Preparation method of hydroxy substituted dibenzazepine compounds

Abstract

The present invention relates to the field of pharmaceutical synthesis, and in particular to a method for preparing a hydroxy-substituted dibenzazepine #imgabs0# compound. The process for preparing a hydroxy-substituted dibenzazepine #imgabs1# compound of the present invention includes three steps: a nucleophilic addition reaction of an aldehyde compound, a reduction reaction of a nitro group, and a carbon-nitrogen coupling reaction. The entire route has the technical advantages of high product yield and high purity, and has the prospect of industrial scale-up application. #imgabs2#

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical synthesis, and in particular to hydroxy-substituted dibenzazepines Preparation method of compounds. Background Art

[0002] Hydroxy-substituted dibenzazepines These compounds are intermediates of both carbamazepine and oxcarbazepine.

[0003] Carbamazepine, also known as 5H-dibenzo[b,f]azepine in Chinese -5-Carboxamide is an anti-epileptic drug that is most effective for psychomotor seizures, and is also effective for grand mal seizures, localized seizures, and mixed epilepsy. It is particularly suitable for epilepsy with mental symptoms to alleviate mental abnormalities. The structural formula of carbamazepine is shown below:

[0004]

[0005] Oxcarbazepine is called Oxcarbazepine in English and its chemical name is 10,11-dihydro-10-oxo-5H-dibenzo[b,f]azepine-5-carboxamide. Oxcarbazepine is a 10-keto derivative of carbamazepine and its efficacy is similar to or slightly stronger than that of carbamazepine. Oxcarbazepine and its metabolites have anticonvulsant activity and highly selective inhibitory effects on cerebral cortical movement. Its role may be to block the voltage-dependent sodium channels of brain cells, thereby preventing the spread of lesion discharges.

[0006]

[0007] Chinese Journal of Pharmaceutical Industry, 2006, 37(7), 443-444. 2,2'-bis(2-nitrophenyl)ethane was obtained by condensation of o-nitrotoluene with formate and strong base, and then reduced and phosphorylated to obtain 2,2'-bis(2-aminophenyl)ethane diphosphate. 10,11-dihydro-5H-dibenzo[b,f]azepine was prepared by cyclization at 260-300℃. . Then, 5-chloroformyl iminostilbene is obtained by chlorination, bromination and elimination, and then oxcarbazepine is prepared by bromination addition, methoxylation, formiation and hydrolysis demethylation, with a total yield of 14.8%. This method for preparing 10-methoxyiminostilbene from o-nitrotoluene has a long route, cumbersome operation, high cyclization reaction temperature, low yield, low product purity, cumbersome purification, large amount of three wastes, and is not suitable for industrial production.

[0008]

[0009] The Chinese patent application filed by Xinfa Pharmaceutical Co., Ltd. on June 6, 2018, with publication number CN110563652A, discloses a method for preparing carbamazepine, specifically: in solvent A, under the action of an acid-binding agent, a compound of formula II and 2-halogenated benzonitrile undergo a substitution reaction to prepare a compound of formula III; in solvent B, under the action of a base 1, the compound of formula III undergoes an intramolecular condensation reaction, and then undergoes a hydrolysis reaction in the presence of water, and is acidified with hydrochloric acid to obtain a compound of formula I; in solvent C, the compound of formula I undergoes a reduction reaction under the action of a reducing agent to reduce the carbonyl group to a hydroxyl group, and then is acidified with hydrochloric acid to obtain a compound of formula IV, wherein R4 in the structural formula of the compound of formula IV is -CONH2, and the compound of formula IV is carbamazepine.

[0010]

[0011] The above preparation method requires that the raw materials have amide groups at the very beginning, which does not meet the requirements for industrial scale-up.

