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Novel preparation method of eslicarbazepine acetate

A technology of eslicarbazepine acetate and potassium carbonate, applied in the field of drug synthesis, can solve the problems of unstable yield of eslicarbazepine acetate, inability to obtain a product, complicated operation, etc., and achieves simplified technological process and operation time, The effect of low cost and optimized reaction conditions

Pending Publication Date: 2022-04-12
BEIJING AOHE DRUG RES INST +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] This method has reduced material loss, and production cost has been greatly reduced, yet in step 3 preparation (10S)-10-acetyliminostilbene intermediate post-processing process, produces a large amount of triethylamine acetate, needs to carry out six times Washing, complicated operation; And, in the further preparation process of eslicarbazepine acetate, reaction produces a large amount of yellow-green solids between residual triethylamine acetate and chlorosulfonic acid isocyanate, makes the produced eslicarbazepine acetate produce The rate is unstable, and sometimes the product cannot be obtained

Method used

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  • Novel preparation method of eslicarbazepine acetate
  • Novel preparation method of eslicarbazepine acetate
  • Novel preparation method of eslicarbazepine acetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] (1) Preparation of 10-carbonyliminostilbene

[0062] Add 880ml of methanol, 220ml of purified water, 220g of 10-methoxyiminostilbene, and 11ml of concentrated hydrochloric acid into the reaction flask, and heat up to 65°C-70°C for reaction. After the reaction was completed, the temperature was lowered to 25°C-30°C, 220ml of purified water was added, and stirring was continued for 1h after the addition. After the reaction is completed, filter, wash the filter cake with a large amount of water until it becomes neutral, and air-dry at 50° C. to obtain 200 g of a yellow powder.

[0063] (2) Preparation of (10S)-10-hydroxyiminostilbene

[0064] Under nitrogen protection, add 600ml of dichloromethane and 1.25mol of borane dimethyl sulfide into the reaction flask, cool down to -10°C to -5°C, add 38ml of (R)-2-methyl-CBS-oxazoboridine Toluene solution (1mol / L), add dropwise a mixed solution of 200g 10-carbonyliminostilbene and dichloromethane (1200ml), and control the tempera...

Embodiment 2

[0070] (1) Preparation of 10-carbonyliminostilbene

[0071] Add 660ml of methanol, 220ml of purified water, 220g of 10-methoxyiminostilbene, and 10ml of concentrated hydrochloric acid into the reaction flask, and heat up to 60°C-65°C for reaction. After the reaction was completed, the temperature was lowered to 20°C-25°C, 220ml of purified water was added, and stirring was continued for 1h after the addition. After the reaction was completed, filter, wash the filter cake with a large amount of water until it became neutral, and dry it with air at 50°C to obtain 198 g of yellow powder.

[0072] (2) Preparation of (10S)-10-hydroxyiminostilbene

[0073] Under nitrogen protection, add 600ml of dichloromethane and 1.25mol of borane dimethyl sulfide into the reaction flask, cool down to -10°C to -5°C, add 38ml of (R)-2-methyl-CBS-oxazoboridine Toluene solution (1mol / L), add dropwise the mixed solution of 198g 10-carbonyliminostilbene and dichloromethane (1200ml), dropwise process ...

Embodiment 3

[0079] (1) and (2) are the same as Comparative Example 1.

[0080] (3) Preparation of (10S)-10-acetyliminostilbene

[0081] Add 150g of (10S)-10-hydroxyiminostilbene, 750ml of dichloromethane, 170.0g of potassium carbonate, and 120.1g of acetic anhydride obtained in step (2) into the reaction flask, raise the temperature to about 50°C, that is, the solvent reflux state, and keep The reaction system was refluxed for 5h. After the reaction was completed, the temperature was lowered to 20° C., filtered, and the organic phase was washed successively with sodium bicarbonate (1 L), purified water (1 L), dried over magnesium sulfate, and filtered. The organic phase was directly used in the next reaction.

[0082] (4) synthesis of eslicarbazepine acetate

[0083] Add 840ml of dichloromethane into the reaction flask, cool down to -5°C to 5°C, add 130.0ml of chlorosulfonic acid isocyanate, control the temperature at -5°C to 5°C and stir for 10 minutes; drop the organic phase of the pr...

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Abstract

The invention provides a preparation method of eslicarbazepine acetate, which is stable in process and low in production cost, and is characterized in that any one or a combination of potassium carbonate and sodium carbonate is added in the step 1; in the reaction step 1, a solid alkaline reagent potassium carbonate or sodium carbonate is used for controlling the alkaline environment of a reaction system, so that the reaction is smoothly carried out and is easy to remove (only filtering is needed, and a concentration step is not needed), a reaction solvent does not need to be washed for multiple times after the reaction is completed, and the technological process and the operation time are greatly simplified; moreover, by optimizing the reaction conditions and simplifying the process flow, the production of three wastes can be reduced to the greatest extent while a low-cost and high-quality eslicarbazepine acetate raw material medicine can be obtained, the pollution to the environment is reduced, and the method conforms to the green and environment-friendly sustainable development direction.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a novel preparation method of eslicarbazepine acetate. Background technique [0002] Eslicarbazepine acetate (eslicarbazepine) is a derivative of the antiepileptic drug carbamazepine, which was later discovered to have a therapeutic effect and was developed into a drug for the adjuvant treatment of partial seizures in adults with or without secondary epilepsy. [0003] The commonly used synthetic route of eslicarbazepine acetate is to take oxcarbazepine as starting material, obtain eslicarbazepine acetate through reduction, resolution, acetylation, yet, in the resolution process > 50% oxcarbazepine passes through The split remains in solution, resulting in material loss. [0004] Liu Lei et al. (Chinese Journal of Medicinal Chemistry, 2016, 26(1) 129, 20160201) developed a new synthetic process, and the synthetic route is as follows: [0005] [0006] This method...

Claims

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Application Information

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IPC IPC(8): C07D223/22
Inventor 孙会谦牛玉乐甄志彬张景朋王喜宾王志军
Owner BEIJING AOHE DRUG RES INST
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