Oxcarbazepine intermediate compound and preparation method thereof

Abstract

The invention relates to the field of medicine synthesis, in particular to a preparation method of an oxcarbazepine key intermediate. Specifically, a compound of a formula 4 is selectively prepared into a compound of a formula A under the action of a ring-opening reagent, an esterification reagent, a protection reagent, a hydrolysis reagent and a chlorination reagent, then the compound of the formula A is subjected to a ring closing reaction to prepare a compound of a formula 10, and finally oxcarbazepine is prepared from the compound of the formula 10. The route provided by the invention realizes a high conversion rate, and has more advantages in cost control. In the reaction formula, R3 is OR1 or R2, R1 is hydrogen, C1-C6 alkyl or substituted alkyl or Na, K and 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.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemical industry, and specifically relates to a key intermediate for preparing oxcarbazepine and a preparation method thereof. Background Art

[0002] The national new anti-epileptic drug - oxcarbazepine is an upgraded product of carbamazepine. It has good anti-epileptic, anti-trigeminal neuralgia and affective psychosis effects, definite efficacy and few side effects. It is currently mainly used as a first-line anti-epileptic drug.

[0003] Prior art, such as the journal document Tetrahedron Letters (2004), 45 (27), 5275-5278, discloses a synthetic process route for oxcarbazepine and its intermediate (2-(acetylphenylamino)phenylacetic acid). However, the yield is low when preparing this intermediate (the compound of formula 8-1 of the present invention). The use of n-butyl lithium reagent requires low temperature (-10°C) and moisture control, which are harsh conditions, and the reagent cost is expensive. At the same time, phosgene is used as an acylating agent in the preparation process, which poses a great risk in industrialization and is difficult to achieve industrial production. When the intermediate is used to prepare the compound of formula 10 of the present invention, the corresponding product cannot be obtained. As a result, it is impossible to achieve industrial preparation of the compound of formula 10 of the present invention and the subsequent product oxcarbazepine.

[0004] In addition, Novartis disclosed another synthetic route in its international patent application (WO2001056992) applied for in February 2001:

[0005]

[0006] Specifically, N-phenylindole is used as the starting material to synthesize the key intermediate 10-methoxyiminostilbene, and oxcarbazepine is prepared through six steps of reaction. The reaction steps of this route are relatively long, and the reaction process is accompanied by the production of many by-products. The finished product also needs to be refined, which loses yield. Among them, n-butyl lithium reagent is used, which requires low temperature and moisture control, the conditions are relatively harsh, and the reagent cost is relatively expensive. In view of the shortcomings of the existing technology, it is necessary to develop and prepare a route with more technical advantages and suitable for industrial scale. Summary of the invention

[0007] The invention provides an oxcarbazepine synthesis route with higher conversion rate and greater advantages in cost control.

[0008] In order to achieve the technical purpose of the present invention, the technical solution of the present invention is:

[0009] The present invention first provides a compound of formula A, the structural formula of which is:

[0010]

[0011] Among them, R 3 OR 1 or R 2 ,R 1 is C2-C6 alkyl or substituted alkyl or Na, K, Li; R 2 Cl or -OCOR 5 , R 5 is C1-C6 alkyl or substituted alkyl, aryl, substituted aryl, phenyl, benzyl or substituted benzyl; R 4 It is C1-C6 alkyl, substituted alkyl, aryl, substituted aryl, benzyl, substituted benzyl.

[0012] Among them, preferably, R 3 OR 1 ,R 1 is a C2-C6 alkyl group or a substituted alkyl group, R 4 It is a C1-C6 alkyl group or a substituted alkyl group.

[0013] Among them, preferably, R 3 For R 2 ,R 2 Cl or -OCOR 5 , R 5 is C1-C6 alkyl or substituted alkyl, aryl, substituted aryl, phenyl, benzyl or substituted benzyl, R 4 It is a C1-C6 alkyl group or a substituted alkyl group.

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

[0015]

[0016] Among them, R 4 is C1-C6 alkyl or substituted alkyl, aryl, substituted aryl, R 1 It is a C2-C6 alkyl group or a substituted alkyl group.

[0017] Preferably, a compound of formula 9 is provided, the structural formula is:

[0018]

[0019] Among them, R 2 Cl, R 4 It is C1-C6 alkyl or substituted alkyl, aryl, or substituted aryl.

