10/10/2020 CN102807528 Preparation method of 10-methoxy iminostilbene

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1. CN102807528-PREPARATION METHOD OF 10-

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Preparation method of 10-methoxyimino stilbene

Technical field
The invention relates to a preparation method of 10-methoxyiminostilbene, in particular to a preparation
method of 10-methoxyiminostilbene using iminostilbene-5-formyl halide or a mixture thereof as raw
materials.
Background technique
10-Methoxyiminostilbene, molecular formula is C15H13NO, molecular weight is 223.2, appearance is
bright yellow crystalline solid; its structural formula is:

It is an important intermediate of the antiepileptic drugs oxcarbazepine and carbamazepine. At present, its
synthesis methods mainly include the following methods:
1. GB943277 describes a synthesis method of 10-methoxyiminostilbene, the route is as follows

In this method, raw material III reacts with alkali metal hydroxide to obtain II, and then reacts with alkali
metal alkanoate to obtain I. The reaction time of the first step takes 14 hours, and the reaction of the second
step takes 18 hours, but the yield is Low, yield ≤65%, poor product quality, purity ≤98%.
2. WO2005096709 describes another preparation method of 10-methoxyiminostilbene, the route is as
follows,

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10/10/2020 CN102807528 Preparation method of 10-methoxy iminostilbene

This method uses sodium methoxide to react with IV to form I. The reaction time is 16 hours. The
company’s experimenters failed to obtain satisfactory results within the specified time, and a large amount of
dimer impurities were formed, resulting in the failure to obtain high-quality I , The purity of the crude product
is only 70-80%.
3. CN101423496 improves the above two methods. It uses alkali metal hydroxide or alkali metal alkoxide
to react in a mixed solvent, which shortens the reaction time and increases the yield; but this method is
compared with the previous two methods, Can not get high purity I, product purity ≤97%; the route is as
follows,

The above methods all have the problem of low product purity. However, due to the increasing
requirements for raw materials, the quality requirements for key intermediates are also getting higher and
higher. There is an urgent need to develop a method for preparing 10-methoxyiminostilbene. Method of purity.
Summary of the invention
In view of the above shortcomings, the purpose of the present invention is to provide a method for
preparing 10-methoxyiminostilbene which can improve the purity of 10-methoxyiminostilbene.
The technical content of the present invention is as follows: a preparation method of 10-
methoxyiminostilbene, the steps are as follows:
(1). Take methanol and add iminostilbene-5-formyl halide or iminostilbene-5-formyl halide mixture, stir
evenly and gradually heat to reflux, then add alkali metal alkoxide solution dropwise, and the addition is
complete Afterwards, the reaction was completed by HPLC. The reaction solution was gradually cooled to 0-
10°C to obtain iminostilbene-5-methyl formate solid, which was filtered out and washed with pure water for 2
to 5 times. Dry it for later use; wherein iminostilbene-5-formyl halide is iminostilbene-5-formyl chloride,
iminostilbene-5-formyl bromide, iminostilbene-5-formyl fluoride or iminostilbene-5 -Formyl iodide, the
weight ratio of methanol to iminostilbene-5-formyl halide is 1:1～3:1; the mixture of iminostilbene-5-formyl
halide is iminostilbene-5-formyl chloride or/ A mixture of iminostilbene-5-formyl bromide or/and
iminostilbene-5-formyl fluoride or/and iminostilbene-5-formyl iodide, a mixture of methanol and
iminostilbene-5-formyl halide The weight ratio of the alkali metal alkoxide is 1:1～3:1; the alkali metal
alkoxide solution is sodium methoxide solution or potassium methoxide solution, the weight concentration of
the alkali metal alkoxide solution is 10-50%, and the addition amount of the alkali metal alkoxide solution is
sub 0.5 to 2 times the weight of the mixture of aminostilbene-5-formyl halide or iminostilbene-5-formyl
halide;
(2) Take methanol again, then add the iminostilbene-5-methyl carboxylate solid prepared in step (1) and
dibromohydantoin, stir, and keep the solution temperature at -5～5℃, HPLC detection After the reaction is
complete, the solid is filtered out, washed with methanol at -5～5℃ for 2～5 times and then dried to obtain
the solid 10-methoxy-11-bromo-10,11-dihydroiminostilbene-5-carboxylic acid methyl ester. Spare; wherein
the weight ratio of methanol to iminostilbene-5-methyl formate is 1.6:1～4:1, and the weight ratio of
dibromohydantoin to iminostilbene-5-methyl formate is 0.3:1 to 1.5: 1;
(3) Take toluene and add triethylamine and 10-methoxy-11-bromo-10,11-dihydroiminostilbene-5-methyl
formate prepared in step (2), and gradually increase the temperature after stirring After refluxing, the reaction
was followed by HPLC, and then filtered, and the filtrate was cooled to 0～10℃, and a white solid 10-
methoxyiminostilbene-5-carboxylic acid methyl ester was precipitated, and then washed with toluene for 1 to
3 times and dried. Spare; the weight ratio of toluene and 10-methoxy-11-bromo-10,11-dihydroiminostilbene-5-
methyl formate is 2.4:1～8:1; triethylamine and 10-methoxy The weight ratio of -11-bromo-10,11-
dihydroiminostilbene-5-methyl formate is 0.3:1 to 1.5:1; 
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10/10/2020 CN102807528 Preparation method of 10-methoxy iminostilbene

