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CAS No. : | 28721-07-5 | MDL No. : | MFCD00865307 |
Formula : | C15H12N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CTRLABGOLIVAIY-UHFFFAOYSA-N |
M.W : | 252.27 | Pubchem ID : | 34312 |
Synonyms : |
GP 47680
|
Num. heavy atoms : | 19 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.07 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 75.36 |
TPSA : | 63.4 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.62 cm/s |
Log Po/w (iLOGP) : | 1.96 |
Log Po/w (XLOGP3) : | 1.71 |
Log Po/w (WLOGP) : | 2.26 |
Log Po/w (MLOGP) : | 2.14 |
Log Po/w (SILICOS-IT) : | 1.73 |
Consensus Log Po/w : | 1.96 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.88 |
Solubility : | 0.33 mg/ml ; 0.00131 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.66 |
Solubility : | 0.556 mg/ml ; 0.0022 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.29 |
Solubility : | 0.0131 mg/ml ; 0.0000519 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.67 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.3% | With sodium tetrahydroborate In methanol; water at 20 - 45℃; for 1.5 h; | At room temperature,The (100.0g, 0.4mol) oxcarbazepine,400 mL methanol and 200 mL water were added to a 1 L round bottom flask,Sodium borohydride (15.0 g, 0.4 mol) was added portionwise,After stirring at room temperature for 30min, the reaction was continued at 45 ° C for 1h.The reaction is completed,The reaction mixture was concentrated under reduced pressure to 200-300 mL,filter,Washed 3 times,Got pale yellow solid powder 99.0g,For compound 1,Yield 97.3percent. |
94% | With sodium tetrahydroborate In ethanol; water at 45 - 50℃; | Sodium borohydride (6.0 g, 0.162 mol) was portion-wise added to the suspension of Azepine amide (45.0 g, 0.178 mol) in Ab. Ethanol (185 ml) and DM water (103 ml) at an ambient temperature. Reaction mixture was allowed to stir for 2-3 hr at 45-50° C. Progress of reaction was monitored by TLC (Solvent system: 10percent Methanol in DCM). After completion of reaction, acetone was slowly added to reaction mixture at 10-15° C. Reaction mixture was further stirred for 30 min. at an ambient temperature. Organic solvents from reaction mixture were distilled off under reduced pressure at 45-50° C. Residue thus obtained was stirred in DM water (100 ml) for 1-2 hr at 0-5° C. Suspension was filtered and washed with ice-cold water (2*25 ml). Air dry the product for 12-15 hr at 50-60° C. to get pure desired compound (42.8 g, 94percent) with 99percent purity by HPLC. |
93.8% | With sodium tetrahydroborate; water In methanol at 25 - 65℃; for 2.75 h; | Sodium borohydride (15.6 g, 0.412 mol) was added to a stirred suspension of oxcarbazepine (200 g, 0.793 mol) in a mixture of methanol (400 mL) and water (220 mL) at 25°C to 30°C in three portions at 15 minutes intervals. The reaction mixture was stirred at 60°C to 65°C for 2 hours and cooled to 25°C to 30°C and pH was adjusted to 6.8 to 7.2 using diluted hydrochloric acid (31 mL concentrated hydrochloric acid in 100 mL deionised water). Deionised water (700 mL) was added to the reaction mixture with stirring and was cooled to 0°C to 5°C for 3 hours. The crystalline product was filtered, washed with deionised water (100 mL) and dried at 40°C to 45°C to constant weight to give the titled compound. Yield: 189.1 g (93.8percent) Purity: 99.93percent |
93.8% | With sodium tetrahydroborate; water In methanol at 25 - 65℃; for 2.25 h; | Sodium borohydride (15.6 g, 0.412 mol) was added to a stirred suspension of oxcarbazepine (200 g, 0.793 mol) in a mixture of methanol (400 mL) and water (220 mL) at 25° C. to 30° C. in three portions at 15 minutes intervals. The reaction mixture was stirred at 60° C. to 65° C. for 2 hours and cooled to 25° C. to 30° C. and pH was adjusted to 6.8 to 7.2 using diluted hydrochloric acid (31 mL concentrated hydrochloric acid in 100 mL deionised water). Deionised water (700 mL) was added to the reaction mixture with stirring and was cooled to 0° C. to 5° C. for 3 hours. The crystalline product was filtered, washed with deionised water (100 mL) and dried at 40° C. to 45° C. to constant weight to give the titled compound. Yield: 189.1 g (93.8percent) Purity: 99.93percent |
2.42 kg | With sodium tetrahydroborate In ethanol at 20℃; for 4.5 h; Large scale | To a 200 L autoclave, oxcarbazepine (2.52 kg, 10 mol)And ethanol (25 L),Stir at room temperature to completely dissolve.Sodium borohydride (0.378 kg, 10 mol) was aliquoted into 5 batches,Each batch of 30 minutes,Add to the above solution with stirring.After the addition is complete, stirring is continued for 2 hours at room temperature.After the reaction was complete, add water (50L)After stirring and adjusting the pH of the reaction solution to 7 with concentrated hydrochloric acid,The precipitated solid was filtered and collected.The filtrate was then concentrated to 50 L and filtered once and the solid was collected.Two batches of solids were combined and dried,2.42 kg of licacizidine (rac) solid was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.3% | With sodium tetrahydroborate; In methanol; water; at 20 - 45℃; for 1.5h; | At room temperature,The (100.0g, 0.4mol) oxcarbazepine,400 mL methanol and 200 mL water were added to a 1 L round bottom flask,Sodium borohydride (15.0 g, 0.4 mol) was added portionwise,After stirring at room temperature for 30min, the reaction was continued at 45 C for 1h.The reaction is completed,The reaction mixture was concentrated under reduced pressure to 200-300 mL,filter,Washed 3 times,Got pale yellow solid powder 99.0g,For compound 1,Yield 97.3%. |
