Intermediate compound of oxcarbazepine and preparation method therefor

Abstract

The present invention relates to the field of pharmaceutical synthesis, and specifically relates to a method for preparing a key intermediate of oxcarbazepine. Specifically, a compound represented by formula A is prepared from a compound represented by formula 4 under the action of a ring-opening reagent and selectively under the action of an esterification reagent, a protective reagent, a hydrolysis reagent and a chlorination reagent; a compound represented by formula 10 is prepared from the compound represented by formula A by means of a ring-closing reaction; and finally oxcarbazepine is prepared from the compound represented by formula 10. The route of the present invention achieves a relatively high conversion rate, and is more advantageous in the aspect of cost control. The reaction formulas are shown in formula (I), wherein R3 is OR1 or R2; R1 is hydrogen, a C1-C6 alkyl or substituted alkyl, or Na, K or Li; R2 is Cl or -OCOR5; R5 is a C1-C6 alkyl or substituted alkyl, an aryl, a substituted aryl, a phenyl, a benzyl or a substituted benzyl; and R4 is a C1-C6 alkyl, a substituted alkyl, an aryl, a substituted aryl, a benzyl or a substituted benzyl.

Description

An oxcarbazepine intermediate compound and its preparation method

[0001] This application claims priority to the Chinese patent application filed with the China Patent Office on August 23, 2023, with application number 202311069320.8 and invention name “A kind of oxcarbazepine intermediate compound and its preparation method”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present invention belongs to the field of pharmaceutical chemicals, and particularly relates to a key intermediate for preparing oxcarbazepine and a preparation method thereof. Background Art

[0003] The national new anti-epileptic drug - oxcarbazepine is an upgraded product of carbamazepine and is a recommended product in the national "15th Five-Year Plan". It has good anti-epileptic, anti-trigeminal neuralgia and affective psychosis effects, with definite efficacy and few side effects. It is currently mainly used as a first-line anti-epileptic drug.

[0004] Prior art, such as the journal Tetrahedron Letters (2004), 45(27), 5275-5278, discloses a synthetic process for oxcarbazepine and its intermediate (2-(acetylphenylamino)phenylacetic acid). However, the yield of the intermediate (the compound of Formula 8-1 of the present invention) is low, and the use of n-butyl lithium reagent requires a low temperature (-10°C) and moisture control, which are relatively harsh conditions. The reagent cost is also relatively expensive. In addition, the use of phosgene as an acylating agent in the preparation process poses a significant risk in industrialization, making industrial production difficult. When the intermediate is further used to prepare the compound of Formula 10 of the present invention, the corresponding product cannot be obtained. This makes it impossible to industrially prepare the compound of Formula 10 of the present invention and the subsequent product, oxcarbazepine.

[0005] In addition, Novartis disclosed another synthetic route in its international patent application (WO2001056992) filed in February 2001:

[0006] Specifically, N-phenylindole is used as a starting material to synthesize the key intermediate 10-methoxyiminostilbene, which is then synthesized through a six-step reaction to produce oxcarbazepine. This route involves a long reaction process, the production of numerous byproducts, and the finished product requires purification, resulting in a loss in yield. The use of n-butyllithium reagents requires harsh conditions such as low temperatures and moisture control, and the reagents are expensive. Given the shortcomings of the existing technology, it is necessary to develop a more technologically superior route suitable for industrial scale.

[0007] Summary of the Invention

[0008] The present invention provides an oxcarbazepine synthesis route with higher conversion rate and greater advantages in cost control.

[0009] In order to achieve the technical purpose of the present invention, the technical solution of the present invention is:

[0010] The present invention first provides a compound of formula A, the structural formula of which is:

[0011] Wherein, R3 is OR1 or R2, R1 is C2-C6 alkyl or substituted alkyl or Na, K, Li; R2 is Cl or -OCOR5, R5 is C1-C6 alkyl or substituted alkyl, aryl, substituted aryl, phenyl, benzyl or substituted benzyl; R4 is C1-C6 alkyl, substituted alkyl, aryl, substituted aryl, benzyl, or substituted benzyl.

[0012] Among them, more preferably, R3 is OR1, R1 is C2-C6 alkyl or substituted alkyl, and R4 is C1-C6 alkyl or substituted alkyl.

[0013] Among them, more preferably, R3 is R2, R2 is Cl or -OCOR5, R5 is C1-C6 alkyl or substituted alkyl, aryl, substituted aryl, phenyl, benzyl or substituted benzyl, and R4 is C1-C6 alkyl or substituted alkyl.

[0014] More preferably, the present invention provides a compound of formula 7, the structural formula is:

[0015] Wherein, R4 is a C1-C6 alkyl or substituted alkyl, aryl, or substituted aryl; and R1 is a C2-C6 alkyl or substituted alkyl.

