A method for synthesizing a key intermediate of oxcarbazepine

Abstract

The invention discloses a method for synthesizing a key intermediate of oxcarbazepine. The method uses compound 2 as a raw material, undergoes acetic acid hydrolysis to obtain compound 3, and then performs serial hydrolysis to obtain a hydroxyl compound, namely compound 4. The hydroxyl compound is subjected to copper-catalyzed air oxidation to obtain a carbonyl compound, namely compound 5, thereby obtaining the key intermediate of oxcarbazepine. The reaction formula is as follows: the process of the invention has a short synthesis process, uses inexpensive and readily available materials, has mild conditions in each step, and has a high yield; compared with a traditional process for direct hydrolysis of bromides, the process for acetic acid hydrolysis followed by hydrolysis of the bromide can effectively inhibit the alkaline elimination of the bromide, and significantly improves the selectivity of the hydrolysis reaction; and the step for oxidizing the hydroxyl compound to prepare the carbonyl compound uses oxygen as an oxygen source, which has clear advantages in terms of economy and safety compared with a traditional sodium hypochlorite / TEMPO oxidation process.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing a key intermediate of oxcarbazepine. Background Art

[0002] Oxcarbazepine (OCBZ), chemically known as 10,11-dihydro-10-oxo-5H-dibenzo[b,f]azepine-5-carboxamide, is a 10-keto derivative of carbamazepine. Due to its readily absorbable, low toxicity, and lack of liver enzyme induction, it is widely used as a first-line anti-epileptic drug by epilepsy patients worldwide. Oxcarbazepine is also used to treat trigeminal neuralgia, central nervous system uremia, Parkinson's disease, and other conditions.

[0003] At present, the synthesis routes of oxcarbazepine can be mainly divided into four categories according to its starting materials: iminodibenzyl method, iminostilbene method, carbamazepine method and 10-methoxyiminostilbene method. Each method has significant advantages and disadvantages. Among them, the more studied and relatively mature synthesis route mainly uses iminodibenzyl as the raw material, undergoes N-chloroformylation, benzyl bromination, elimination to obtain olefin, olefin and liquid bromine addition to obtain dibromide, dibromide is subjected to elimination and tandem alcoholysis in sodium methoxide methanol solution to obtain enether, enether is further N-chloroformylated, aminolyzed, and finally the enether is rearranged by acid-catalyzed ether bond cleavage to obtain the target product oxcarbazepine. Overall, this process route has many steps and involves two brominations. Among them, the elimination and tandem alcoholysis step of dibromide in sodium methoxide methanol solution has the problems of low reaction activity, long time consumption and low yield. At the same time, the chloroformyl group is easily removed in this step, and the chloroformyl group needs to be reintroduced in the subsequent step, resulting in low atom utilization and obvious process defects. The specific reaction formula is as follows:

[0004]

[0005] Two previous patent documents reported the synthesis of oxcarbazepine using 5-cyano-10,11-dihydro-5H-diphenyl[b,f]azepine as a raw material through a four-step reaction (U.S. Patent US 6384217 and Chinese Patent 200810062785.X). U.S. Patent US 6384217 used NBS as a bromination reagent and carried out benzylic bromination, alkaline hydrolysis, oxidation with a calcium hypochlorite / TEMPO system, and sulfuric acid-catalyzed cyanolysis to obtain the target product. Chinese Patent 200810062785.X also used 5-cyano-10,11-dihydro-5H-diphenyl[b,f]azepine as a raw material, using liquid bromine as a bromination reagent, benzylic bromination, alkaline hydrolysis, oxidation with a calcium hypochlorite / TEMPO system, and cyanolysis with an alkaline hydrogen peroxide system to obtain the target product. In both of the aforementioned patented routes, direct alkaline hydrolysis of a benzyl bromide intermediate is used to prepare hydroxyl compounds. However, research has revealed that this step involves a significant elimination side reaction, generating a significant amount of olefins as a byproduct alongside the hydroxyl compound. This increases the difficulty of post-reaction processing, significantly reduces reaction yield, and increases synthesis costs. In the alcohol oxidation step to prepare carbonyl compounds, sodium hypochlorite / TEMPO is used as the oxidation system to oxidize the hydroxyl compound to produce the carbonyl compound, which is relatively costly and presents certain safety risks. Summary of the Invention