94% | With sodium tetrahydroborate; In ethanol; water; at 45 - 50℃; | Sodium borohydride (6.0 g, 0.162 mol) was portion-wise added to the suspension of Azepine amide (45.0 g, 0.178 mol) in Ab. Ethanol (185 ml) and DM water (103 ml) at an ambient temperature. Reaction mixture was allowed to stir for 2-3 hr at 45-50 C. Progress of reaction was monitored by TLC (Solvent system: 10% Methanol in DCM). After completion of reaction, acetone was slowly added to reaction mixture at 10-15 C. Reaction mixture was further stirred for 30 min. at an ambient temperature. Organic solvents from reaction mixture were distilled off under reduced pressure at 45-50 C. Residue thus obtained was stirred in DM water (100 ml) for 1-2 hr at 0-5 C. Suspension was filtered and washed with ice-cold water (2*25 ml). Air dry the product for 12-15 hr at 50-60 C. to get pure desired compound (42.8 g, 94%) with 99% purity by HPLC. |
93.8% | With sodium tetrahydroborate; water; In methanol; at 25 - 65℃; for 2.75h; | Sodium borohydride (15.6 g, 0.412 mol) was added to a stirred suspension of oxcarbazepine (200 g, 0.793 mol) in a mixture of methanol (400 mL) and water (220 mL) at 25C to 30C in three portions at 15 minutes intervals. The reaction mixture was stirred at 60C to 65C for 2 hours and cooled to 25C to 30C and pH was adjusted to 6.8 to 7.2 using diluted hydrochloric acid (31 mL concentrated hydrochloric acid in 100 mL deionised water). Deionised water (700 mL) was added to the reaction mixture with stirring and was cooled to 0C to 5C for 3 hours. The crystalline product was filtered, washed with deionised water (100 mL) and dried at 40C to 45C to constant weight to give the titled compound. Yield: 189.1 g (93.8%) Purity: 99.93% |
93.8% | With sodium tetrahydroborate; water; In methanol; at 25 - 65℃; for 2.25h; | Sodium borohydride (15.6 g, 0.412 mol) was added to a stirred suspension of oxcarbazepine (200 g, 0.793 mol) in a mixture of methanol (400 mL) and water (220 mL) at 25 C. to 30 C. in three portions at 15 minutes intervals. The reaction mixture was stirred at 60 C. to 65 C. for 2 hours and cooled to 25 C. to 30 C. and pH was adjusted to 6.8 to 7.2 using diluted hydrochloric acid (31 mL concentrated hydrochloric acid in 100 mL deionised water). Deionised water (700 mL) was added to the reaction mixture with stirring and was cooled to 0 C. to 5 C. for 3 hours. The crystalline product was filtered, washed with deionised water (100 mL) and dried at 40 C. to 45 C. to constant weight to give the titled compound. Yield: 189.1 g (93.8%) Purity: 99.93% |
With sodium tetrahydroborate; In ethanol; water; at 25 - 45℃; | Oxcarbazepine (50gm, 0.20mol) is suspended in a mixture of water (1 16mL) and ethanol (203mL). Sodium borohydride (5.8 lgm, 0.15mol) is added to this suspension in three equal portions over 15 min at about 25-300C. The temperature of reaction mixture is raised to about 40-450C and continued stirring at about 40-450C for about 3 hours. After completion of the reaction, reaction mixture is cooled to about 10-150C and acetone (43.5mL) is added at about 10-150C. The reaction mixture is concentrated at about 40- 45C under reduced pressure. The residue is triturated with water (125mL) at room temperature to obtain the product as solid. The product is filtered, washed with, water (25mL) and dried at about 40-450C under reduced pressure to get racemic 10,11-Dihydro-10-hydroxy-5H-dibenz[b,fJazepine-5-carboxamide (46.75gm). | |
Oxcarbazepine (200 g), ethanol (800 mL) and water (200 mL) are charged into a round-bottom flask and stirred for 5 minutes. Sodium borohydride (24.1 g) is charged slowly to the mixture at 25-35C and stirred for 10 minutes. The mixture is heated to 40-45C and maintained for 2-3 hours. The solvent from the reaction mixture is evaporated completely at 45- 50C. Water (2000 mL) is added to the mass and stirred at 30C for 1-2 hours. The obtained solid is collected by filtration, washed with water (200 mL), and dried at 70C, to afford 190.0 g of the title compound. Purity by HPLC: 99.1 % | ||
