Preparation method of oxcarbazepine impurity

Abstract

The invention relates to a method for preparing oxcarbazepine impurities, which comprises the following steps of: reacting iminostilbene serving as a raw material with an oxidizing agent N-methylmorpholine-N-oxide under the catalysis of potassium osmate and DABCO to generate a diol intermediate; oxidizing the diol intermediate in the presence of an oxidizing agent 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone to obtain an alpha-hydroxy ketone intermediate; oxidizing the alpha-hydroxy ketone intermediate (III) in the presence of ammonium nitrate and copper acetate to obtain a diketone intermediate; and reacting the diketone intermediate (II) with isocyanate chlorosulfonate to obtain the oxcarbazepine impurity 11-ketone oxcarbazepine (I). The preparation method has the advantages of being convenient to operate, high in yield and good in product purity. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of medical chemistry, and more specifically, to the preparation of oxcarbazepine impurities, namely the preparation of 11-keto-oxcarbazepine. Background Art

[0002] Oxcarbazepine, with the chemical name 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide, is an antiepileptic drug and can be used for partial and generalized seizures. Its efficacy is slightly stronger than that of carbamazepine and can be used for patients intolerant to carbamazepine.

[0003] Multiple synthetic routes of oxcarbazepine have been reported in the existing literature. Apotex Pharmachem Inc. reported a method starting from 10-methoxyimino stilbene (US20050282797A1). First, the enol ether is hydrolyzed to a ketone under the action of hydrochloric acid, and then a nucleophilic addition reaction occurs with chlorosulfonyl isocyanate. After water treatment, the chlorosulfonyl group is removed to obtain oxcarbazepine.

[0004] 。

[0005] EP1600443A1 reported another route also starting from 10-methoxyimino stilbene. First, a formylation reaction occurs with triphosgene, and then the acyl chloride generates a substituted urea under the action of ammonia. Finally, the enol ether is hydrolyzed under the action of an acid to obtain oxcarbazepine.

[0006] 。

[0007] In the quality research of drug substances, the types and sources of impurities and how to control the generation of process impurities are important contents for drug researchers. 11-keto-oxcarbazepine is a degradation product of oxcarbazepine. Conditions such as light, oxidation, and heating will all promote the conversion of oxcarbazepine into this impurity. Therefore, the synthesis of this impurity is of great significance for the quality control of oxcarbazepine (such as impurity HPLC localization, content determination, degradation research, etc.). According to the literature report, this impurity is also the initial point for the generation of other degradation products in the photolysis reaction of oxcarbazepine. Therefore, the synthesis of this impurity also has certain significance for the recovery and degradation of wastewater. Summary of the Invention

[0008] In order to make up for the gap in the preparation process of oxcarbazepine impurity 11-keto-oxcarbazepine, the present invention designs a synthetic route. The present invention uses imino stilbene (V), a starting material commonly used in the synthesis of oxcarbazepine and carbamazepine, as the raw material, and obtains 11-keto-oxcarbazepine through three-step oxidation and one-step nucleophilic addition.

[0009] 。

[0010] It is oxidized to a diol intermediate (IV) by N-methylmorpholine-N-oxide (NMO) under the catalysis of potassium osmate and DABCO; the diol intermediate (IV) is then oxidized to an α-hydroxy ketone intermediate (III) by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ); the α-hydroxy ketone intermediate (III) is oxidized to a dione intermediate (II) by copper acetate in the presence of ammonium nitrate; finally, the dione intermediate (II) undergoes a nucleophilic addition reaction with isocyanato sulfonyl chloride, and the chlorosulfonyl group is removed by adding water to obtain 11-keto oxcarbazepine (I). Using the technical solution provided by the present invention to prepare 11-keto oxcarbazepine has the advantages of convenient operation, high product purity, and high yield.

[0011] To better understand the content of the present invention, the following is further illustrated with specific examples. It should be understood that the following specific examples are only used to illustrate the present invention and are not intended to limit the present invention. Specific Embodiments

[0012] Example 1: Step 1) Synthesis of the diol intermediate: (10R,11S)-10,11-dihydro-5H-dibenzo[b,f]azepine-10,11-diol (IV) A mixture of iminostilbene (19.34 g, 0.1 mol), N-methylmorpholine-N-oxide (29.79 g, 0.22 mol, 2.2 eq), 1,4-diazabicyclo[2,2,2]octane (DABCO, 1.1 g, 0.01 mol, 0.1 eq), and potassium osmate (0.04 g, 0.1 mmol, 0.001 eq) was stirred in an aqueous acetone solution with a volume fraction of 50% (400 mL) at 15 - 20 °C for 24 hours. After the reaction was completed, saturated sodium sulfite solution (120 mL) was added and stirred for 30 minutes. Acetone was evaporated under reduced pressure, and the crude product was extracted three times with dichloromethane (400 mL). The combined organic phases were washed successively with water (120 mL) and saturated brine (120 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 20.92 g of product (IV), with a yield of 92%, which was directly used for the next step of the reaction.