(4). Take methanol again, then add the 10-methoxyiminostilbene-5-methyl formate prepared in step (3),
add alkali metal hydroxide or alkali metal alkoxide, stir and heat to Reflux, and HPLC tracked the completion
of the reaction; then the reaction solution was cooled to 0～10℃ and poured into pure water at 0～10℃,
bright yellow crystals were precipitated, bright yellow crystals were filtered out and dried to obtain high purity
10-methoxy Base iminostilbene; wherein the weight ratio of methanol to 10-methoxyiminostilbene-5-methyl
formate is 1.6:1～5:1; the metal hydroxide is sodium hydroxide or potassium hydroxide, and the added
amount is The weight of 10-methoxyiminostilbene-5-methyl formate is 0.3 to 1 times; the alkali metal
alkoxide is sodium methoxide or potassium methoxide, and the added amount is the weight of 10-
methoxyiminostilbene-5-methyl formate The amount of pure water at 0-10°C is 3-10 times the weight of 10-
methoxyiminostilbene-5-methyl formate.
The reaction formula of the present invention is as follows:

Compared with the prior art, the present invention has the advantages that: the reaction product of the
present invention does not need to be refined, and the purity reaches more than 99%; at the same time, the
existing 10-methoxyiminostilbene preparation routes all adopt the dibromo route. One of the bromine has only
been used as a substituent, and only one bromine atom participates in the reaction in the preparation route of
the present invention, which reduces the usage of dibromohydantoin by half, thereby reducing production
costs and reducing pollution; The starting materials used in the technology are not industrialized large raw
materials, and there is no stable market source. The starting material iminostilbene-5-formyl halide or the
mixture of iminostilbene-5-formyl halide in the present invention is industrialized large Raw materials have a
stable market source.
Specific embodiment
In the following examples, methanol and toluene are industrially pure.
Example 1: (1) Put 250ml methanol, 30g iminostilbene carbonyl chloride and 70g iminostilbene carbonyl
bromide into a 500ml glass four-necked flask with mechanical stirring, stir well and gradually heat to reflux,
and then drip Add 74.25 grams of sodium methoxide with a concentration of 28% by weight, and reflux after
the dropwise addition. After the reaction is completed by HPLC, it is gradually cooled to 0-10°C to obtain
iminostilbene-5-methyl formate solid, and the iminostilbene-methyl ester is filtered out. The solid methyl 5-
formate was washed twice with pure water and dried to obtain 84 grams of solid methyl iminostilbene-5-
formate for use, with a yield of 95.5%;
(2) Add 250ml methanol and 84g iminostilbene-5-methyl formate prepared in step (1) into a 500ml glass
four-neck flask with mechanical stirring, and then add 52.5g dibromohydantoin Stir and bring the temperature
of the solution to -5～5℃. After HPLC detects that the reaction is complete, the solid is filtered out, washed
twice with methanol at -5～5℃ and dried to obtain 114.7 g of 10-methoxy-11-bromo-10. 11-
Dihydroiminostilbene-5-carboxylic acid methyl ester is used as a solid, and the yield is 94.8%;
(3) Add 560ml of toluene, 64.2 grams of triethylamine and 114.7 grams of 10-methoxy-11-bromo-10,11-
dihydroiminostilbene-5-methyl formate prepared in step (2) Into a 1000ml four-necked flask with mechanical
stirring, gradually heat up to reflux, and HPLC tracked the completion of the reaction; then filter, cool the
filtrate to 0-10°C, and precipitate 10-methoxyiminostilbene-5-methyl formate as white The solid was washed
twice with toluene and then dried to obtain 90 g of 10-methoxyiminostilbene-5-methyl carboxylate solid for
use;
(4). Add 90 g of 10-methoxyiminostilbene-5-carboxylic acid methyl ester prepared in step (3) and 35.6 g
of sodium hydroxide to 250 ml of methanol, heat to reflux, and HPLC tracks the completion of the reaction;
The reaction solution was cooled to 0～10℃ and then added to 500ml of pure water at 0～10℃. Bright
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10/10/2020 CN102807528 Preparation method of 10-methoxy iminostilbene