With sodium tetrahydroborate; water; In methanol; at 25 - 60℃; for 7h;Product distribution / selectivity; | Example- 1: Preparation of 10-hydroxy-10,H-dihydro-5H-dibenz[b,fJazepine-5- carboxamide compound of formuIa-4; Sodium borohydride (11.3 g) was added to the solution of 10-oxo-10,l 1-dihydro- 5H-dibenz[b,fJazepine-5-carboxamide compound of formula-2 (50 g) in water (100 ml), followed by methanol (200 ml) at 25-35C. The reaction mixture was heated to 55-60C and then stirred for 7 hours at 55-60C. After completion of the reaction, distilled off methanol completely under reduced pressure and then cooled to 25-30C. Water was added to the reaction mixture and then stirred for 60 minutes at 25-30C. Filtered the solid, washed with water and then dried to get the title compound. Yield: 45 grams | |
With sodium tetrahydroborate; In methanol; dichloromethane; at 5 - 30℃; | 100 gm of oxcarbazepine and 10.6 gm of sodium borohydride were dissolved in 300 ml of methylene dichloride in a dry round bottom flask. The solution was then cooled to 5-15C. 300 ml of methanol was added to the above solution over 1.0 to 1.5 hours, and the solution was maintained at 20-30C for 1.0 hour. The solution was then distilled under atmospheric condition until 300 ml volume of methanol remained. Next, 500 ml of distilled mineral water at 50C was added to the solution. The solution was cooled to 20-30C and maintained at this temperature for 15-30 minutes. The reaction mass was then filtered and the obtained solid was washed twice with 100 ml of distilled mineral water. The product, namely, (+/-)-10,l l-dihydro-10-hydroxy-5H- dibenz[b,f]azepine-5-carboxamide (step 1 product) was dried in an oven at 70C. The dry weight of the step 1 product was 90 gm (with a chemical purity of 99.4%). | |
2.42 kg | With sodium tetrahydroborate; In ethanol; at 20℃; for 4.5h;Large scale; | To a 200 L autoclave, oxcarbazepine (2.52 kg, 10 mol)And ethanol (25 L),Stir at room temperature to completely dissolve.Sodium borohydride (0.378 kg, 10 mol) was aliquoted into 5 batches,Each batch of 30 minutes,Add to the above solution with stirring.After the addition is complete, stirring is continued for 2 hours at room temperature.After the reaction was complete, add water (50L)After stirring and adjusting the pH of the reaction solution to 7 with concentrated hydrochloric acid,The precipitated solid was filtered and collected.The filtrate was then concentrated to 50 L and filtered once and the solid was collected.Two batches of solids were combined and dried,2.42 kg of licacizidine (rac) solid was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In dichloromethane; at 0 - 5℃;Inert atmosphere; | To a solution of azepine-10-One (25 g, 0.119 mol) in Dichloromethane (200 ml) was dropwise added the solution of chloro sulphonyl isocyanate (32.6g, 0.230 mol) in Dichloromethane (100 ml) under nitrogen atmosphere at 0-5 C. After the addition of chloro sulphonyl isocyanate, reaction mixture was stirred for 1-2 hrs at 0-5 C. The Progress of reaction was monitored by TLC. Reaction mixture was quenched with Glacial acetic acid (25 ml) followed by addition of DM water (150 ml) at 10-15 C. Layers were separated and Aq. layer was re-extracted with Dichloromethane (3*200 ml). Combined Dichloromethane layer was distilled off at reduced pressure at 40-45 C. Product was further crystallized with Isopropyl alcohol (100 ml) to get pure azepine amide (27.90 g, 93%) with 98.52% Purity by HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.0% | With hydrogenchloride; In water; at 25 - 85℃; for 4 - 6h; | To the organic layer resulting from Example 1A was added 2N HCl (50.0 ml) and the reaction mass was maintained at a temperature ranging from about 40 C. to about 50 C. for about 4 to about 6 hours. After completion of the reaction (detected by TLC) the reaction mass was cooled to a temperature ranging from about 0 C. to about 5 C. for about one hour and the separated solids were filtered and washed with dichloromethane (15.0 ml). Purification: To a 3 L 4-necked round bottom flask was added 1125 ml of methanol and 75 gm crude oxcarbazepine prepared by the process of Example 1B and stirred at room temperature, about 25 C. to about 30 C. The reaction mass slurry was heated to reflux, a temperature of about 65 C., and further stirred for about 30 to about 40 minutes. 450 ml acetic acid was added under reflux which resulted in a clear solution. The solution was stirred under reflux at a temperature of about 70 C. for about 30 to about 40 minutes. 