[0013] Step 2) Synthesis of the α-hydroxy ketone intermediate: 11-hydroxy-5,11-dihydro-10H-dibenzo[b,f]azepine-10-one (III) The glycol intermediate (20.0 g, 0.088 mol) was dissolved in 1,4-dioxane (300 mL) at 10 - 15 °C, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 22.0 g, 0.097 mol, 1.1 eq) was added in batches under constant temperature. Stirring was continued at 10 - 15 °C for 10 hours. After the reaction was completed, filtration was carried out, and the filtrate was concentrated under reduced pressure. The obtained solid was dissolved in dichloromethane (100 mL), and the filtrate obtained after filtration again and concentration under reduced pressure. The obtained solid was recrystallized with dichloromethane to obtain 16.84 g of α-hydroxy ketone intermediate with a yield of 85%, which was directly used for the next reaction step.

[0014] Step 3) Synthesis of dione intermediate: 5H-dibenzo[b,f]azepine-10,11-dione (II) The α-hydroxy ketone intermediate (16.22 g, 0.072 mol), ammonium nitrate (5.76 g, 0.072 mol, 1 eq), and copper acetate (0.65 g, 0.004 mol, 0.05 eq) were added to an acetic acid aqueous solution with a volume fraction of 80% (240 mL), and the mixture was heated to 80 °C and reacted for 1 hour. After the reaction was completed, it was cooled to room temperature and extracted three times with dichloromethane (300 mL). The combined organic phases were washed successively with water (180 mL) and saturated brine (180 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained solid was recrystallized with dichloromethane to obtain 10.61 g of dione intermediate (II) with a yield of 66%, which was directly used for the next reaction step.

[0015] Step 4) Synthesis of 11-keto oxcarbazepine (I) The dione intermediate (10 g, 0.045 mol) was dissolved in 100 mL of dichloromethane, stirred at 10 - 15 °C for 10 minutes, and then chlorosulfonyl isocyanate (12.68 g, 0.09 mol, 2 eq) was slowly added dropwise while controlling the temperature. After addition, stirring was carried out for 30 minutes at the same temperature. Pure water (50 mL) precooled to 0 - 5 °C was slowly added to the reaction solution, and after addition, the temperature was raised to 25 - 30 °C and stirred for 6 hours. After the reaction was completed, it was allowed to stand for layer separation, the aqueous phase was discarded, the organic phase was washed once more with pure water (50 mL), concentrated under reduced pressure, and the obtained solid was washed with an aqueous isopropanol solution to obtain 11.14 g of 11-keto oxcarbazepine (I) with a yield of 93% and a content of 98%.

Claims

1. A method for preparing oxcarbazepine impurities, the method comprising the following steps: a) Iminostilbene (V) reacts with oxidant N-methylmorpholine-N-oxide in the presence of potassium osmate and DABCO to generate diol intermediate (IV); b) the diol intermediate (IV) is oxidized in the presence of an oxidant 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to give an α-hydroxyketone intermediate (III); c) α-Hydroxyketone intermediate (III) is oxidized in the presence of ammonium nitrate and copper acetate to give diketone intermediate (II); d) the diketone intermediate (II) reacts with chlorosulfonic acid isocyanate to obtain 11-ketooxcarbazepine (I); 。 2. The method according to claim 1a, characterized in that Potassium osmate and DABCO are selected as catalysts, and N-methylmorpholine-N-oxide is selected as oxidant.

3. The method according to claim 1a, characterized in that Suitable reaction conditions include using acetone aqueous solution as solvent, a suitable volume fraction of 40% to 60%, and a suitable reaction temperature of 15 to 35°C.

4. The method according to claim 1b, characterized in that The oxidant is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

5. The method according to claim 1b, characterized in that Suitable reaction conditions include using 1,4-dioxane and tetrahydrofuran as solvents, and suitable reaction temperature is 15-25°C.

6. The method according to claim 1c, characterized in that Ammonium nitrate and copper acetate were used as oxidants.

7. The method according to claim 1c, characterized in that Suitable reaction conditions include using aqueous acetic acid as solvent, a suitable volume fraction of 70% to 90%, and a suitable reaction temperature of 70 to 90°C.

8. The method according to claim 1d, characterized in that Suitable reaction conditions include using dichloromethane or chloroform as solvent and suitable reaction temperature is 10-20°C.

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