[0012] In view of the prior art, hydroxy-substituted dibenzazepine The properties of these compounds critically determine the feasibility of subsequent processes. It is necessary to study and obtain preparation processes with more technological advantages to meet the needs of green pharmaceutical production. Summary of the invention

[0013] In order to develop more hydroxy-substituted dibenzazepines with competitive advantages The present invention has conducted a series of studies on the preparation process of the compound, and finally obtained a preparation process with high yield and industrial scale-up production potential. In order to achieve the technical purpose of the present invention, the technical solution of the present invention is:

[0014] First, the present invention provides a new intermediate compound A, the structural formula of which is as follows:

[0015]

[0016] The compound of formula B can be further prepared by CN coupling reaction,

[0017]

[0018] The specific reaction conditions of the CN coupling reaction are: the reaction is carried out in the presence of a metal catalyst and a bidentate phosphine ligand. The metal catalyst may be palladium, copper, or the like.

[0019] The preferred metal catalyst is: palladium acetate or iodide;

[0020] Preferred bidentate phosphine ligands are: P(t-Bu)3, JosiPhos, Binap or XantPhos, etc.

[0021] More preferably, the metal catalyst is palladium acetate, and the most preferably, the bidentate phosphine ligand is XantPhos.

[0022] The carbon-nitrogen coupling reaction is carried out in the presence of a base and a solvent, and the base can be an organic base or an inorganic base, such as sodium tert-butoxide, potassium tert-butoxide, potassium phosphate, potassium carbonate, potassium hydroxide, etc.;

[0023] The solvent is an organic solvent, such as DMF, DMSO, dioxane, toluene, methanol, ethanol, isopropanol, tert-butanol or tetrahydrofuran.

[0024] The molar ratio of the materials can be in the range of: compound of formula A and: palladium acetate: Xantphos, potassium carbonate = 1.0: (0.03-0.10): (0.03-0.20): (1.0-4.0).

[0025] The compound of formula A of the present invention is prepared by reduction reaction.

[0026]

[0027] The reducing agent for the reduction reaction can be Fe powder, Pt / C / H2, etc.

[0028] The 1-(2-chlorophenyl)-2-(2-nitrophenyl)-1-ol of the present invention is prepared by the nucleophilic addition reaction of o-chlorobenzaldehyde and o-nitrotoluene.

[0029]

[0030] This step of reaction is carried out in the presence of a base. The base can be an organic base or an inorganic base such as potassium phosphate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, DBU, etc. Potassium phosphate is most preferred.

[0031] The researchers of the present invention unexpectedly discovered that when potassium phosphate is used, it can not only be repeatedly applied multiple times, but also the impurity content can be effectively controlled. The structure of the impurity is:

[0032]

[0033] The content of the impurity can be controlled below 1%. Among them, the HPLC content of 1-(2-chlorophenyl)-2-(2-nitrophenyl)ethane-1-ol is greater than 98%. This step of reaction achieves the technical effects of high yield, high purity and effectively controlled impurity content.

[0034] The present invention provides a method for preparing a compound of formula B. The synthetic route is:

[0035]

[0036] It includes three steps: nucleophilic addition reaction, reduction reaction, and coupling reaction. The whole route has high product yield, high purity, and has the prospect of industrial scale-up application. For example:

[0037] In the above reaction steps, the technical difficulties in the CN coupling reaction are overcome. The technical problems are solved, and the method has substantial characteristics and significant progress, and is creative. The technical difficulties overcome are specifically embodied in:

[0038] In the prior art, there are reports on the coupling reaction of 4-methylchlorobenzene and aniline, using palladium acetate as a catalyst, cesium carbonate as a base, and 1,4-dioxane as a solvent to prepare 4-methyl-N-phenylaniline. The preferred ligand is 2-(cyclohexylphosphine)-3-(2-methoxyphenyl)imidazole[1,2-θ]pyridine.

[0039]

[0040] On the one hand, the selection of ligand plays a more important role in the coupling reaction. But on the other hand, the structure of the substrate itself also determines the carrying out of the coupling reaction. The substrate of the present invention is compared with the above-mentioned 4-methylchlorobenzene and aniline, although the substrate structure is slightly complicated, there is a difference between intermolecular coupling and intramolecular coupling.