[0006] In view of the shortcomings of the existing technology, the present invention provides a new, cheaper and feasible method for synthesizing a key intermediate of oxcarbazepine and oxcarbazepine. The preparation method of the key intermediate of oxcarbazepine and oxcarbazepine provided by the present invention comprises the following steps:

[0007] (1) Compound 1 (5-cyano-10,11-dihydro-5H-diphenyl[b,f]azepine) is used as the starting material, NBS is used as the bromination reagent, and BPO is used as the initiator, and the monobromide, compound 2, is obtained by benzylic bromination;

[0008] (2) Compound 2 was used as the raw material and acetic acid was used as the solvent in the presence of a base to produce compound 3;

[0009] (3) Compound 3 was used as the raw material and hydrolyzed under the action of alkali to obtain compound 4;

[0010] (4) Compound 4 is used as a raw material and oxygen is used as an oxygen source to obtain carbonyl compound 5 by copper-catalyzed oxidation. Compound 5 is the key intermediate of oxcarbazepine;

[0011] (5) Compound 5 was used as raw material and sulfuric acid was used as catalyst to obtain the target compound 6, oxcarbazepine, by acidic hydrolysis. The reaction formula is as follows:

[0012]

[0013] Furthermore, in step (1), 5-cyano-10,11-dihydro-5H-diphenyl[b,f]azepine is used as a starting material, and the specific process for synthesizing compound 2 by benzyl bromination is as follows: compound 1 is used as a starting material, the molar amount of compound 1 is 1 eq., 1.0-1.1 eq. NBS is used as a bromination reagent, 0.02-0.1 eq. BPO is used as an initiator, and the reaction is carried out in carbon tetrachloride solvent to achieve benzyl bromination to obtain compound 2.

[0014] Furthermore, the reaction of synthesizing compound 2 using compound 1 as the starting material has a reaction temperature of 55-65° C. until the reaction is monitored to be complete; after the reaction is completed, the following post-processing steps are also included: cooling, filtering, concentrating the filtrate under reduced pressure, recrystallizing the concentrated residue with acetone, and filtering and collecting the solid to obtain compound 2.

[0015] Furthermore, in step (2), the synthesis of compound 3 is carried out using compound 2 as a starting material and acetic acid as a solvent in the presence of a base to obtain compound 3 by acetic acid hydrolysis; the base is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium phosphate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, one or more of which are mixed in any ratio, and the molar ratio of the base to compound 2 is 1.0:1 to 2.0:1.

[0016] Furthermore, the acetic acid hydrolysis reaction is stirred at room temperature until the reaction is complete. After the reaction is completed, the acetic acid solvent is recovered under reduced pressure, and the residual liquid is directly used for the next reaction.

[0017] Furthermore, in step (3), the synthesis of compound 4 is obtained by hydrolysis in the presence of a base, the base is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, one or more of which are mixed in any ratio, the reaction solvent of the hydrolysis reaction is an organic solvent-water mixed solvent, the organic solvent is a low-boiling point solvent miscible with water such as ethanol, methanol, tetrahydrofuran, acetonitrile, acetone, etc., the volume ratio of the organic solvent to water can be 1:0.5~2, the molar ratio of the base in the hydrolysis reaction to the raw material compound 2 in the previous step is 1.0:1~3.0:1, and the temperature range of the hydrolysis reaction is 20~80°C.

[0018] Furthermore, the synthesis of compound 4 uses compound 2 as the starting material to prepare compound 3 through acetic acid hydrolysis reaction. Compound 3 does not need to be purified. After the acetic acid hydrolysis reaction is complete, the solvent is recovered under reduced pressure and then water is directly added and alkali is added to undergo hydrolysis reaction to obtain compound 4.