[0020] 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 protection reagent, a hydrolysis reagent, and a chlorination reagent:

[0021]

[0022] Among them, R 4 is C1-C6 alkyl, substituted alkyl, aryl, substituted aryl, benzyl, substituted benzyl; R 3 Can be OR 1 or R 2 ; R 1 is hydrogen, C1-C6 alkyl or substituted alkyl, Na, K, Li, etc.; R 2 Cl or -OCOR 5 , R 5 It can be a C1-C6 alkyl or substituted alkyl, aryl, substituted aryl, phenyl, benzyl or substituted benzyl, substituted benzyl, and the like.

[0023] 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.

[0024] 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 protection reagent, and a hydrolysis reagent:

[0025]

[0026] Among them, R 4 It can be C1-C6 alkyl or substituted alkyl, aryl, substituted aryl, R 1 It is hydrogen, C1-C6 alkyl or substituted alkyl, Na, K, Li, etc.

[0027] Preferably, the compound of formula 4 is prepared in turn under the action of sodium hydroxide, diethyl sulfate, acetyl chloride / Lewis acid, and sodium hydroxide to obtain the compound of formula 8-1:

[0028]

[0029] Specifically, when preparing the compound of the following formula 8,

[0030]

[0031] Among them, R 4 is C1-C6 alkyl or substituted alkyl, aryl, substituted aryl, R 1 For hydrogen.

[0032] 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.

[0033] Most preferred is sodium hydroxide.

[0034] The molar ratio of the base to the compound of formula 4 is (1-2):1, preferably (1.03-1.1):1.

[0035] The above esterification reagent is SO 2 (OR 6 ) 2 , R 6 is C1-C6 alkyl or substituted alkyl; or XR 7 , X is I, Br or Cl, R 7 is C1-C6 alkyl or substituted alkyl; or CO(OR 8 ) 2 , R 8 It is a C1-C6 alkyl or substituted alkyl, preferably diethyl sulfate, dimethyl sulfate, and most preferably diethyl sulfate.

[0036] The molar ratio of the esterification agent to the compound of formula 4 is (1.2-3):1, preferably (1.2-2.0):1.

[0037] The above-mentioned protecting reagent is an acyl chloride reagent or an acyl chloride reagent / Lewis acid.

[0038] Wherein, 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-toluoyl chloride, etc.), methanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride, substituted benzenesulfonyl chloride (such as p-nitrobenzenesulfonyl chloride, p-toluenesulfonyl 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.

[0039] 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.

[0040] 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.

[0041] Most preferred is sodium hydroxide.

[0042] The molar ratio of the hydrolysis agent to the compound of formula 4 is (1-2):1, preferably (1.03-1.1):1.

[0043] The above reaction is carried out in the presence of a solvent.

[0044] 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,

[0045] Most preferred are tetrahydrofuran, dimethylformamide (DMF), methanol or water.

[0046] The volume ratio of the solvent is (2-5):1, preferably (2-3):1.

[0047] 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:

[0048]

[0049] Among them, R 3 'For OR 1 ' or R 2 ,R 1 ' is hydrogen, R 2 Cl or -OCOR 5 , R 5 is C1-C6 alkyl or substituted alkyl, aryl, substituted aryl, phenyl, benzyl or substituted benzyl; R 4 It can be a C1-C6 alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, a benzyl group, or a substituted benzyl group.

[0050] Preferably, the compound of formula 10-1 is prepared by first subjecting the compound of formula A to a chlorination agent and then to a Friedel-Crafts reaction agent:

[0051] Where R 3 'For OR 1 ' or R 2 ,R 1 ' is hydrogen, R 2 Cl or -OCOR 5 , R 5 is C1-C6 alkyl or substituted alkyl, aryl, substituted aryl, phenyl, benzyl or substituted benzyl; R 4 It is methyl.

[0052] 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.

[0053] More preferably, the compound of formula 8-1 is prepared by reacting a chlorinating agent to obtain the compound of formula 9-1.

[0054]

[0055] Specifically, the present invention provides a method for preparing a compound of formula 9-1 by using a compound of formula 8-1 in a solvent under the action of a chlorinating agent.

[0056] Wherein, the chlorination reagent is thionyl chloride or oxalyl chloride.

[0057] Most preferred is thionyl chloride.

[0058] The solvent is selected from dichloromethane and n-heptane,

[0059] Most preferred is dichloromethane.