[0016] More preferably, a compound of formula 9 is provided, the structural formula being:

[0017] Wherein, R2 is Cl, and R4 is C1-C6 alkyl or substituted alkyl, aryl, or substituted aryl.

[0018] Another aspect of the present invention provides a method for preparing a compound of formula A, specifically, preparing a compound of formula A from a compound of formula 4 in the presence of a ring-opening reagent, and optionally in the presence of an esterification reagent, a protecting reagent, a hydrolysis reagent, and a chlorination reagent:

[0019] Among them, R4 is C1-C6 alkyl, substituted alkyl, aryl, substituted aryl, benzyl, substituted benzyl; R3 can be OR1 or R2; R1 is hydrogen, C1-C6 alkyl or substituted alkyl, Na, K, Li, etc.; R2 is Cl or -OCOR5, R5 can be C1-C6 alkyl or substituted alkyl, aryl, substituted aryl, phenyl, benzyl or substituted benzyl, substituted benzyl, etc.

[0020] The substituted alkyl group of the present invention is a non-hydrogen substituted alkyl group, an isopropyl substituted alkyl group, a tert-butyl substituted alkyl group, a halogen substituted alkyl group or a sulfur substituted alkyl group.

[0021] More preferably, the present invention provides a method for preparing a compound of formula 8, specifically, preparing a compound of formula 8 from a compound of formula 4 in the presence of a ring-opening reagent, and optionally in the presence of an esterification reagent, a protecting reagent, and a hydrolysis reagent:

[0022] Among them, R4 can be C1-C6 alkyl or substituted alkyl, aryl, substituted aryl, R1 is hydrogen, C1-C6 alkyl or substituted alkyl, Na, K, Li, etc.

[0023] More preferably, the compound of formula 4 is prepared in the presence of sodium hydroxide, diethyl sulfate, acetyl chloride / Lewis acid, and sodium hydroxide to obtain the compound of formula 8-1:

[0024] Specifically, when preparing the compound of formula 8,

[0025] Wherein, R4 is C1-C6 alkyl or substituted alkyl, aryl, substituted aryl, and R1 is hydrogen.

[0026] The ring-opening reagent is a base, which is an organic base or an inorganic base, wherein the inorganic base is sodium hydroxide or potassium hydroxide, and the organic base is triethylamine.

[0027] Most preferred is sodium hydroxide.

[0028] The molar ratio of the base to the compound of formula 4 is (1-2):1, preferably (1.03-1.1):1.

[0029] The above-mentioned esterification reagent is SO2(OR6)2, R6 is a C1-C6 alkyl or substituted alkyl; or XR7, X is I, Br or Cl, R7 is a C1-C6 alkyl or substituted alkyl; or CO(OR8)2, R8 is a C1-C6 alkyl or substituted alkyl, preferably diethyl sulfate, dimethyl sulfate, and most preferably diethyl sulfate.

[0030] The molar ratio of the esterification agent to the compound of formula 4 is (1.2-3):1, preferably (1.2-2.0):1.

[0031] The protecting reagent is an acyl chloride reagent or an acyl chloride reagent / Lewis acid.

[0032] Among them, the acyl chloride reagent can be methoxycarbonyl chloride, acetyl chloride, C2-C6 alkyl or substituted alkylcarbonyl chloride, benzoyl chloride, trifluoroacetyl, substituted benzoyl chloride (such as p-chlorobenzoyl chloride, p-nitrobenzoyl chloride, p-methylbenzoyl chloride, etc.), methanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride, substituted benzenesulfonyl chloride (such as p-nitrobenzenesulfonyl chloride, p-methylbenzenesulfonyl chloride, etc.), preferably acetyl chloride; the Lewis acid is zinc chloride, zinc bromide, ferric chloride, aluminum chloride, ethylaluminum chloride, ethylmagnesium chloride, cuprous iodide, nickel chloride, phosphorus pentoxide, titanium dioxide or tetraisopropyl titanate, preferably zinc chloride.

[0033] The molar ratio of the Lewis acid reagent to the compound of formula 4 is (0.2-1):1, preferably (0.3-0.5):1.

[0034] The hydrolysis agent is a base, which is an organic base or an inorganic base, wherein the inorganic base is sodium hydroxide or potassium hydroxide, and the organic base is triethylamine.

[0035] Most preferred is sodium hydroxide.

[0036] The molar ratio of the hydrolysis reagent to the compound of formula 4 is (1-2):1, preferably (1.03-1.1):1.

[0037] The above reaction is carried out in the presence of a solvent.