7.5 g of charcoal was added to the solution and stirred under reflux for about 20 to about 30 minutes. The reaction mass was filtered and washed twice in a hyflow bed with 75 ml of acetic acid and methanol in a 2:5 ratio at a temperature of about 70 C. The filtrate was cooled in a 3 L 4-necked round bottom flask to a temperature of about 30 C. for about 1 hour, and further cooled to a temperature of about 0 C. for about 30 min. The precipitated product was filtered and dried to get pure oxcarbazepine. Yield=73.0%, m.p. 222 C., purity>99.5%, 1H NMR Spectrum (CDCl3, TMS as internal standard) shows 6 at 3.3 (1H,d), 4.4(1H,d), 5.0(2H.br.s), 7.2-8.2 (8H,m&d).EXAMPLE 2B Preparation of Oxcarbazepine The residue obtained in Example 2A was transferred to a 2 L 4-necked round bottom flask and 500 ml of 2N aqueous HCl was added at a temperature ranging from about 25 C. to about 30 C. The reaction mass was heated to a temperature ranging from about 80 C. to about 85 C. and maintained for between 4 to 5 hours. After completion of the reaction (detected by HPLC/TLC), the reaction mass was cooled to a temperature ranging from about 50 C., and 500 ml of toluene was charged to the reaction mass and maintained for 30 minutes at a temperature of about 50 C. The reaction mass was further stirred at a temperature ranging from about 25 C. to about 30 C. for about 30 minutes. The solids were filtered, separated, and then washed twice with 100 ml of toluene. The product was dried to get crude oxcarbazepine of 97-98% purity as determined by HPLC. Purification: The purification of the oxcarbazepine prepared in Example 2A was carried in substantially the same manner as in Example 1. |
With hydrogenchloride; In water; toluene; at 20 - 89℃; for 0.25h; | In a three-neck flask (500 ml), equipped with a mechanical stirring apparatus, 15 ml water was introduced, followed by pyridinium bromide (71.75 g, 0.45 mole; Chemadaa' (Nir Yitshak, Israel) ). The mixture was stirred at room temperature [(22 C)] for about 10 minutes. Then 250 ml toluene was added, followed by 50 g (0.224 mol) of [10-METHOXY-5H-] dibenz [[BZF] AZEPINE] (compound of formula (4), wherein R4 is methoxy). [Note: 10-methoxy-5H- dibenz [[B, T] AZEPINE] may be obtained from [IMINOSTILBENE] according to the process disclosed in U. S. Patent No. 5,808, 058. [10-METHOXY-5H-DIBENZ [B FLAZEPINE] also is commercially available from various suppliers, including Zhejiang Jiuzhou Pharmaceutical Co. , Ltd. (Zhejiang, China), and Ningbo Chongyangtang Biologic Tech Co. , Ltd. (Ningbo, China)] [NAOCN] (45 g, 0.69 mol ; OCI Corp. , South Korea) was added and the reaction was mixed for about 7-8 hours at room temperature [(22C).] After [7-8] hours, [125ML] of water was added, and the mixture was stirred for about 15 minutes. The resulting solid carbamate of formula (1), 10-methoxy-5H- dibenz [[B2TAZEPINE-5-CARBOXAMIDE,] was filtered and washed with 50 ml of water. The organic layer was separated and washed with water (2 x [50ML).] In a 500 ml three necked flask, the organic phase from above was introduced, to which the solid carbamate of formula (1) [(10-METHOXY-5H-DIBENZ [B2FLAZEPINE-5-CARBOXAMIDE)] was added to form a slurry. The mixture was heated to 89 C to clarify the solution, and 250 ml of 10% [HC1] was added dropwise with stirring. When thin layer chromatography indicated that the intermediate carbamate of formula (1) had been substantially consumed, the reaction mixture was cooled to room temperature and the mixture was stirred at this temperature for 15-30 minutes. The product, [10-OXO-10,] [11-DIHYDRO-5H-DIBENZ [B2FLAZEPINE-5-CARBOXAMIDE] (oxcarbazepine), was filtered and the crude oxcarbazepine cake was thoroughly washed with water until the pH reached 6-7. The mixture was then washed with toluene (50 ml), and the solids were dried to yield 34.4 g (0.137 mol) crude oxcarbazepine as a yellow-brown powder (yield relative to (2) is [61%).] The crude oxcarbazepine was slurried in 408 ml of boiling 80: 20 isopropanol : water for about 1 hour. The solid was separated by filtration and dried to afford 30.6 g oxcarbazepine [(89%] purification yield). Further purification was carried out in 765 ml of boiling 80: 20 isopropanol: water, hot filtration and cooling to room temperature. Filtration and drying of the solid precipitate afforded 26.5 g of purified oxcarbazepine (yield relative to starting material (2) is 47%, and purification yield is 87%). | |
With hydrogenchloride; In water; isopropyl alcohol; at 20 - 82℃; for 2h; | The carbamoylation reaction was performed as in Example 1, except that [150] ml toluene was used instead of 250 ml. The resulting solid carbamate of formula (1), 10-methoxy-5H- dibenz [[B2FLAZEPINE-5-CARBOXAMIDE,] was isolated as described in Example 1. In a three necked flask, 330 ml of isopropyl alcohol, 78 ml of 12% HCl, and the solid 10- [METHOXY-SH-DIBENZ [B2FLAZEPINE-S-CARBOXAMIDE] were introduced. The mixture was heated to [78] [- 82 C] for about 1 hour. When TLC indicated that the carbamate of formula (1) was consumed, the reaction mixture was cooled to room temperature and stirred for 1 hour. The separated solids were filtered and washed with water to provide crude 10-oxo-10, [11-DIHYDRO-SH-DIBENZ [BFLAZEPINE-S-] carboxamide (oxcarbazepine), which was purified as described in Example 1. Yield relative to starting material of formula (2) was 43-45%. |
