-5H-dibenzo[b,f]azepine.
Background technique
10-methoxy-5H-dibenz[b,f]azepine (10-methoxy-5H-dibenz[b,f]azepine), molecular formula: C 15 H 13
NO, molecular weight: 223.27, appearance is bright yellow crystalline powder, its structural formula is as
follows:

It is a chemical intermediate and has a wide range of uses in the chemical and pharmaceutical synthesis
fields.
At present, there are two main routes for the chemical synthesis of 10-methoxy-5H-dibenzo[b,f]azepine:
A. British patent GB 943277, the announcement date is: December 4, 1963, the name is:
Dibenz[b,f]azepines and their preparation process (Dibenz[b,f]azepines and process for their preparation),
describes a synthetic method of 10-methoxy-5H-dibenzo[b,f]azepine, the route is as follows:

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10/5/2020 CN101423496 Chemical synthesis method of 10-methoxyl-5H-dibenz[b,f]azapine

In this method, raw material III is reacted with alkali metal hydroxide to obtain product II, and then
excess alkali metal alkanoate is refluxed to obtain product I. The reaction process of this method is relatively
long. It is mentioned in the example of the patent specification that in the above two-step reaction, when X is
CH 3 At this time, the first reaction requires 14 hours at room temperature, and the second reaction requires
reflux for 18 hours. At the same time, it is also revealed that the direct conversion of the final product I using
the raw material III requires 32-40 hours. Moreover, those skilled in the art operate according to the examples
in this patent (Examples 1 and 2, R is a methyl group) to obtain crude 10-methoxy-5H-dibenzo[b,f]azepine
The yield is low, only 64.1%, and the yield after refining according to the conventional method is only 62.3%.
B. PCT patent WO 2005096709, the announcement date is: October 20, 2005, the name is: a 10,11-
dihydro-10-oxo-5H-dibenzo[b,f]azepine-5 -The preparation method of carboxamide (A process for the
preparation of 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide), describing 10-methoxy-5H-
diphenyl And [b, f] Azepine another synthetic method, the route is as follows:

The synthesis method uses sodium methoxide to react with raw material IV to obtain product I through
three stages, and the reaction time takes 16 to 20 hours. Only the yield of the final product oxcarbazepine is
published, and those skilled in the art follow the example (Example 2) in which 10-methoxy-5H-
dibenzo[b,f]azepine is synthesized. The yield is only 65.6%, and the yield after refining by conventional
methods is only 61.4%.
Therefore, in the above two routes A and B, there are problems of long reaction process time and low
reaction yield. In particular, the use of sodium methoxide in route B has the disadvantages of incomplete
reaction and low product yield.
Summary of the invention
The main purpose of the present invention is to solve the above problems and shortcomings, improve the
prior art, and provide a chemical synthesis method of 10-methoxy-5H-dibenzo[b,f]azepine, which The process
is reasonable, the reaction time is short, the reaction yield is high, and it is suitable for large-scale industrial
production.
In order to achieve the above objectives, the technical solutions adopted by the present invention are as
follows:
The 10-methoxy-5H-dibenzo[b,f]azepine chemical synthesis method is characterized in that it uses 10,11-
dibromoiminodibenzyl as a raw material and is combined with alkali metal hydroxide or The alkali metal
alkoxide reacts in a mixed solvent to generate the 10-methoxy-5H-dibenzo[b,f]azeppine.
Preferably, the mixed solvent is a mixed solvent containing an aromatic solvent.
More preferably, the aromatic solvent is selected from toluene, xylene or a mixture thereof.
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Preferably, the mixed solvent further includes methanol, and the ratio of the methanol to the aromatic
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solvent is 1: (0.5-10).
Preferably, the ratio of the mixed solvent to the 10,11-dibromoiminodibenzyl is: (3-20):1.
Preferably, the mixed solvent includes methanol and toluene/xylene, and the synthesis method is to first
add the alkali metal hydroxide or alkali metal alkoxide to methanol, and then add the toluene/dimethylbenzene
after heating and refluxing to dissolve. Toluene and the 10,11-dibromoiminodibenzyl are heated to reflux to
generate the 10-methoxy-5H-dibenzo[b,f]azepine.
More preferably, the alkali metal hydroxide is selected from potassium hydroxide; the alkali metal
alkoxide is selected from potassium methoxide. The reaction equation can be expressed as:

More preferably, the heating and refluxing time is 6-8 hours.