[0038] The solvent is a single solvent or a mixed solvent of tetrahydrofuran, ethanol, 1,4-dioxane, dimethylformamide (DMF), acetone, dichloromethane, toluene, chlorobenzene, EA, acetonitrile, n-heptane, ethyl acetate, methanol, ethanol or water,

[0039] Most preferred are tetrahydrofuran, dimethylformamide (DMF), methanol or water.

[0040] The volume ratio of the solvent is (2-5):1, preferably (2-3):1.

[0041] The present invention further provides a method for preparing an oxcarbazepine intermediate compound of formula 10, wherein the compound of formula A is first treated with a chlorination reagent and then treated with a Friedel-Crafts reaction reagent to prepare the compound of formula 10:

[0042] Wherein, R3' is OR1' or R2, R1' is hydrogen, R2 is Cl or -OCOR5, R5 is C1-C6 alkyl or substituted alkyl, aryl, substituted aryl, phenyl, benzyl or substituted benzyl; R4 can be C1-C6 alkyl, substituted alkyl, aryl, substituted aryl, benzyl, substituted benzyl.

[0043] Preferably, the compound of formula 10-1 is prepared by first subjecting the compound of formula A to a chlorination reagent and then to a Friedel-Crafts reaction reagent:

[0044] Wherein R3' is OR1' or R2, R1' is hydrogen, R2 is Cl or -OCOR5, R5 is C1-C6 alkyl or substituted alkyl, aryl, substituted aryl, phenyl, benzyl or substituted benzyl; and R4 is methyl.

[0045] The substituted alkyl group of the present invention is a non-hydrogen substituted alkyl group, an isopropyl substituted alkyl group, a tert-butyl substituted alkyl group, a halogen substituted alkyl group or a sulfur substituted alkyl group.

[0046] More preferably, the compound of formula 8-1 is prepared by reacting the compound of formula 9-1 with a chlorination agent.

[0047] Specifically, the present invention provides a method for preparing a compound of formula 9-1 by reacting a compound of formula 8-1 in a solvent under the action of a chlorinating agent.

[0048] Wherein, the chlorination reagent is thionyl chloride or oxalyl chloride,

[0049] Most preferred is thionyl chloride.

[0050] The solvent is selected from dichloromethane and n-heptane,

[0051] Most preferred is dichloromethane.

[0052] More preferably, the present invention provides a method for preparing a compound of formula 10-1 by reacting a compound of formula 9-1 with a Friedel-Crafts reaction reagent.

[0053] Wherein, the Friedel-Crafts reaction reagent is aluminum trichloride.

[0054] The solvent is selected from dichloromethane, 1,2-dichloroethane, and n-heptane.

[0055] Most preferred is dichloromethane.

[0056] The present invention further provides a method for preparing oxcarbazepine, wherein oxcarbazepine is prepared from a compound of formula 10-1 under the action of a deprotecting agent and an acyluide reagent:

[0057] Wherein, the deprotection reagent is a base, and the base is an organic base or an inorganic base,

[0058] The inorganic base is sodium hydroxide or potassium hydroxide, and the organic base is triethylamine.

[0059] Most preferred is potassium hydroxide.

[0060] The deprotection reaction solvent is ethylene glycol.

[0061] Wherein, the ureide reagent is chlorosulfonyl isocyanate.

[0062] The ureide reaction solvent is dichloromethane.

[0063] A preferred embodiment of the above reaction is:

[0064] The compound of formula 4 is sequentially reacted with a ring-opening reagent, an esterification reagent, a protection reagent, a hydrolysis reagent, a chlorination reagent, a Friedel-Crafts reaction reagent, a deprotection reagent, and an acyluide reagent to prepare oxcarbazepine.

[0065] In the process of preparing the compound of formula 5 from the compound of formula 4,

[0066] Wherein, the ring-opening reagent is a base, and the base is an organic base or an inorganic base. The inorganic base is sodium hydroxide or potassium hydroxide, and the organic base is triethylamine, and most preferably sodium hydroxide.

[0067] The molar ratio of the base to the compound of formula 4 is (1-2):1, preferably (1.03-1.1):1.

[0068] During the process of preparing the compound of formula 6 from the compound of formula 5, an esterification reagent is added dropwise to carry out an esterification reaction to prepare the compound of formula 6.

[0069] The esterification reagent is diethyl sulfate or dimethyl sulfate.

[0070] Most preferred is diethyl sulfate.

[0071] The molar ratio of the esterification agent to the compound of formula 4 is (1.2-3):1, preferably (1.2-2.0):1.

[0072] In the process of preparing the compound of formula 7-1 from the compound of formula 6, the protecting reagent is acyl chloride / Lewis acid.