[0060] More preferably, the present invention provides a method for preparing a compound of formula 10-1 by treating a compound of formula 9-1 with a Friedel-Crafts reaction reagent.

[0061]

[0062] Wherein, the Friedel-Crafts reaction reagent is aluminum trichloride.

[0063] The solvent is selected from dichloromethane, 1,2-dichloroethane, and n-heptane.

[0064] Most preferred is dichloromethane.

[0065] 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 agent:

[0066]

[0067] Wherein, the deprotection reagent is a base, and the base is an organic base or an inorganic base,

[0068] The inorganic base is sodium hydroxide or potassium hydroxide, and the organic base is triethylamine.

[0069] Most preferred is potassium hydroxide.

[0070] The deprotection reaction solvent is ethylene glycol.

[0071] Wherein, the ureide reagent is chlorosulfonyl isocyanate.

[0072] The ureide reaction solvent is dichloromethane.

[0073] A preferred embodiment of the above reaction is:

[0074] 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.

[0075] In the process of preparing the compound of formula 5 from the compound of formula 4,

[0076]

[0077] 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 the most preferred is sodium hydroxide.

[0078] The molar ratio of the base to the compound of formula 4 is (1-2):1, preferably (1.03-1.1):1.

[0079] In the process of preparing the compound of formula 6 from the compound of formula 5, an esterification agent is added dropwise to carry out an esterification reaction to prepare the compound of formula 6.

[0080]

[0081] The esterification agent is diethyl sulfate or dimethyl sulfate.

[0082] Most preferred is diethyl sulfate.

[0083] The molar ratio of the esterification agent to the compound of formula 4 is (1.2-3):1, preferably (1.2-2.0):1.

[0084] 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.

[0085]

[0086] Wherein, the Lewis acid is zinc chloride, zinc bromide, aluminum chloride, cuprous iodide, nickel chloride, phosphorus pentoxide, titanium dioxide, and tetraisopropyl titanate.

[0087] The most preferred are zinc bromide and zinc chloride.

[0088] The molar ratio of the Lewis acid to the compound of formula 4 is (0.2-1):1, preferably (0.3-0.5):1.

[0089] Among them, the acid chloride is preferably acetyl chloride.

[0090] In the process of preparing the compound of formula 8-1 from the compound of formula 7-1, the hydrolysis agent is a base,

[0091]

[0092] Wherein, the base is an organic base or an inorganic base. The inorganic base is sodium hydroxide, lithium hydroxide, potassium hydroxide, and the organic base is triethylamine, and the most preferred is sodium hydroxide.

[0093] 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. The most preferred solvent is tetrahydrofuran, dimethylformamide (DMF), methanol or water.

[0094] The volume ratio of the solvent is (2-10):1, preferably (2-5):1.

[0095] 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.

[0096]

[0097] Wherein, the chlorination reagent is thionyl chloride or oxalyl chloride.

[0098] Most preferred is thionyl chloride.

[0099] The Friedel-Crafts reaction reagent is aluminum trichloride.

[0100] Wherein, in the above reaction, the solvent is dichloromethane, 1,2-dichloroethane, or n-heptane.

[0101] Most preferred is dichloromethane.

[0102] In the process of preparing the compound of formula 11 from the compound of formula 10-1, under the action of a deprotecting agent,

[0103]

[0104] The deprotection 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.

[0105] The most preferred are potassium hydroxide and sodium hydroxide.

[0106] The deprotection reaction solution is ethylene glycol, water, methanol, ethanol or a mixed solvent thereof.

[0107] The most preferred are ethylene glycol and water.

[0108] In the process of preparing oxcarbazepine from the compound of formula 11, under the action of an acyluide reagent,

[0109]

[0110] The ureide reagent is chlorosulfonyl isocyanate,

[0111] The ureide reaction solvent is dichloromethane.

[0112] In the preparation of the compound of formula 8, the present invention does not need to use 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.

[0113] In the ring-closing 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, has achieved a major technical breakthrough and is creative.

[0114] Finally, the present invention provides an efficient synthesis route for an oxcarbazepine intermediate, which uses N-phenylindolone as a raw material and introduces new compounds 7 and 9 through different group protection forms, and has great creativity.