Preferably, after generating the 10-methoxy-5H-dibenzo[b,f]azepine, a subsequent separation and
purification step is also included.
More preferably, the subsequent separation and purification steps include: adding water and stirring,
washing with water, standing to remove the water layer, evaporation under reduced pressure, cooling
chromatography, filtration and drying, so as to obtain pure 10-methoxy-5H-dibenzo [b, f] Azepine.
Because the present invention uses 10,11-dibromoiminodibenzyl as a raw material, it reacts with alkali
metal hydroxide or alkali metal alkoxide in a mixed solvent to generate the 10-methoxy-5H-dibenzo[ b, f]
Azepine, its beneficial effects are: the use of mixed solvents in the reaction process makes the reaction
complete, the reaction cycle is greatly shortened (within 10 hours, the prior art: 16-40 hours), and a high-
quality product yield High (above 80%, more than 18% higher than the existing technology), which is
significantly higher than the direct use of sodium methoxide as a reactant, suitable for industrial production,
and has greater implementation value and social and economic benefits.
detailed description
In order to better understand the content of the present invention, further description will be given below
in conjunction with specific embodiments.
Among them, 10,11-dibromoiminodibenzyl is prepared with reference to the method disclosed in Chinese
Patent CN 100999497 (application number: 200610155099.8).
Example 1
Add 250ml of methanol to a 2000ml flask, and then add 115g of KOH, and reflux until dissolved. Add
1200ml of toluene, add 65g of 10,11-dibromoiminodibenzyl, and heat to reflux for 6-8 hours; add 300ml of
water and stir, wash with water, stand to remove the water layer, distill out about 250ml of toluene under
reduced pressure, and cool and crystallize. Filtered and dried to obtain 30.0 g of 10-methoxy-5H-dibenzo[b,f]
azepine, with a yield of 85.8%.
Example 2
Add 50ml of methanol to a 1000ml flask, then add 120g of CH 3 OK (supplier: Zibo Fuxier Chemical Co., 
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10/5/2020 CN101423496 Chemical synthesis method of 10-methoxyl-5H-dibenz[b,f]azapine

Ltd.), heat up and reflux to dissolve. Add 500ml of toluene, add 55g of 10,11-dibromoiminodibenzyl, heat to
reflux for 6-8 hours; add 300ml of water and stir, wash with water, stand to remove the water layer, distill out
about 120ml of toluene under reduced pressure, cool and crystallize, Filtered and dried to obtain 24.1 g of 10-
methoxy-5H-dibenzo[b,f]azepine, with a yield of 81.7%.
Example 3
Add 250ml of methanol into a 1000ml flask, then add 200g of KOH, and reflux until dissolved. Add
120ml of xylene, add 105g of 10,11-dibromoiminodibenzyl, heat to reflux for 6-8 hours; add 300ml of water
and stir, wash with water, let stand to remove the water layer, distill out about 30ml of xylene under reduced
pressure, and cool to precipitate Crystallized, filtered, and dried to obtain 47.3 g of 10-methoxy-5H-
dibenzo[b,f] azepine, with a yield of 84.2%.
Example 4
Add 50ml methanol to a 1000ml flask, then add 215gCH 3 OK (supplier: Zibo Fuxier Chemical Co.,
Ltd.), heat up and reflux to dissolve. Add 500ml of xylene, add 100g of 10,11-dibromoiminodibenzyl, and heat
to reflux for 6-8 hours; add 300ml of water and stir, wash with water, stand to remove the water layer,
evaporate about 120ml of xylene under reduced pressure, and cool to separate Crystallized, filtered and dried
to obtain 43.3 g of 10-methoxy-5H-dibenzo[b,f]azepine, with a yield of 80.6%.
In summary, the chemical synthesis method of 10-methoxy-5H-dibenzo[b,f]azepine of the present
invention has reasonable process, short reaction time, high reaction yield, and is suitable for large-scale
industrial production.
It should be noted that all documents mentioned in the present invention are cited as references in this
application, just as if each document is individually cited as a reference. In addition, it should be understood
that the above are the specific embodiments of the present invention and the technical principles used. After
reading the above content of the present invention, those skilled in the art can make various changes or
modifications to the present invention without departing from the present invention. The spirit and scope of
these equivalent forms also fall within the scope of the present invention.

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