[0073] Wherein, the Lewis acid is zinc chloride, zinc bromide, aluminum chloride, cuprous iodide, nickel chloride, phosphorus pentoxide, titanium dioxide, and tetraisopropyl titanate.

[0074] Most preferred are zinc bromide and zinc chloride.

[0075] The molar ratio of the Lewis acid to the compound of formula 4 is (0.2-1):1, preferably (0.3-0.5):1.

[0076] Among them, the acid chloride is preferably acetyl chloride.

[0077] In the process of preparing the compound of formula 8-1 from the compound of formula 7-1, the hydrolysis reagent is a base,

[0078] The base is an organic base or an inorganic base. The inorganic base is sodium hydroxide, lithium hydroxide, or potassium hydroxide. The organic base is triethylamine, and most preferably sodium hydroxide.

[0079] Wherein, in the above reaction, the solvent is a single solvent or a mixed solvent of tetrahydrofuran, ethanol, 1,4-dioxane, dimethylformamide (DMF), acetone, dichloromethane, toluene, chlorobenzene, EA, acetonitrile, n-heptane, ethyl acetate, methanol, ethanol or water.

[0080] Most preferred are tetrahydrofuran, dimethylformamide (DMF), methanol or water.

[0081] The volume ratio of the solvent is (2-10):1, preferably (2-5):1.

[0082] In the process of preparing the compound of formula 10-1 from the compound of formula 8-1, the compound of formula 10-1 is prepared under the action of a chlorination reagent and a Friedel-Crafts reaction reagent.

[0083] Wherein, the chlorination reagent is thionyl chloride or oxalyl chloride,

[0084] Most preferred is thionyl chloride.

[0085] The Friedel-Crafts reaction reagent is aluminum trichloride.

[0086] Wherein, in the above reaction, the solvent is dichloromethane, 1,2-dichloroethane, or n-heptane.

[0087] Most preferred is dichloromethane.

[0088] In the process of preparing the compound of formula 11 from the compound of formula 10-1, under the action of a deprotecting agent,

[0089] The deprotection reagent is a base, which is an organic base or an inorganic base. The inorganic base is sodium hydroxide or potassium hydroxide, and the organic base is triethylamine.

[0090] Most preferred are potassium hydroxide and sodium hydroxide.

[0091] The deprotection reaction solution is ethylene glycol, water, methanol, ethanol or a mixed solvent thereof.

[0092] The most preferred are ethylene glycol and water.

[0093] In the process of preparing oxcarbazepine from the compound of formula 11, under the action of an acyluide reagent,

[0094] The ureide reagent is chlorosulfonyl isocyanate,

[0095] The ureide reaction solvent is dichloromethane.

[0096] In the preparation of the compound of formula 8, the present invention does not require the use of low-temperature conditions, and the operation is more friendly. In the prior art, there is no other technical inspiration and the same disclosure. The yield of the compound of formula 8-1 of the present invention is greater than 90%, which has made significant progress compared with journal literature, has substantial characteristics, and is creative.

[0097] In the ring-closure reaction step of the present invention, compound 10 was synthesized for the first time through acylation and Friedel-Crafts reaction, which has not been disclosed in the prior art. It has achieved a major technical breakthrough and is creative.

[0098] Finally, the present invention provides an efficient synthesis route for an oxcarbazepine intermediate, which uses N-phenylindole as a raw material and introduces new compounds 7 and 9 through different group protection forms, which has great creativity.

[0099] The one-pot method does not require separation or simple post-processing separation, and has industrial operability. The compound of formula 8 is prepared directly from the compound of formula 4, realizing a jump synthesis of multi-step reactions, breaking the limitations of the existing process. The compound of formula 8 is then used to continue the subsequent reaction, and a high conversion rate is achieved. For example, the process of preparing the compound of formula 10 from the compound of formula A through a ring-closing reaction, and finally preparing oxcarbazepine from the compound of formula 10, has a yield of ≥90%, which is unattainable in the prior art, and has achieved significant advantages in process production. At the same time, the materials used in the route of the present invention are relatively cheap, and it is also more advantageous in cost control, and has achieved great success in commercialization. BRIEF DESCRIPTION OF THE DRAWINGS

[0100] FIG1 is a diagram of the compound of formula 8-1 in Example 1 of the present invention. 1 H-NMR spectrum.

[0101] FIG2 is a graph showing the compound of formula 6 in Example 2 of the present invention. 1 H-NMR spectrum.

[0102] FIG3 is a graph showing the compound of formula 9-1 in Example 5 of the present invention. 1 H-NMR spectrum.

[0103] FIG4 is a graph showing the compound of formula 8-2 in Example 6 of the present invention. 1 H-NMR spectrum.