With o-toluenesulfonic acid; In 1,2-dichloro-ethane; at 20 - 80℃; for 4h; | Step 3 Preparation of cxcarbazepine-from 10-Methoxy-5H-dibenz (b, f) azepine 5- carboxamide 85 gm of 10-Methoxy-5H-dibenz [b, fj azepine-5-carboxamide is dissolved in 425 ml of ethylene dichloride. To this 800 mi of 2N o-toluene sulfonic acid is added and heated to 75-80C & maintained for bout 3 hours. It is then cooled to 20C & maintained for about 1 hour. The product oxcarbazepine is separated by filtration. This is then purified in acetone-water to yield 55 gms of pure oxcarbazepine. | |
Preparation of oxcarbazepine (I) 600 ml of water are added to the round-bottomed flask containing the suspension of 10- methoxy-5H-dibenzo [b, faazepine-5-carboxamide (IV) from Example 1, and about 12 g of 37% HC1 are added dropwise to pH = 1. The suspension is stirred at about 95 DEG C for 4 hours. The mixture is cooled to 25 DEG C and about 14 g of 30% NaOH are added dropwise to bring the pH from 1.0 to 7.0-7. 5. The reaction suspension is filtered at 25 DEG C and the cake is washed twice with water (2 x 100 ml), the filtration and washing waters then being removed. The cake is washed three times with methanol (3 x 100 ml) at 12-14 DEG C and the waters are then removed. The wet cake (160-170 g) is suspended in dimethylacetamide (400 ml) while heating at 110 DEG C until the solid has dissolved. The product is filtered off at a temperature above 80 DEG C (temperature of start of recrystallization). The filtrate is cooled to 60 DEG C, 400 ml of methanol are then added to the suspension, and the resulting mixture is cooled first to 25 DEG C and then to 0-5 DEG C. After 1 hour at 0-5 DEG C, the cake is washed with 150 ml of methanol at 12-14 DEG C and the methanolic washing phase is removed. The cake is dried under vacuum at 40 DEG C for 6 hours. | ||
With water; oxalic acid; at 90℃; for 17h;Product distribution / selectivity; | b) Preparation of Oxcarbazepine from 10-methoxy carbamazepine; 100 g of <strong>[28721-09-7]10-methoxycarbamazepine</strong> in 1000 ml water and 69.24 g of oxalic acid solution was heated to 9O0C and maintained for about 17 hrs. After completion of the reaction the reaction mixture was cooled to room temperature (RT). The resulting reaction mass was filtered and washed with 1000 ml of DM water. The wet material obtained was charged with isopropyl alcohol and DM water. The obtained reaction mixture was heated to reflux for about 2 h. the reaction mixture was cooled to 15- 250C, filtered and washed with 100 ml of IPA-water mixture. The resulting compound is dried at 6O0C for 6 h to produce 90 g of Oxcarabzepine. | |
With hydrogenchloride; In methanol; water; at 75 - 80℃; | The crude [XXI] was taken in a RB flask and methanol (600 ml) was added. The reaction mixture was heated to reflux. The reaction mixture was cooled, methanol was distilled off and toluene (50 ml) was added and further distilled. The residual [XXI] was cooled and toluene (500 ml) was added and stirred. Water was added followed by addition of cone. HCl. The reaction mixture was heated at 75-80C. The reaction mixture was cooled and the crude oxcarbazepine [I] was filtered, washed with toluene, 5% NaHCO3 and DM water and vacuum dried to give crude oxcarbazepine of formula[I] (yield = 82 g). The oxcarbazepine thus formed can be purified by dissolving in methanol (600 ml). The reaction mixture was stirred for 15-20 min. The pH of the <n="16"/>reaction mixture was maintained in the range of 7.5-8.5. The reaction mixture was stirred and heated to reflux at 65-70C for 2 h, and cooled, filtered and washed with methanol and dried to give oxcarbazepine [I], which was further purified by heating in methanol (1400 ml) and dichlormethane (1400 mL). The reaction mixture was refluxed for 30 min and treated with activated carbon. The reaction mixture was filtered through Hyflo bed and washed with methanol and dichloromethane mixture (1:1). The solvent was distilled to residual volume of 1000 mL. The reaction mixture was cooled and maintained. The reaction mixture was filtered through buchner funnel and washed with methanol and dried under vacuum at 50-60C to give pure oxcarbazepine (90 g). | |
With water;oxalic acid; at 90℃; for 19h;Reflux;Product distribution / selectivity; | b) Preparation of Oxcarbazepine from 10-methoxy carbamazepine 100 g of <strong>[28721-09-7]10-methoxycarbamazepine</strong> in 1000 ml water and 69.24 g of oxalic acid solution was heated to 90 C. and maintained for about 17 hrs. After completion of the reaction the reaction mixture was cooled to room temperature (RT). The resulting reaction mass was filtered and washed with 1000 ml of DM water. The wet material obtained was charged with isopropyl alcohol and DM water. The obtained reaction mixture was heated to reflux for about 2 h. the reaction mixture was cooled to 15-25 C., filtered and washed with 100 ml of IPA-water mixture. The resulting compound is dried at 60 C. for 6 h to produce 90 g of Oxcarabzepine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Heating / reflux; | Oxcarbazepine formic acid solvate [00207] Oxcarbazepine was dissolved in formic acid using heat. The <strong>[28721-07-5]oxcarbazepine</strong> formic acid solvate was recovered via slow