[0019] Furthermore, in step (4), the synthesis of compound 5 uses the synthesized compound 4 as a starting material, and in the presence of a copper salt ligand and a reaction solvent, oxygen is used as an oxygen source to catalyze oxidation by copper salt to obtain compound 5; the copper salt is selected from one of copper acetate, copper sulfate, copper hexafluorophosphate, copper trifluoroacetate, copper chloride, copper bromide, cuprous iodide, cuprous bromide, cuprous chloride, cuprous oxide, and cupric oxide, or a mixture of two or more of them in any ratio, and the amount of the copper salt is 1% to 20% of the molar amount of compound 4, preferably 2.5% to 10%. The copper salt ligand is selected from dinitrogen ligands, namely, at least one of phenanthroline, ethylenediamine, N,N'-di-tert-butylethylenediamine, N,N'-dimethylethylenediamine, N,N,N',N'-tetramethylethylenediamine, bipyridine, bipyridine derivatives, cyclohexanediamine and cyclohexanediamine derivatives. The amount of the copper salt ligand is 100% to 200% of the molar amount of the copper salt. The reaction solvent is a commonly used solvent such as at least one of dichloromethane, dichloroethane, chloroform, benzene, toluene, cyclohexane and ethyl acetate. The reaction temperature is 20 to 150° C., preferably 20 to 80° C.

[0020] Furthermore, the synthesis of compound 5 is carried out in the presence of DMAP, and the amount of DMAP used is 10-20% of the molar amount of compound 4.

[0021] Furthermore, after the reaction for synthesizing compound 5 is completed, the following post-treatment steps are further included: filtration, washing the filtrate with 0.5-2N hydrochloric acid and water, drying, and concentrating. The residual liquid is recrystallized with chloroform solvent, and the solid product is collected by filtration to obtain compound 5.

[0022] Furthermore, in step (5), the synthesis of compound 6 is carried out by acid-catalyzed hydrolysis of the synthesized compound 5 as a starting material in an acetic acid solution with sulfuric acid as a catalyst to obtain the target product, compound 6 oxcarbazepine. After the synthesis reaction of compound 6 is completed, the following post-treatment steps are also included: the reaction solution is poured into ice water, stirred thoroughly, filtered, the filter cake is washed thoroughly with ice water, and dried to obtain a solid product, namely compound 6.

[0023] The beneficial effects achieved by the present invention are:

[0024] (1) The reagents are cheap and readily available;

[0025] (2) The reaction conditions in each step are mild and the post-processing is simple;

[0026] (3) The total yield is high, which has obvious advantages in production costs.

[0027] The significant differences and advantages of the synthesis process of the present invention over the above-mentioned process are: ① The benzyl bromide intermediate is first subjected to acetic acid hydrolysis and then to dilute alkaline hydrolysis to prepare a hydroxyl compound, which can significantly suppress and eliminate side reactions and achieve effective conversion of the bromide to the hydroxyl compound with nearly 100% reaction selectivity; ② In the step of oxidizing the hydroxyl compound to ketone, oxygen is used as the oxygen source for copper-catalyzed oxidation instead of the sodium hypochlorite TEMPO system, resulting in a clean and efficient reaction and a significant advantage in synthesis cost. DETAILED DESCRIPTION

[0028] The present invention will be further described in detail below with reference to specific embodiments, but the protection scope of the present invention is not limited thereto.

[0029] Example 1 Preparation of 5-cyano-10-bromo-10,11-dihydro-5H-diphenyl[b,f]azepine (Compound 2)

[0030] To 4.4 g (20.0 mmol) of compound 1, add 20.0 mL of carbon tetrachloride and stir to dissolve. Then add 121 mg (0.5 mmol) of BPO and 3.56 g (20.0 mmol) of NBS. Heat at 60 ° C for 3 h until the reaction is complete. Then cool to 10 ° C, filter, and concentrate the filtrate under reduced pressure. The residue is recrystallized from acetone to obtain 5.26 g of a light yellow solid, namely compound 2 (5-cyano-10-bromo-10,11-dihydrophenyl[b,f]azepine), with a yield of 88%.