[0104] FIG5 is a graph showing the compound of formula 10-2 in Example 7 of the present invention. 1 H-NMR spectrum.

[0105] FIG6 is a graph showing the compound of formula 8-3 in Example 8 of the present invention. 1 H-NMR spectrum.

[0106] FIG7 is a graph showing the compound of formula 10-3 in Example 9 of the present invention. 1 H-NMR spectrum.

[0107] FIG8 is a graph showing the compound of formula 11 in Example 10 of the present invention. 1 H-NMR spectrum.

[0108] FIG9 is a graph showing the oxcarbazepine compound in Example 11 of the present invention. 1 H-NMR spectrum. DETAILED DESCRIPTION

[0109] In order to further understand the present invention, the present invention is described in detail below with reference to the embodiments. It should be understood that these embodiments are only for further illustrating the features of the present invention, and are not intended to limit the scope of the present invention or the scope of the claims of the present invention.

[0110] Example 1:

[0111] One-pot preparation of compound 8:

[0112] To a 500ml four-necked flask, add 50g (0.239mol) of compound 4, 125ml of THF, and 10.05g (0.251mol) of sodium hydroxide. Heat to reflux and react for 3-6 hours. TLC indicates the reaction is complete, yielding a solution of compound 5. Add 7.25g (0.072mol) of triethylamine and 55.27g (0.358mol) of diethyl sulfate to the reaction solution. Heat to 35-45°C and incubate for 2-5 hours. TLC indicates the reaction is complete. Distill under reduced pressure to dryness to yield compound 6. Add 125ml of DMF and stir at 20-30°C to dissolve. Add 93.79g (1.19mol) of acetyl chloride and 16.14g (0.072mol) of zinc bromide and control the temperature at 20-30°C. Incubate for 2-5 hours. TLC indicates the reaction is complete. Add 60ml of ethanol. Distill under reduced pressure until no droplets are visible to obtain compound 7-1. Add 250 ml of 80% methanol aqueous solution to the system, add 28.67 g (0.717 mol) of sodium hydroxide, and react at 25-35°C for 2-5 hours. TLC indicates the reaction is complete. Add 100 ml of water and 150 ml of EA. Separate the layers, and extract the aqueous layer once more with 150 ml of EA. Separate the layers, add hydrochloric acid to the aqueous layer, and adjust the pH to 3-5. After adjustment, filter, rinse with 100 ml of water, and dry to obtain 52.35 g of compound 8-1, with a yield of 81%. 1H NMR (400MHz, DMSO-d6) δ12.45 (s, 1H), 7.54-7.22 (m, 8H), 3.51 (s, 2H), 1.88 (s, 3H).

[0113] Example 2:

[0114] Add 5g (0.024mol) of compound 4, 12.5ml of THF, and 1.01g (0.025mol) of sodium hydroxide to a 100ml four-necked flask, heat to reflux, and react for 3-6h. TLC shows that the reaction is complete to obtain a solution of compound 5. Add 0.73g (0.007mol) of triethylamine and 5.53g (0.036mol) of diethyl sulfate to the reaction solution, heat to 35-45°C, and keep warm for 2-5h. TLC shows that the reaction is complete. Add dilute hydrochloric acid to quench the reaction and adjust the pH to 6-8. Extract twice with EA, combine the organic layers, and wash twice with water. Evaporate the organic layer to dryness to obtain 5.58g of oily compound 6 with a yield of 91%. 1 H NMR (400MHz, DMSO-d6) δ7.42 (s, 1H), 7.23-7.13 (m, 5H), 7.00-6.96 (m, 1H), 6.82-6.79 ( m, 2H), 6.75-6.71 (m, 1H), 4.01-3.95 (q, J=7.1Hz, 2H), 3.68 (s, 2H), 1.10-1.07 (t, 3H).

[0115] Example 3:

[0116] To a 100ml four-necked flask, add 5g (0.020mol) of compound 6 and 10ml of DMF. Add 7.69g (0.098mol) of acetyl chloride and 1.32g (0.006mol) of zinc bromide. Incubate at 20-30°C for 2-5h. TLC indicates the reaction is complete. Quench the reaction by adding 10ml of ethanol. Add 10ml of water and 20ml of EA. Separate the layers and extract once more with 20ml of EA. Combine the organic layers and concentrate to dryness under reduced pressure to obtain 5.20g of crude compound 7-1, with a yield of 89%.

[0117] Example 4:

[0118] To a 100ml four-necked flask, add 5g (0.017mol) of compound 7-1 and 25ml of 80% aqueous methanol. Add 2.02g (0.050mol) of sodium hydroxide. React at 25-35°C for 2-5h. TLC indicates the reaction is complete. Add 10ml of water and extract with 15ml of DCM. Separate the layers, and extract the aqueous layer once more with 15ml of DCM. Separate the layers, and add hydrochloric acid dropwise to the aqueous layer to adjust the pH to 3-5. Filter, rinse with 100ml of water, and dry to obtain 4.25g of compound 8-1, a 94% yield.