[0041] Further examples are: the following two-step coupling reaction in the prior art,

[0042] #imgpt18#

[0043] It also belongs to intermolecular coupling. The technical purpose of the intermolecular coupling reaction itself is relatively clear, and the technical difficulty is smaller than that of the intramolecular coupling reaction. The technical difficulty of the intramolecular coupling reaction of the present invention is that in addition to the main reaction intramolecular coupling, a side reaction of intermolecular coupling will also occur. The present invention needs to be able to overcome such technical difficulties.

[0044] After research by R&D personnel, it was finally possible to overcome the influence of side reactions and obtain a high yield and high purity intramolecular coupling reaction product. Therefore, the coupling reaction of the present invention has technical advantages and creativity. In the nucleophilic addition reaction, the use of potassium phosphate can not only be repeatedly applied, but also effectively control the impurity content, which has no technical inspiration in the prior art, and has technical advantages and creativity. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 This is the HPLC spectrum of 1-(2-chlorophenyl)-2-(2-nitrophenyl)ethan-1-ol prepared in Example 1.

[0046] Figure 2This is the HPLC spectrum of the compound of formula B prepared in Example 5. DETAILED DESCRIPTION

[0047] In order to better understand the content of the present invention, further description is given below in conjunction with specific embodiments, but the specific implementation methods are not intended to limit the content of the present invention.

[0048] Embodiment 1:

[0049] In a 1000mL four-necked flask, add 100mL of DMSO, then add 42.4g (0.20mol) of potassium phosphate and 274.3g (2.00mol) of o-nitrotoluene, stir, and add 281.1g (2.00mol) of o-chlorobenzaldehyde dropwise at a temperature of 10℃~35℃. After the addition is completed, seal the flask and keep it at 10℃~35℃ for 24 hours, then start TLC to monitor the reaction progress.

[0050] After the reaction is finished, add 200 mL of toluene, filter and recover potassium phosphate, wash the filter cake with 100 ml of toluene, and combine the filtrate. Wash the filtrate twice with 200 mL*2 of water, concentrate under reduced pressure to remove toluene, add 200 mL of hexane for recrystallization, filter, and dry to obtain 1-(2-chlorophenyl)-2-(2-nitrophenyl)ethan-1-ol with a yield of 90% to 95% and a purity of 98%.

[0051] Embodiment 2:

[0052] In a 1000mL four-necked flask, add 100mL of DMSO, then add 42.4g (0.20mol) of potassium phosphate, stir, control the temperature at 10℃~35℃, and drop a mixed solution of 281.1g (2.00mol) of o-chlorobenzaldehyde and 274.3g (2.00mol) of o-nitrotoluene. After the dropwise addition, seal, keep warm at 10℃~35℃ for 24 hours, and start TLC to monitor the reaction progress. After the reaction is completed, add 200mL of toluene, then wash twice with 200mL*2 water, concentrate under reduced pressure to remove toluene, add 200mL of hexane for recrystallization, filter, and dry to obtain 1-(2-chlorophenyl)-2-(2-nitrophenyl)-1-ol, with a yield of 90%~95% and a purity of 98%.

[0053] Embodiment 3:

[0054] In a 1000mL four-necked flask, add 150.0g (0.54mol) of 1-(2-chlorophenyl)-2-(2-nitrophenyl) ethanol-1-ol, 120.7g (2.16mol) of iron powder, 3.0g (0.06mol) of ammonium chloride, 600mL of ethanol, and 150mL of water, stir and heat to reflux, after reflux and heat preservation for 2 hours, start TLC to monitor the reaction process. After the reaction is completed, hot filtration is performed, the filter cake is washed with hot ethanol (100ml), the filtrate is combined, the temperature is raised to dissolve, and then the temperature is lowered for recrystallization, filtration is performed, and drying is performed to obtain 1-(2-chlorophenyl)-2-(2-aminophenyl) ethanol-1-ol, with a yield of 92% to 98% and a purity of 99%.