evaporation of the formic acid. [00208] Crystal data: (Bruker SMART-APEX CCD Diffractometer), triclinic P- 1; a = 9.334(2) angstroms, b = 10.757(2) angstroms, c = 14.113(3) angstroms, alpha = 97.020(4) degrees, beta = 107.988(4) degrees, gamma = 94.617(4), Z = 2. [00209] IR spectroscopy (Nicolet Avatar 320 FTIR) showed peaks at: 3419, 3187, 1717, 1658, 1595, 1397, 1147, and 767 cm"1. [00210] MEL-TEMP showed a melting point of about 223-225 degrees C for the <strong>[28721-07-5]oxcarbazepine</strong> formic acid solvate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With pyridine; dmap; In dichloromethane; at 20℃; for 4.16h; | Preparation of enol acetate (R = methyl); To a suspension of <strong>[28721-07-5]oxcarbazepine</strong> (69.3 g, 0.275 mol), DMAP (1.025 g) and acetic anhydride (38.07 g) in dichloromethane (700 mL) was added drop wise a solution of 30.1 g pyridine in 50 mL dichloromethane at room temperature. The addition completed in 10 min. After stirring at room temperature for 75 min, the system became clear. Three hours after the addition, the system became cloudy again. The suspension was then stirred at room temperature for one more hour and washed with 2 x 400 mL <n="15"/>of 1 N HCl, 2 x 400 mL of 10% NaHCO3 and 2 x 400 mL of H2O. Concentration under reduced pressure afforded a light yellow solid. Isopropyl alcohol (700 mL) was added and the mixture was refluxed for 3 min. When it cooled down, the solid was filtered off and washed with 2 x 100 mL isopropyl alcohol. Isopropyl alcohol (500 mL) was added and the mixture was refluxed for 2 min. When it cooled down, the solid was filtered off and washed with 3 x 100 mL isopropyl alcohol (This second wash may not be necessary). The final product was dried under vacuum and obtained as a white solid (71.5 g) in 88% yield. IH NMR (DMSO-d6, 360 MHz): delta = 7.53-7.30 (m, 8H), 6.92 (s, IH), 5.66 (b, 2H), 2.32 (s, 3H) ppm. 13C NMR (DMSO-d6, 90 MHz): delta = 169.5, 156.2, 146.8, 140.7, 140.4, 132.8, 132.1, 131.1, 129.8, 129.7, 129.4, 127.9, 127.6, 125.9, 120.8, 21.1 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; In acetic acid; at 20℃; for 0.0833333 - 0.166667h; | 10-memoxy-5H-dibenz[b,f]azepine-5-carbomtrile (100 g, 0.4032 mole) was taken in acetic acid (600 ml) at room temperature. To the resulting mixture, sulfuric acid (150 ml) was added within 5-10 minutes under stirring. The resulting reaction mixture was added to the cold water under vigorous stirring. The solid was precipitated, which was filtered, washed with water and dried at 60-65C for 15-16 h, to obtain crude 10-oxo- 10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide. The resulting compound was taken in methanol and the pH of the reaction mixture was maintained in the range of 7-8. The reaction mixture was heated to reflux at 65-70C for 2 h under stirring and then cooled, filtered, washed. with methanol and dried to give title compound [I]. The resulting semi pure oxcarbaz^pine was further purified by treating the resulting y compound taken in a mixture of methanol and dichloromethanol, and was heated. The reaction mixture was filtered through Hyflo bed, washed with methanol and dichloromethane mixture (1:1). The solvent was distilled off partially and the <n="16"/>resulting mixture was cooled to precipitate the solid. The solid was filtered, washed with methanol and dried under vacuum at 50-60C to give pure title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; benzoic acid; In water; toluene; | EXAMPLE 1 Using benzoic acid and sodium cyanate A mixture of 100 gms of 10-methoxyiminostilbene in 2000 mL of toluene containing 274 gms of benzoic acid and 370 gms of sodium cyanate were heated to reflux temperature under stirring and maintained for 12 hours. The reaction mixture was then cooled to room temperature and filtered. The clear toluene filtrate was washed with 5% sodium carbonate solution followed by water. The toluene layer was then added to 1000 mL of 2N hydrochloric acid and the mixture was heated at 75-90 C. for a period of 2 hours under good agitation. It was then cooled to 0-5 C., maintained for 2 hours and the product oxcarbazepine was separated by filtration. This was then purified once in a dichloromethane:methanol mixture to furnish 46 gms of pure oxcarbazepine. | |