[0119] Example 5:

[0120] To a 250ml four-necked flask, add 2g (0.007mol) of compound 8-1, 20ml of DCM, and 0.1ml of DMF and stir. Add 1.32g (0.011mol) of thionyl chloride and allow to react at 25-35°C for 2-5h. TLC indicates the reaction is complete. Concentrate under reduced pressure to obtain 2.08g of compound 11-1, with a yield of 97%. Add 20ml of DCM and 1.97g (0.015mol) of aluminum trichloride and allow to react overnight at 20-30°C. TLC indicates the reaction is complete. Wash with 20ml of water and separate the layers. Evaporate the organic layer to dryness to obtain 1.52g of compound 9-1, with a total yield of 81%. 1 H NMR (400MHz, CDCl3) δ8.12-8.10 (d, J=7.9Hz, 1H), 7.61-7.57 (m, 2H), 7.41-7.32 (m, 5H), 4.37-4.33 (d, J=14.6Hz, 1H), 3.88-3.85 (d, J=14.6Hz, 1H), 2.12 (s, 3H).

[0121] Example 6:

[0122] To a 100ml four-necked flask, add 5g (0.020mol) of compound 6, 19ml of acetonitrile, and 9.00g of triethylamine. Add 9.28g (0.066mol) of benzoyl chloride. Reflux and react for 2-5h. TLC indicates the reaction is complete. Add 10ml of ethanol to quench the reaction. Add 10ml of water and 20ml of EA. Extract and separate the layers, and extract the water once more with 20ml of EA. Combine the organic layers and concentrate to dryness under reduced pressure. Add 15ml of 80% aqueous methanol and 2.7g (0.113mol) of lithium hydroxide. React at 25-35°C for 2-5h. TLC indicates the reaction is complete. Add 80ml of DCM and 80ml of water. Adjust the pH to 3-5. Separate the layers, and extract the aqueous layer with 60ml of DCM. Combine the organic layers and evaporate to dryness to obtain 6.1g of crude product. After column purification, 3.1 g of compound 8 (benzoyl substituted compound) (Formula 8-2) was obtained with a yield of 47.77%. 1 H NMR (400MHz, DMSO-d6) δ12.47 (s, 1H), 7.43-7.06 (m, 14H), 3.59 (s, 2H).

[0123] Example 7:

[0124] To a 100ml four-necked flask, add 3g (0.009mol) of compound 8 (Formula 8-2), 30ml of DCM, and 0.3ml of DMF. Stir, then add 1.24g (0.010mol) of thionyl chloride. Stir at room temperature for 1h. TLC indicates the reaction is complete. Evaporate to dryness under reduced pressure. Add 30ml of DCM, stir until clear, add 4.23g (0.032mol) of aluminum trichloride, and reflux for 5-6h. TLC indicates the reaction is complete. Add 30ml of water, let stand to separate, and extract the aqueous layer with 15ml of DCM. Combine the organic layers, wash with 15ml of 5% hydrochloric acid, then with 15ml of 5% aqueous sodium bicarbonate solution. Concentrate the organic layers to dryness under reduced pressure to obtain 2.32g of compound 10 (Formula 10-2), with a yield of 81.81%. 1 H NMR (400MHz, DMSO-d6) δ7.98-7.96 (dd, J=7.8, 1.6Hz, 1H), 7.50-7.24 (m, 12H), 4.82-4.78 (d, J=15.0Hz, 1H), 3.97-3.94 (d, J=15.0Hz, 1H).

[0125] Example 8:

[0126] To a 100ml four-necked flask, add 2g (0.008mol) of compound 6, 8ml of acetonitrile, and 3.2g of triethylamine. Add 4.12g (0.024mol) of 4-chlorobenzoyl chloride. Reflux and react for 2-5h. TLC indicates the reaction is complete. Concentrate the reaction solution directly and purify it by column chromatography. Obtain 1.5g of the p-chlorobenzoyl substituted compound 7. Add 14ml of 80% aqueous methanol and 0.23g of lithium hydroxide. React at 25-35°C for 2-5h. TLC indicates the reaction is complete. Add 10ml of DCM and 10ml of water. Separate the layers, adjust the pH of the aqueous layer to 2-5, and extract once with 20ml of DCM. Separate the layers, and wash the organic layer twice with water. Evaporate the organic layer to dryness to obtain 1g of the p-chlorobenzoyl substituted compound 8 (Formula 8-3). 1 H NMR (400MHz, DMSO-d6) δ12.48 (s, 1H), 7.95-7.93 (dd, J=6.7, 2.0Hz, 1H), 7.58-7.56 (dd, J=6.7, 2.0Hz, 1H), 7.45-7.09 (m, 11H), 3.58 (s, 2H).