[0115] It is industrially feasible through a one-pot method without separation or simple post-treatment separation. The compound of formula 8 is prepared directly from the compound of formula 4, realizing the jump synthesis of multi-step reactions and 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 price of the materials used in the route of the present invention is relatively cheap, and it is also more advantageous in cost control, and has achieved great success in commercialization. BRIEF DESCRIPTION OF THE DRAWINGS

[0116] Figure 1 is the compound of formula 8-1 in Example 1 of the present invention 1 H-NMR spectrum.

[0117] Figure 2 is the compound of formula 6 in Example 2 of the present invention 1 H-NMR spectrum.

[0118] Figure 3 is the compound of formula 9-1 in Example 5 of the present invention 1 H-NMR spectrum.

[0119] Figure 4 is the compound of formula 8-2 in Example 6 of the present invention 1 H-NMR spectrum.

[0120] Figure 5 is the compound of formula 10-2 in Example 7 of the present invention 1 H-NMR spectrum.

[0121] Figure 6 is the compound of formula 8-3 in Example 8 of the present invention1 H-NMR spectrum.

[0122] Figure 7 is the compound of formula 10-3 in Example 9 of the present invention 1 H-NMR spectrum.

[0123] Figure 8 is the compound of formula 11 in Example 10 of the present invention 1 H-NMR spectrum.

[0124] Fig. 9 is the oxcarbazepine compound in Example 11 of the present invention 1 H-NMR spectrum. DETAILED DESCRIPTION

[0125] In order to further understand the present invention, the present invention is described in detail below in conjunction with the embodiments. It should be understood that these embodiments are only for further describing the features of the present invention in detail, and are not intended to limit the scope of the present invention or the scope of the claims of the present invention.

[0126] Embodiment 1:

[0127] One-pot preparation of compound 8:

[0128] Add 50g (0.239mol) of compound 4, 125ml of THF, and 10.05g (0.251mol) of sodium hydroxide to a 500ml four-necked bottle, heat to reflux, and react for 3-6h. TLC, the reaction is complete, and a solution of compound 5 is obtained. Add 7.25g (0.072mol) of triethylamine and 55.27g (0.358mol) of diethyl sulfate to the reaction solution, heat to 35-45℃, and keep warm for 2-5h. TLC, the reaction is complete. Distill to dryness under reduced pressure to obtain compound 6. Add 125ml of DMF, stir at 20-30℃ 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℃. Keep warm for 2-5h. TLC, the reaction is complete. Add 60ml of ethanol. Distill under reduced pressure until no obvious droplets are found 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, react at 25-35°C for 2-5 hours, TLC, the reaction is complete. Add 100 ml of water and 150 ml of EA. Layer the layers, and extract the water layer with 150 ml of EA again. Layer the layers, add hydrochloric acid to the water layer, and adjust the pH to 3-5. After adjustment, filter with suction, 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).

[0129] Embodiment 2:

[0130] 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, the reaction is complete, and a solution of compound 5 is obtained. 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, the reaction is complete. Add dilute hydrochloric acid to quench the reaction and adjust the pH to 6-8. Add EA to extract twice, combine the organic layers, and wash with water twice. 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).

[0131] Embodiment 3:

[0132] Add 5g (0.020mol) of compound 6 and 10ml of DMF to a 100ml four-necked bottle. Add 7.69g (0.098mol) of acetyl chloride and 1.32g (0.006mol) of zinc bromide. Keep the reaction at 20-30℃ for 2-5h. TLC shows that 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 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%.

[0133] Embodiment 4:

[0134] Add 5g (0.017mol) of compound 7-1 and 25ml of 80% methanol aqueous solution to a 100ml four-necked bottle. Add 2.02g (0.050mol) of sodium hydroxide. React at 25-35℃ for 2-5h, TLC, the reaction is complete. Add 10ml of water and extract with 15ml of DCM. Separate the layers, and extract the water layer with 15ml of DCM again. Separate the layers, add hydrochloric acid dropwise to the water layer, and adjust the pH to 3-5. After adjustment, filter, rinse with 100ml of water, and dry to obtain 4.25g of compound 8-1, with a yield of 94%.

[0135] Embodiment 5:

[0136] Add 2g (0.007mol) of compound 8-1, 20ml of DCM, and 0.1ml of DMF to a 250ml four-necked bottle and stir. Add 1.32g (0.011mol) of thionyl chloride and keep at 25-35℃ for 2-5h. TLC shows that the reaction is over. 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 chloride, and react at 20-30℃ overnight. TLC shows that the reaction is over. Add 20ml of water to wash 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 (400 MHz, CDCl 3 )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).