yellow crystals were precipitated. After cooling and filtering, 64.8 g of 10-methoxyiminostilbene, a high-
purity product, with a purity of 99.2%, yield 91.5%.
Example 2: (1) Put 250ml methanol and 89.5g iminostilbene carbonyl chloride into a 500ml glass four-
necked flask with mechanical stirring, stir evenly and gradually heat to reflux, then add 74.25g of 28% by
weight dropwise Sodium methoxide, reflux after dripping. After the reaction is completed by HPLC, gradually
cool to 0～10℃ to obtain iminostilbene-5-methyl formate solid, filter out iminostilbene-5-methyl formate
solid and use pure water After washing twice, drying to obtain 83 grams of iminostilbene-5-methyl
carboxylate solid for use, with a yield of 94.4%;
(2) Add 250ml of methanol and 83 grams of iminostilbene-5-methyl formate prepared in step (1) into a
500ml glass four-neck flask with mechanical stirring, and then add 52.5 grams of dibromohydantoin Stir and
bring the temperature of the solution to -5～5℃. After HPLC detects that the reaction is complete, the solid is
filtered out, washed twice with methanol at -5～5℃ and dried to obtain 112.5 g of 10-methoxy-11-bromo-10.
11-Dihydroiminostilbene-5-carboxylic acid methyl ester is used as a solid, and the yield is 93.0%;
(3) Add 560ml of toluene, 63 grams of triethylamine and 112.5 grams of 10-methoxy-11-bromo-10,11-
dihydroiminostilbene-5-methyl formate prepared in step (2) Into a 1000ml four-necked flask with mechanical
stirring, gradually heat up to reflux, and HPLC tracked the completion of the reaction; then filter, cool the
filtrate to 0-10°C, and precipitate 10-methoxyiminostilbene-5-methyl formate as white The solid was washed
twice with toluene and then dried to obtain 89 g of methyl 10-methoxyiminostilbene-5-carboxylate for use;
(4) Add 89 g of 10-methoxyiminostilbene-5-carboxylic acid methyl ester prepared in step (3) and 48.9 g
of potassium hydroxide into 250 ml of methanol, heat to reflux, and HPLC tracks the completion of the
reaction; The reaction solution was cooled to 0～10℃ and then added to 500ml of 0～10℃ pure water. Bright
yellow crystals were precipitated. After cooling and filtering, 62.8 g of 10-methoxyiminostilbene, a high-
purity product, was obtained with a purity of 99.3%. Yield 90%.
Example 3: (1) Add 250ml of methanol and 105g of iminostilbanoyl bromide into a 500ml glass four-
necked flask with mechanical stirring, stir evenly and gradually heat to reflux, then add 74.25g dropwise to a
concentration of 28% After the addition of the sodium methoxide, reflux after the completion of the dropwise
addition. After the HPLC detects that the reaction is complete, it is gradually cooled to 0-10°C to obtain
iminostilbene-5-methyl formate solids. The iminostilbene-5-methyl formate solids are filtered and purified.
Washed with water twice and dried to obtain 85.3 grams of iminostilbene-5-methyl formate solid for use, with
a yield of 97%;
(2) Add 250ml methanol and 85.3g iminostilbene-5-methyl carboxylate prepared in step (1) into a 500ml
glass four-neck flask with mechanical stirring, and then add 53.5g dibromohydantoin Stir and bring the
temperature of the solution to -5～5℃, filter out the solid after HPLC detects that the reaction is complete,
wash twice with methanol at -5～5℃ and dry to obtain 117 g of 10-methoxy-11-bromo-10, 11-
Dihydroiminostilbene-5-carboxylic acid methyl ester is used as a solid, and the yield is 95.1%;
(3) Add 560ml of toluene, 65.5 grams of triethylamine and 117 grams of 10-methoxy-11-bromo-10,11-
dihydroiminostilbene-5-methyl formate prepared in step (2) Into a 1000ml four-necked flask with mechanical
stirring, gradually heat up to reflux, and HPLC tracked the completion of the reaction; then filter, cool the
filtrate to 0-10°C, and precipitate 10-methoxyiminostilbene-5-methyl formate as white The solid was washed
twice with toluene and then dried to obtain 92 grams of 10-methoxyiminostilbene-5-methyl carboxylate solid
for use;
(4). Add 92 g of 10-methoxyiminostilbene-5-carboxylic acid methyl ester prepared in step (3) and 36.3 g
of sodium hydroxide into 250 ml of methanol, heat to reflux, and HPLC tracks the completion of the reaction;
The reaction solution was cooled to 0～10℃ and then added to 500ml of pure water at 0～10℃. Bright
yellow crystals were precipitated. After cooling and filtering, 66.2 grams of 10-methoxyiminostilbene, a high-
purity product, with a purity of 99.3%, was obtained. Yield 91.8%.

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