[0031] Example 2. Preparation of 5-cyano-10-acetoxy-10,11-dihydro-5H-diphenyl[b,f]azepine (Compound 3)

[0032] 5.98 g (20.0 mmol) of compound 2 was dissolved in 16.0 mL of glacial acetic acid, cooled to 10°C, and 1.96 g (20.0 mmol) of potassium acetate was added. The temperature was naturally raised to room temperature and stirring was continued for about 1.5 h until the reaction was complete. The solvent was recovered under reduced pressure at a temperature below 30°C. The residual liquid was used directly in the next step without further purification.

[0033] Example 3. Preparation of 5-cyano-10-hydroxy-10,11-dihydro-5H-diphenyl[b,f]azepine (Compound 4)

[0034] The residual liquid obtained in Example 2 was dissolved in 20 mL of methanol, and 20 mL of 1 M NaOH aqueous solution was added. The mixture was kept at 40° C. for 2 h until the reaction was complete. Most of the methanol was evaporated under reduced pressure at a temperature not higher than 30° C. 60 mL of water was added, and the mixture was extracted twice with ethyl acetate. The mixture was dried and concentrated under reduced pressure. The residual liquid was recrystallized from acetone to obtain 4.54 g of a light yellow solid. The total yield of the acetic acid hydrolysis and hydrolysis steps was 96%.

[0035] Example 4. Preparation of 5-cyano-10-acetoxy-10,11-dihydro-5H-diphenyl[b,f]azepine (Compound 3)

[0036] 5.98 g (20.0 mmol) of compound 2 was dissolved in 32.0 mL of glacial acetic acid, and 4.24 g (40.0 mmol) of sodium carbonate was added. The temperature was naturally raised to room temperature and stirring was continued for about 4 h until the reaction was complete. The solvent was recovered under reduced pressure at a temperature below 30°C. The residual liquid was used directly in the next step without further purification.

[0037] Example 5. Preparation of 5-cyano-10-hydroxy-10,11-dihydro-5H-diphenyl[b,f]azepine (Compound 4)

[0038] The residual liquid obtained in Example 4 was dissolved in 40 mL of acetonitrile, 40 mL of water was added, 2.12 g (20.0 mmol) of sodium carbonate was added, and the mixture was kept at 80° C. for 2 h until the reaction was complete. Most of the acetonitrile was evaporated under reduced pressure at a temperature below 30° C., 60 mL of water was added, and the mixture was extracted twice with ethyl acetate, dried, and concentrated under reduced pressure. The residual liquid was recrystallized from acetone to obtain 4.20 g of a light yellow solid. The total yield of the two steps of acetic acid hydrolysis and hydrolysis was 89%.

[0039] Example 6. Preparation of 5-cyano-10-oxa-10,11-dihydro-5H-diphenyl[b,f]azepine (Compound 5)

[0040] 220 mg (1.0 mmol) of copper bromide and 220 mg (1.0 mmol) of bipyridine were added to 40 mL of anhydrous ethyl acetate and stirred for 10 min. 4.72 g (20.0 mmol) of compound 4 and 240 mg (2.0 mmol) of DMAP were added. 1 atm of O2 was introduced and stirred at room temperature for 40 h until the reaction was complete. The mixture was filtered and the filtrate was washed with 1N HCl and water, dried, and concentrated. The residual liquid was recrystallized from chloroform to obtain 3.93 g of a light yellow solid with a yield of 84%.

[0041] Example 7. Preparation of 5-cyano-10-oxa-10,11-dihydro-5H-diphenyl[b,f]azepine (Compound 5)

[0042] 706 mg (2.0 mmol) of copper hexafluorophosphate and 288 mg (2.0 mmol) of diisopropylethylenediamine were added to 40 mL of anhydrous dichloromethane and stirred for 10 min. 4.72 g (20.0 mmol) of compound 4 and 480 mg (4.0 mmol) of DMAP were added. 1 atm O2 was introduced and the mixture was kept at 50°C for 10 h until the reaction was complete. The mixture was filtered and the filtrate was washed with 1N HCl and water, dried, and concentrated. The residual liquid was recrystallized from chloroform to obtain 4.31 g of a light yellow solid with a yield of 92%.