[0137] Embodiment 6:

[0138]

[0139] Add 5g (0.020mol) of compound 6, 19ml of acetonitrile, and 9.00g of triethylamine to a 100ml four-necked flask. Add 9.28g (0.066mol) of benzoyl chloride. Reflux and react for 2-5h. TLC, the reaction is over. 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 with 20ml of EA. Combine the organic layers and concentrate to dryness under reduced pressure. Add 15ml of 80% methanol aqueous solution and 2.7g (0.113mol) of lithium hydroxide. React at 25-35℃ for 2-5h, TLC, the reaction is over. 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 (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).

[0140] Embodiment 7:

[0141]

[0142] Add 3g (0.009mol) of compound 8 benzoyl substituted (Formula 8-2), 30ml DCM, 0.3ml DMF to a 100ml four-necked bottle, stir, add 1.24g (0.010mol) thionyl chloride, stir at room temperature for 1h. TLC, the reaction is complete. Evaporate to dryness under reduced pressure. Add 30ml DCM, stir to dissolve, add 4.23g (0.032mol) aluminum chloride, reflux and keep warm for 5-6h. TLC, the reaction is complete. Add 30ml water, stand and separate, and extract the water layer with 15ml DCM. Combine the organic layers, wash with 15ml 5% hydrochloric acid, and then wash with 15ml 5% sodium bicarbonate aqueous solution. The organic layer is concentrated to dryness under reduced pressure to obtain 2.32g of compound 10 benzoyl substituted (Formula 10-2), with a yield of 81.81%. 1 HNMR (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).

[0143] Embodiment 8:

[0144]

[0145] Add 2g (0.008mol) of compound 6, 8ml of acetonitrile, and 3.2g of triethylamine to a 100ml four-necked flask. Add 4.12g (0.024mol) of 4-chlorobenzoyl chloride. Reflux and react for 2-5h. TLC, the reaction is over. The reaction solution is directly concentrated and purified by column. 1.5g of compound 7 p-chlorobenzoyl substituent is obtained. Add 14ml of 80% methanol aqueous solution and 0.23g of lithium hydroxide. React at 25-35℃ for 2-5h, TLC, the reaction is over. Add 10ml of DCM and 10ml of water. Separate the layers, adjust the pH of the aqueous layer to 2-5, and add 20ml of DCM to extract once. Separate the layers, and wash the organic layer with water twice. Evaporate the organic layer to dryness to obtain 1g of compound 8 p-chlorobenzoyl substituent (Formula 8-3). 1 HNMR (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).

[0146] Embodiment 9:

[0147]

[0148] Add 0.51g (0.001mol) of compound 8 p-chlorobenzoyl substituent (Formula 8-3), 5ml DCM, 0.1ml DMF to a 100ml four-necked flask, stir, add 0.25g (0.002mol) of thionyl chloride, stir at room temperature for 1h. TLC, the reaction is complete. Evaporate to dryness under reduced pressure. Add 10ml DCM, add 0.65g (0.005mol) of aluminum chloride, reflux and keep warm for 2-6h. TLC, the reaction is complete. Add 5ml of water, stand and separate, and extract the water layer with 5ml DCM. Combine the organic layers, wash with 5ml 5% hydrochloric acid, and then wash with 5ml 5% sodium bicarbonate aqueous solution. The organic layer is concentrated to dryness under reduced pressure to obtain 0.40g of compound 10 p-chlorobenzoyl substituent (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).

[0149] Embodiment 10:

[0150] Add 5.00g (0.020mol) of compound 10-1, 1.58g (0.024mol) of potassium hydroxide, and 10ml of ethylene glycol to a 100ml four-necked bottle. Heat to 160°C and keep warm for 2-5h. TLC shows that the reaction is complete. Cool down, add 10ml of water and 10ml of DCM, and stir to separate the layers. Extract the water layer once with 15ml of DCM and separate the layers. Combine the organic layers and wash with water until neutral. Concentrate the organic layer under reduced pressure to dryness to obtain 3.89g of compound 11, with a yield of 93%. 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).

[0151] Embodiment 11:

[0152] In a 250ml four-necked bottle, 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, the reaction is over. Add 30ml of water to quench the reaction. Add 10% sodium hydroxide aqueous 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 to dryness under reduced pressure. Add 40ml of toluene, heat to 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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