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Intermediate compound, carbamazepine and derivative thereof as well as preparation method of oxcarbazepine and derivative thereof

A carbamazepine and compound technology, applied in the field of intermediate compounds, can solve the problems of high raw material price, unsuitable for industrial production and the like

Active Publication Date: 2019-12-13
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above-mentioned method also has the high price of raw materials and is not suitable for suitability for industrialized production.

Method used

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  • Intermediate compound, carbamazepine and derivative thereof as well as preparation method of oxcarbazepine and derivative thereof
  • Intermediate compound, carbamazepine and derivative thereof as well as preparation method of oxcarbazepine and derivative thereof
  • Intermediate compound, carbamazepine and derivative thereof as well as preparation method of oxcarbazepine and derivative thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] Example 1: Oxcarbazepine (5-carbamoyl-10-oxa-10,11-dihydro-5H-dibenzo[b,f]azepine I 1 ) preparation

[0105] Step (1): N-cyano-N-2'-cyanophenyl-2-aminophenylacetic acid methyl ester (Ⅲ 1 ) preparation

[0106] In the 500 milliliter four-necked flask that is connected with stirring, thermometer, reflux condenser, add 250 grams of N,N-dimethylformamide, 38.0 grams (0.2 moles) of methyl 2-cyanoaminophenylacetic acid, 38.0 grams ( 0.21 mol) of 2-bromobenzonitrile, 35.0 g of potassium carbonate, and reacted with stirring at 95 to 100° C. for 5 hours. Cool to 20 to 25°C, filter, wash the filter cake with 30 g of N,N-dimethylformamide, combine the filtrates, distill under reduced pressure to recover the solvent, add 200 g of isopropyl ether to the residue for recrystallization, and obtain 52.2 g N-cyano-N-2'-cyanophenyl-2-aminophenylacetic acid methyl ester (Ⅲ 1 ), the yield is 89.7%, and the liquid phase purity is 99.3%.

[0107] Step (2): Oxcarbazepine (5-carbamoyl-10...

Embodiment 2

[0109] Embodiment 2: Oxcarbazepine (Ⅰ 1 ) preparation

[0110] Step (1): Ethyl N-cyano-N-2'-cyanophenyl-2-aminophenylacetate (Ⅲ 4 ) preparation

[0111] In a 500 ml four-neck flask connected with stirring, a thermometer and a reflux condenser, add 250 grams of N,N-dimethylformamide, 40.8 grams (0.2 moles) of ethyl 2-cyanoaminophenylacetate, 38.0 grams ( 0.21 mol) of 2-bromoxynil, 35.0 g of potassium carbonate, and reacted with stirring at 100 to 105° C. for 4 hours. Cool to 20 to 25°C, filter, wash the filter cake with 30 g of N,N-dimethylformamide, combine the filtrates, distill under reduced pressure to recover the solvent, add 200 g of isopropyl ether to the residue for recrystallization, and obtain 55.1 g N-cyano-N-2'-cyanophenyl-2-aminophenylacetic acid ethyl ester (Ⅲ 4 ), the yield is 90.3%, and the liquid phase purity is 99.2%.

[0112] Step (2): Oxcarbazepine (Ⅰ 1 ) preparation

[0113] To a 500 ml four-necked flask connected with stirring, a thermometer, a refl...

Embodiment 3

[0116] Embodiment 3: Carbamazepine (5-carbamoyliminostilbene, IV 1 ) preparation

[0117] In the 250 milliliters of four-neck flasks that are connected with stirring, thermometer, reflux condenser, add 20 grams of methanol, 2.52 grams (10 mmol) of oxcarbazepine (I) prepared in embodiment 1 1 ), 0.31 g (8 mmol) of sodium borohydride, and stirred at 45 to 50° C. for 3 hours. Cool to 20 to 25°C, use 35wt% hydrochloric acid acidification system pH value 2.0-2.5, 25 to 30°C stirring reaction for 2 hours, add 20 grams of water, filter, dry to obtain 2.16 grams of carbamazepine (IV 1 ), the yield is 91.5%, and the liquid phase purity is 99.7%.

[0118] The NMR data of the resulting product are as follows:

[0119] 1 H-NMR (CDCl 3 , 400MHz) δ: 7.28–7.47 (8H, m), 6.92 (2H, s), 4.81 (2H, br).

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Abstract

The invention provides an intermediate compound, carbamazepine and a derivative thereof as well as a preparation method of oxcarbazepine and a derivative thereof. 2-substituted aminophenylacetate or 2-substituted aminophenylacetonitrile and 2-halobenzonitrile are used as raw materials, substitution reaction, intramolecular condensation reaction, hydrolysis and hydrochloric acid acidification are carried out to obtain the oxcarbazepine and the derivative 5-substituent-10-oxa-10, 11-dihydro-5H-dibenzo [b, f] aza thereof, and the derivative of the oxcarbazepine can be used as a raw material to prepare the carbamazepine and the derivative 5-substituted iminostilbene thereof, an intermediate compound iminostilbene and intermediate compounds 5-substituted-10-methoxyiminostilbene and 10-methoxyiminostilbene. The raw materials used in the method are cheap and easy to obtain, and the cost is low; the preparation method is simple, conditions are easy to realize, the method is simple, convenientand safe to operate, and the process flow is short; the production amount of three wastes is small, and thus, the method is environmentally friendly; and a target product has high yield and purity, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of an intermediate compound, carbamazepine and its derivatives, and oxcarbazepine and its derivatives, and belongs to the technical field of pharmaceutical chemistry and chemical engineering. Background technique [0002] Oxcarbazepine (I 1 ), the English name is Oxcarbazepine, and the Chinese name is 10,11-dihydro-10-oxo-5H-diphenyl[b,f]azepine -5-Carboxamide or 5-carbamoyl-10-oxa-10,11-dihydro-5H-dibenzo[b,f]azepine Oxcarbazepine is an antiepileptic drug developed by the Swiss company Novartis. Since it was launched in Denmark in 1990, oxcarbazepine has gradually become a global first-line broad-spectrum antiepileptic drug with its unique antiepileptic mechanism, definite efficacy and safety, and has a relatively broad market. Oxcarbazepine (I 1 ) has the following structural formula. [0003] Carbamazepine (Ⅳ 1 ), the English name is Carbamazepine, and the Chinese name is 5H-dibenzo[b,f]azepine...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/22
CPCC07D223/22
Inventor 王保林戚聿新王宝昌腾玉奇张伟赵银龙
Owner XINFA PHARMA
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