[0043] Example 8. Preparation of 5-cyano-10-oxa-10,11-dihydro-5H-diphenyl[b,f]azepine (Compound 5)

[0044] 45 mg (0.5 mmol) of cuprous chloride and 71 mg (0.5 mmol) of N,,N'-dimethylcyclohexanediamine were added to 50 mL of anhydrous toluene and stirred for 10 min. 4.72 g (20.0 mmol) of compound 4 was added, and 1 atm of O2 was introduced. The mixture was kept at 80°C for 24 h until the reaction was complete. The reaction was filtered, and the filtrate was washed with 1N HCl and water, dried, and concentrated. The residual liquid was recrystallized from chloroform to obtain 2.2 g of a light yellow solid with a yield of 47%.

[0045] Example 9. Preparation of 10-oxa-10,11-dihydro-5H-diphenyl[b,f]azepine-5-carboxamide (Compound 6)

[0046] 4.68 g (20.0 mmol) of compound 5 was dissolved in 40.0 mL of glacial acetic acid. The temperature was controlled not to exceed 15° C. 5 mL of 98% concentrated sulfuric acid was added dropwise. After the addition of concentrated sulfuric acid, the temperature was naturally raised and stirring was continued at room temperature for 8 h until the reaction was complete. The reaction solution was slowly poured into 300 g of ice water, stirred thoroughly, filtered, and the filter cake was washed thoroughly with ice water and dried to obtain 4.6 g of a white solid, which was the target product, oxcarbazepine, with a yield of 91%.

Claims

1. A method for synthesizing a key intermediate of oxcarbazepine, characterized in that Compound 2 is used as a raw material and subjected to acetic acid hydrolysis to obtain compound 3, which is then hydrolyzed in series to obtain a hydroxylate, namely compound 4. The hydroxylate is oxidized by copper-catalyzed air to obtain a carbonyl, namely compound 5, which is the key intermediate of oxcarbazepine. The reaction formula is as follows: ； The synthesis of compound 5 uses the synthesized compound 4 as a starting material, and in the presence of DMAP, a copper salt ligand and a reaction solvent, oxygen is used as an oxygen source to oxidize the compound 5 by copper salt catalysis; the copper salt is selected from one or more of copper acetate, copper sulfate, copper hexafluorophosphate, copper trifluoroacetate, copper chloride, copper bromide, cuprous iodide, cuprous bromide, cuprous chloride, cuprous oxide, and cupric oxide in any ratio; the copper salt ligand is selected from a dinitrogen ligand, namely, at least one of phenanthroline, ethylenediamine, N,N'-di-tert-butylethylenediamine, N,N'-dimethylethylenediamine, N,N,N',N'-tetramethylethylenediamine, bipyridine, and cyclohexanediamine; and the reaction solvent is at least one of dichloromethane, dichloroethane, chloroform, benzene, toluene, cyclohexane, and ethyl acetate.

2. A method for synthesizing a key intermediate of oxcarbazepine according to claim 1, characterized in that: The synthesis of compound 2 is carried out using N-cyano-10,11-dihydro-5H-diphenyl[b,f]azepine, i.e., compound 1, as a starting material, and obtaining a monobromide, i.e., compound 2, through benzylic bromination. The specific process is as follows: using compound 1 as a starting material, a molar amount of compound 1 is 1 eq., 1.0 to 1.1 eq. of NBS as a bromination reagent, and 0.02 to 0.1 eq. of BPO as an initiator, the reaction is carried out in a carbon tetrachloride solvent to achieve benzylic bromination to obtain compound 2.

3. A method for synthesizing a key intermediate of oxcarbazepine according to claim 2, characterized in that: The reaction of synthesizing compound 2 using compound 1 as the starting material has a reaction temperature of 55 to 65°C and is monitored until the reaction is complete. After the reaction is completed, the following post-processing steps are also included: cooling, filtering, concentrating the filtrate under reduced pressure, recrystallizing the concentrated residue with acetone, and filtering and collecting the solid to obtain compound 2.