With sulfuric acid; In water; toluene; | EXAMPLE 1 10-oxo-10,11-dihydro-5H-dibenz(b,f)azepin-5-carboxamide 22.3 g (0.1 moles) of 10-methoxy-5H-dibenz(b,f)azepine prepared according to U.S. Pat. No. 27,622 are dissolved in 150 ml of toluene. 8.92 g (0.11 moles) of potassium cyanate and 10.8 g (0.11 moles) of 96% sulfuric acid are added. The mixture is heated between 40 and 50 C. stirring vigorously for 24 hours. When the analytical control detects a starting product content<2%, 50 ml of water are dropped into the mixture, which is stirred and the phases are separated. The organic phase is evaporated to dryness under vacuum and taken up into 100 ml of 10% sulfuric acid. The mixture is refluxed for 2-3 hours, cooled at room temperature and pump-filtered, washing with water; then it is recrystallized from dimethylacetamide (50 ml), filtered through charcoal washing the precipitate on the filter with acetone, and dried under vacuum. The product is identified by IR, NMR and mass spectroscopies. Yield g 15.5 m.p. 222 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With selenium(IV) oxide; In 1,4-dioxane; for 7h;Reflux; | Oxcarbazepine (2, 5.0 g, 19.82 mmol) and SeO2 (5.4g,48.67 mmol) in dioxane (100 mL) were brought to reflux under vigorous stirring for 7 h. Thereaction progress was monitored by TLC analysis (SiO2, CH2Cl2/EtOH 95:5, Rf 1 = 0.27, Rf 3 =0.56). After cooling to r.t. the orange precipitate was filtered and dried under vacuum to afford 3(4.0 g, 90%): the spectroscopic data were in accordance with those reported in the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.6% | Following the procedure of Example 1, but using 30% aqueous formic acid instead of the same volume of 10% aqueous sulfuric acid, the yield is 58.0 (76.6% on theoretical). | |
72.7% | Following the procedure of Example 1, but using an equimolar amount of pyridine instead of triethylamine, the yield is 55.0 g (72.7% on theoretical). | |
68.7% | Following the procedure of Example 4, but using dichloromethane as the solvent instead of toluene, at the reflux temperature, the yield is 52.0 (68.7% on theoretical). |
67.3% | The procedure of Example 6 is followed, but using 1,4-diazabicyclo-[2.2.2]octane is used instead of an equivalent amount of triethylamine. The acid hydrolysis is carried out as in Example 4. The yield is 51.0 g (67.3% on theoretical). | |
64 - 77.3% | a) A solution of 66.9 g (0.3 mols) of 10-methoxy-iminostilbene and 34.92 g (0.34 mols) of triethylamine in 800 ml of toluene is gradually added, during 6 hours and at a temperature of 10-15C, with a solution of 32.67 g (0.11 mols) of triphosgene in 300 ml of toluene. After completion of the reaction (disappearance of methoxy-iminostilbene) 200 ml of 30% aqueous ammonia are added gradually, vigorously stirring at room temperature for some hours. After that, the phases are separated, the toluene phase is washed with water and evaporated to dryness under reduced pressure. Yield: 69.0 g (85% on theoretical) of 10-methoxy-N-aminocarbonyl-iminostilbene (V) of purity higher than 95%.b) The resulting product is hydrolysed by refluxing with 100 ml of 10% H2SO4 for an hour. After cooling to room temperature, filtration and washing with water, the reaction mixture is recrystallized from dimethylformamide, and the precipitate is washed with acetone and dried under vacuum. 57.0 g of oxcarbazepine (yield 75.3% on theoretical) are obtained, the structure being confirmed by IR, NMR and mass spectroscopies. Example 2 Following the procedure of Example 1, but using triphosgene in equimolar amount to 10-methoxyiminostilbene, and proportionally increasing Triethylamine, 58.5 g of oxcarbazepine are obtained (77.3% on theoretical). Example 6 Following the procedure of Example 1, but dropping the solution of 10-methoxyiminostilbene and triethylamine into the solution of triphosgene in toluene, in 2 hours, the yield is 54.7 (72.2% on theoretical). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With water; acetic acid; at 15 - 25℃; for 0.5 - 1h; | EXAMPLE 2; Preparation of 10-Oxo-10,11-dihydro-5H-dibenz[b,f]azepin-5-carboxamide III; A 1-L, three-necked flask equipped with a thermometer, nitrogen inlet, mechanical stirrer and addition funnel, was charged with oximinostilbene IV (prepared above) followed by 400 mL dichloromethane. The suspension was cooled to 0-5 C. and a solution of chlorosulfonyl isocyanate (71.7 g, 0.50 mol) in 200 mL dichloromethane was added dropwise, maintaining the internal temperature at 0-10 C. Following the addition, the reaction mixture was maintained at 0-5 C. until reaction completion. The cold suspension was then filtered and washed giving oxcarbazepine intermediate V (163 g, 97%). The damp solid was suspended in 300 ml glacial acetic acid and cooled to 10-15 C. To the suspension was added 188 mL cold water, portionwise, maintaining the IT<20 C. The mixture was maintained at 15-25 C. for 0.5-1.0 h until reaction completion. The suspension was concentrated to 200-300 ml and 700 mL isopropanol was added to precipitate the product. The suspension was then filtered and washed. The damp cake was purified in an isopropanol:water mixture to furnish oxcarbazepine as a white to off-white solid (101.27 g, 84%, purity of 99.5% by HPLC). 