[0127] Example 9:

[0128] To a 100ml four-necked flask, add 0.51g (0.001mol) of the p-chlorobenzoyl substituted compound 8 (Formula 8-3), 5ml of DCM, and 0.1ml of DMF. Stir, then add 0.25g (0.002mol) of thionyl chloride and stir at room temperature for 1h. TLC indicates the reaction is complete. Evaporate to dryness under reduced pressure. Add 10ml of DCM and 0.65g (0.005mol) of aluminum trichloride, and reflux for 2-6h. TLC indicates the reaction is complete. Add 5ml of water, let stand to separate, and extract the aqueous layer with 5ml of DCM. Combine the organic layers, wash with 5ml of 5% hydrochloric acid, then with 5ml of 5% aqueous sodium bicarbonate solution. Concentrate the organic layers to dryness under reduced pressure to obtain 0.40g of the p-chlorobenzoyl substituted compound 10 (Formula 10-3), with a yield of 82.31%. 1 H NMR (400MHz, DMSO-d6) δ 8.05-8.02 (dd, J=8.6, 1.6Hz, 1H), 7.55-7.33 (m, 11H), 4.91-4.87 (d, J=15.0Hz, 1H), 4.02-3.98 (d, J=15.1Hz, 1H).

[0129] Example 10:

[0130] To a 100ml four-necked flask, add 5.00g (0.020mol) of compound 10-1, 1.58g (0.024mol) of potassium hydroxide, and 10ml of ethylene glycol. Heat to 160°C and maintain for 2-5h. TLC indicates the reaction is complete. Cool, add 10ml of water and 10ml of DCM, and stir to separate the layers. Extract the aqueous layer once with 15ml of DCM and separate the layers. Combine the organic layers and wash with water until neutral. Concentrate the organic layer to dryness under reduced pressure to yield 3.89g of compound 11, a 93% yield. 1 H NMR (400MHz, DMSO-d6) δ9.43 (s, 1H), 7.80-7.77 (dd, J=8.0, 1.6Hz, 1H), 7.49-7.44 (m, 1H), 7.37-7 .35(dd, J=8.3, 0.7Hz, 1H), 7.31-7.23(m, 3H), 7.15-7.11(m, 1H), 6.89-6.85(m, 1H), 3.68(s, 2H).

[0131] Example 11:

[0132] In a 250ml four-necked flask, add 5.00g (0.024mol) of compound 11 and 30ml of DCM, protect with nitrogen, and stir at room temperature to dissolve. Cool to -10°C, add 6.76g (0.048mol) of chlorosulfonyl isocyanate, and keep warm for 1-3h. TLC shows that the reaction is complete. Add 30ml of water to quench the reaction. Add 10% aqueous sodium hydroxide solution to adjust the pH to 6-8. Separate the layers, extract the aqueous layer once with 25ml of DCM, and separate the layers. Combine the organic layers and wash once with 25ml of water. Concentrate the organic layer under reduced pressure to dryness. Add 40ml of toluene, heat and reflux, then cool to 0-5°C, filter, rinse with 5ml of toluene, and dry to obtain 5.44g of oxcarbazepine, with a yield of 90%. 1 H NMR (400MHz, DMSO-d6) δ7.92-7.90 (d, J=7.9Hz, 1H), 7.64-7.63 (d, J=3.6Hz, 1H), 7.50-7.44 (m, 2H), 7.38-7.30 (m, 3H), 6.17 (s, 2H), 4.32-4.29 (d, J=13.6Hz, 1H), 3.83-3.80 (d, J=13.8Hz, 1H).

Claims

1. A compound of formula A, characterized in that The structural formula is: Among them, R3 is OR1 or R2, R1 is C2-C6 alkyl or substituted alkyl or Na, K, Li, R2 is Cl or -OCOR5, R5 is C1-C6 alkyl or substituted alkyl, aryl, substituted aryl, phenyl, benzyl or substituted benzyl, and R4 is C1-C6 alkyl, substituted alkyl, aryl, substituted aryl, benzyl, or substituted benzyl.

2. The compound according to claim 1, characterized in that R3 is OR1, R1 is C2-C6 alkyl or substituted alkyl, and R4 is C1-C6 alkyl, substituted alkyl, aryl, substituted aryl, benzyl, or substituted benzyl.