4. The method for synthesizing a key intermediate of oxcarbazepine according to claim 1, wherein: Compound 3 is synthesized by acetic acid hydrolysis in the presence of a base using compound 2 as a starting material and acetic acid as a solvent to obtain compound 3; the base is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium phosphate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, or one or more thereof mixed in any ratio, with the molar ratio of the base to compound 2 being 1.0:1 to 2.0:

1. The acetic acid hydrolysis reaction is stirred at room temperature until the reaction is complete. After the reaction is completed, the acetic acid solvent is recovered under reduced pressure, and the residual liquid is directly used for the next reaction.

5. The method for synthesizing a key intermediate of oxcarbazepine according to claim 1, wherein: Compound 4 is synthesized by hydrolysis in the presence of a base, wherein the base is selected from one or more of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, and potassium acetate in any ratio. The reaction solvent of the hydrolysis reaction is an organic solvent-water mixed solvent. The molar ratio of the base in the hydrolysis reaction to the raw material compound 2 in the previous step is 1.0:1 to 3.0:1, and the temperature range of the hydrolysis reaction is 20 to 80 ° C.

6. A method for synthesizing a key intermediate of oxcarbazepine according to claim 5, characterized in that: The synthesis of compound 4 is as follows: Compound 2 is used as the starting material to prepare compound 3 through acetic acid hydrolysis reaction. Compound 3 does not need to be purified. After the acetic acid hydrolysis reaction is completed, the solvent is recovered under reduced pressure, and then water is directly added and a base is added to hydrolyze the reaction to obtain compound 4; In the reaction solvent of the hydrolysis reaction, the organic solvent is selected from at least one of ethanol, methanol, tetrahydrofuran, acetonitrile, and acetone, and the volume ratio of the organic solvent to water is 1:0.5-2.

7. The method for synthesizing a key intermediate of oxcarbazepine according to claim 1, characterized in that: In the synthesis steps of compound 5, the amount of copper salt used is 1% to 20% of the molar amount of compound 4; the amount of copper salt ligand used is 100% to 200% of the molar amount of copper salt, and the reaction temperature is 20 to 150°C.

8. The method for synthesizing a key intermediate of oxcarbazepine according to claim 7, characterized in that: In the synthesis steps of compound 5, the amount of copper salt used is 2.5% to 10% of the molar amount of compound 4; the amount of copper salt ligand used is 100% to 200% of the molar amount of copper salt, and the reaction temperature is 20 to 80°C.

9. The method for synthesizing a key intermediate of oxcarbazepine according to claim 1, wherein: In the synthesis step of compound 5, the amount of DMAP used is 10-20% of the molar amount of compound 4. After the reaction for synthesizing compound 5 is completed, the following post-treatment steps are also included: filtration, washing the filtrate with 0.5-2N hydrochloric acid and water, drying, and concentrating. The residual liquid is recrystallized from chloroform solvent, and the solid product is collected by filtration to obtain compound 5.

10. A method for synthesizing oxcarbazepine, characterized in that: The method for synthesizing the key intermediate of oxcarbazepine according to claim 1 also includes a step of synthesizing oxcarbazepine, wherein the oxcarbazepine is 10-oxa-10,11-dihydro-5H-diphenyl[b,f]azepine-5-carboxamide. The synthesis of the synthesized compound 5 is carried out as a starting material, and sulfuric acid is used as a catalyst in an acetic acid solution to hydrolyze the compound 5 to obtain the target product compound 6 oxcarbazepine. The reaction formula is as follows: 。 11. The method for synthesizing oxcarbazepine according to claim 10, wherein: After the synthesis reaction of compound 6 is completed, the following post-processing steps are further included: the reaction solution is poured into ice water, fully stirred, filtered, the filter cake is fully washed with ice water, and dried to obtain a solid product, namely compound 6.

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