1H NMR (DMSO, d): 4.06, 6.19, 7.30-7.39, 7.44-7.51, 7.63, 7.91 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 3 Alternative Use of benzoic acid and sodium cyanate The method of Example 1 was repeated, but using 1000 ml toluene; 164 g benzoic acid and 44 g of sodium cyanate, which were heated to 85-90 C. for 14 hours with the 10-methoxyiminostilbene to result in 55 gms of pure oxcarbazepine, found to be 99.45% pure by HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; at 20℃;Inert atmosphere; | Example 1: Synthesis of oxcarbazepine-7-carboxymethyloxime 2 (Hapten-A) To a solution of oxcarbazepine 1 (2.52g, 10mM) in dry pyridine (50ml) under nitrogen was added <strong>[2921-14-4]carboxymethoxylamine hemihydrochloride</strong> (1.31g, 12mM) and the mixture was stirred overnight at room temperature. The mixture began cloudy but turned clear yellow after few hours. The solvent was removed under vacuum and the residue obtained purified by flash chromatography on silica gel using 10% methanol / 90% chloroform to give 2.3g of the product as a foam. The product was then triturated by ethyl acetate / hexane (1/1) the white solid formed was filtered and dried to give 2g of oxcarbazepine-7-carboxymethyloxime 2 (Hapten-A). M. P. 205C (dec). NMR 13C (CD3OD)(delta: ppm): 171.21, 156.17, 154.49, 143,45, 141.16, 134.25, 130.77, 130.66, 130.57, 129.70, 128.64, 128.58, 128.31, 128.06, 127.6, 71.09 and 32.17. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With peracetic acid; potassium dichromate; hydrogen; In 1,2-dichloro-ethane; at 20℃; for 1h; | Peroxyaceticacid (1.5 mL, 35% in acetic acid) was added dropwise to a suspension of licarbazepine (56, 508 mg, 2.00 mmol) and K2Cr2O7 (23.3 mg, 0.08 mmol) in 5mL of dichloroethane. The reaction mixture was stirred at room temperature for 1 h. The aqueous solution of Na2SO3 (5%) was added to the reaction mixture before stirred overnight. The organic phase was separated. The aqueous phase was extracted with dichloromethane (2 × 50mL). The combined organic phase was washed with brine, and dried with MgSO4. Evaporation of the solvent gave the product as colorless solid (453 mg, 90%). |
65.5% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; In dichloromethane; at 25 - 30℃; for 0.25h; | To a stirred suspension of 10-hydroxy-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide (2.0 g, 0.0078 mol) in dichloromethane (10 mL), TEMPO (13 mg, 0.000078) was charged at 25 C. to 30 C. After stirring at 25 C. to 30 C. for 15 minutes, the reaction mixture was cooled to 0 C. to 5 C. and sodium hypochlorite solution (12.0 mL) (adjusted pH=9.7 using 10% aqueous NaHCO3) was charged dropwise. The reaction mixture was stirred at 0 C. to 5 C. for 1 hour. The organic layer was separated and washed with deionised water (20 mL) and concentrated at about 40 C. to 45 C. under reducing pressure. The solid was stirred with toluene (5 mL) and filtered. The solid obtained was stirred with dimethylformamide (12 mL) at 60 C. to 65 C. After stirring at 60 C. to 65 C. for 15 minutes, the reaction mixture was cooled to 20 C. to 25 C. Deionised water (72 mL) was charged and the mixture was further stirred for 30 minutes. The solid was filtered, washed with deionised water (10 mL) and dried at 60 C. to 65 C. under vacuum for 8 hours to obtain the titled compound. Yield: 1.3 g (65.5%) [0106] Chemical Purity: 90.4% |
1.3 g | To a stirred suspension of 10-hydroxy-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide (2.0 g, 0.0078 mol) in dichloromethane (10 mL), TEMPO (13 mg, 0.000078) was charged at 25C to 30C. After stirring at 25C to 30C for 15 minutes, the reaction mixture was cooled to 0C to 5C and sodium hypochlorite solution (12.0 mL) (adjusted pH= 9.7 using 10% aqueous NaHCOs) was charged dropwise. The reaction mixture was stirred at 0C to 5C for 1 hour. The organic layer was separated and washed with deionised water (20 mL) and concentrated at about 40C to 45C under reducing pressure. The solid was stirred with toluene (5 mL) and filtered. The solid obtained was stirred with dimethylformamide (12 mL) at 60C to 65C. After stirring at 60C to 65C for 15 minutes, the reaction mixture was cooled to 20C to 25C. Deionised water (72 mL) was charged and the mixture was further stirred for 30 minutes. The solid was filtered, washed with deionised water (10 mL) and dried at 60C to 65C under vacuum for 8 hours to obtain the titled compound. Yield: 1.3 g (65.5%) Chemical Purity: 90.4% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.5% | With methanol; sodium tetrahydroborate; at 45 - 50℃; for 3h; | To a 250 ml four-necked flask equipped with a stirrer, thermometer, and reflux condenser was added 20 g of methanol and 2.52 g (10 mmol) of oxcarbazepine (I1) prepared in example 1, 0.31 g (8 mmol) of sodium borohydride. The reaction was stirred at 45 to 50 C for 3 hours. Cooled to 20 to 25 C, the system was acidified with 35% by weight hydrochloric acid to adjust pH 2.0-2.5 , the reaction was stirred for 2 hours at 25 to 30 C, 20 g of water was added, filtered, and dried to obtain 2.16 g of carbamazepine (IV1), Yield was 91.5%, and liquid purity was 99.7%. |
Tags: 28721-07-5 synthesis path| 28721-07-5 SDS| 28721-07-5 COA| 28721-07-5 purity| 28721-07-5 application| 28721-07-5 NMR| 28721-07-5 COA| 28721-07-5 structure
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