3. The compound according to claim 1, characterized in that Wherein, R2 is Cl or -OCOR5, R5 is C1-C6 alkyl or substituted alkyl, aryl, substituted aryl, phenyl, benzyl or substituted benzyl, and R4 is C1-C6 alkyl, substituted alkyl, aryl, substituted aryl, benzyl, or substituted benzyl.

4. A method for preparing a compound of formula A, characterized in that: The compound of formula A is prepared from the compound of formula 4 in the presence of a ring-opening reagent, and optionally in the presence of an esterification reagent, a protection reagent, a hydrolysis reagent, and a chlorination reagent. Among them, R3 is OR1 or R2, R1 is C1-C6 alkyl or substituted alkyl, hydrogen or Na, K, Li, R2 is Cl or -OCOR5, R5 is C1-C6 alkyl or substituted alkyl, aryl, substituted aryl, phenyl, benzyl or substituted benzyl, and R4 is C1-C6 alkyl, substituted alkyl, aryl, substituted aryl, benzyl, substituted benzyl.

5. The preparation method according to claim 4, characterized in that: The compound of formula 7 is prepared from the compound of formula 4 in the presence of a ring-opening reagent, and optionally in the presence of an esterification reagent and a protecting reagent. Wherein, R1 is C1-C6 alkyl or substituted alkyl, hydrogen or Na, K, Li.

6. The preparation method according to claim 4, characterized in that: The compound of formula 8-1 is prepared from the compound of formula 4 in the presence of a ring-opening reagent, and optionally in the presence of an esterification reagent, a protection reagent, and a hydrolysis reagent.

7. The preparation method according to any one of claims 1 to 6, characterized in that: The ring-opening reagent is a base.

8. The preparation method according to any one of claims 1 to 6, characterized in that: The esterification agent is SO2(OR6)2, R6 is a C1-C6 alkyl or substituted alkyl; or XR7, X is I, Br or Cl, R7 is a C1-C6 alkyl or substituted alkyl; or CO(OR8)2, R8 is a C1-C6 alkyl or substituted alkyl.

9. The preparation method according to any one of claims 4 to 6, characterized in that: The protecting reagent is an acyl chloride reagent or an acyl chloride reagent / Lewis acid.

10. The preparation method according to any one of claims 1 to 6, characterized in that: The hydrolysis agent is a base.

11. The preparation method according to claim 9, characterized in that: The acyl chloride reagent is methoxycarbonyl chloride, acetyl chloride, C2-C6 alkyl or substituted alkylcarbonyl chloride, benzoyl chloride, trifluoroacetyl, substituted benzoyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride, substituted benzenesulfonyl chloride; the Lewis acid is zinc chloride, zinc bromide, ferric chloride, aluminum chloride, ethylaluminum chloride, ethylmagnesium chloride, cuprous iodide, nickel chloride, phosphorus pentoxide, titanium dioxide or tetraisopropyl titanate.

12. The preparation method according to any one of claims 1 to 6, characterized in that: The reaction is carried out in the presence of a solvent, which is a single solvent or a mixed solvent of tetrahydrofuran, ethanol, 1,4-dioxane, dimethylformamide (DMF), acetone, dichloromethane, toluene, chlorobenzene, EA, acetonitrile, n-heptane, ethylene glycol, ethyl acetate, methanol, ethanol or water.

13. A method for preparing a compound of formula 10, characterized in that: The compound of formula 10 is prepared from the compound of formula A through a ring-closing process, Wherein, R3' is OR1' or R2, R1' is hydrogen, R2 is Cl or -OCOR5, R5 is C1-C6 alkyl or substituted alkyl, aryl, substituted aryl, phenyl, benzyl or substituted benzyl; R4 is defined as in claim 4.

14. The preparation method according to claim 13, characterized in that: The compound of formula 10-1 is prepared from the compound of formula 8-1 through a ring-closing process, 15. The preparation method according to claim 13, characterized in that: The compound of formula 10-1 is prepared from the compound of formula 9-1 through a ring-closing process, 16. A method for preparing oxcarbazepine, characterized in that: Oxcarbazepine is prepared by a ring-closing process of the compound of formula A, followed by deprotection and ureidation reaction. The definitions of R3 and R4 are the same as those in claim 4.

17. The preparation method according to any one of claims 13 to 16, characterized in that: The ring-closing process comprises acylation with a chlorination reagent and then ring-closing through a Friedel-Crafts reaction.

18. A method for preparing oxcarbazepine, characterized in that: Oxcarbazepine is prepared from the compound of formula 4 in the presence of a ring-opening reagent, an esterification reagent, a protection reagent, a hydrolysis reagent, a chlorination reagent followed by a Friedel-Crafts reaction reagent for ring closure, a deprotection reagent, and an acyluide reagent.

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