[0055] Embodiment 4:

[0056] In a 1000mL autoclave, add 150.0g (0.54mol) of 1-(2-chlorophenyl)-2-(2-nitrophenyl) 1-ol, 600mL of ethanol, 5g of 10% Pt / C, replace with hydrogen three times, control the pressure to 0.03MPa-0.05MPa with hydrogen, control the temperature to 30℃-50℃, stir and react for 4 hours, start TLC to monitor the reaction process. After the reaction is completed, filter, wash the filter cake with hot ethanol (100ml), combine the filtrate, dropwise add 1200mL of water, filter, and dry to obtain 1-(2-chlorophenyl)-2-(2-aminophenyl) 1-ol, with a yield of 95%-100% and a purity of 99%.

[0057] Embodiment 5:

[0058] In a 500mL four-necked flask, add 1-(2-chlorophenyl)-2-(2-aminophenyl)ethan-1-ol 49.5g (0.20mol), palladium acetate 1.7g (0.01mol), Xantphos 5.8g (0.01mol), potassium carbonate 55.2g (0.40mol), THF 300mL, replace with nitrogen three times, stir and heat to 50℃~60℃, keep warm for 2 hours, start TLC to monitor the reaction progress. After the reaction is completed, cool to room temperature, filter, wash the filter cake with THF (100ml), combine the filtrate, concentrate under reduced pressure to recover THF, add 100mL ethanol, heat to dissolve, cool to recrystallize, filter, and dry to obtain the target compound of formula B with a yield of 85%~95% and a purity of 99%.

[0059] Embodiment 6:

[0060] In a 500mL four-necked flask, add 1-(2-chlorophenyl)-2-(2-aminophenyl)ethan-1-ol 49.5g (0.20mol), Pd2(dba) 39.2g (0.02mol), BINAP 12.4g (0.02mol), potassium carbonate 55.2g (0.40mol), THF 300mL, replace with nitrogen three times, stir and heat to 50-60°C, keep warm for 2 hours, start TLC to monitor the reaction process. After the reaction is completed, cool to room temperature, filter, wash the filter cake with THF (100ml), combine the filtrate, concentrate under reduced pressure to recover THF, add 100mL ethanol, heat to dissolve, cool to recrystallize, filter, and dry to obtain the target compound of formula B with a yield of 85%-95% and a purity of 99%.

[0061] Although the present invention has been fully described in conjunction with specific embodiments, it should be noted that various changes and modifications are obvious to those skilled in the art. Such changes and modifications will be understood to be included within the scope of the present invention as defined by the appended claims.

Claims

1. A compound of formula A, having the following structural formula:

2. A method for preparing a compound of formula B, characterized in that: Prepared by carbon-nitrogen coupling reaction of a compound of formula A, The reaction is carried out in the presence of a metal catalyst and a bidentate phosphine ligand; the metal catalyst is palladium acetate or iodide; the bidentate phosphine ligand is P(t-Bu)3, JosiPhos, Binap or XantPhos.

3. A method for preparing a compound of formula A, characterized in that: Prepared by reduction reaction of 1-(2-chlorophenyl)-2-(2-nitrophenyl)ethan-1-ol, 4. The preparation method according to claim 3, characterized in that: The 1-(2-chlorophenyl)-2-(2-nitrophenyl)-1-ol is prepared by a nucleophilic addition reaction between o-chlorobenzaldehyde and o-nitrotoluene. Among them, the base in the nucleophilic addition reaction is potassium phosphate.

5. The preparation method according to claim 2, characterized in that: The reaction is carried out in the presence of a base and a solvent, the base is an organic base or an inorganic base, and the solvent is an organic solvent.

6. The preparation method according to claim 5, characterized in that: The base is sodium tert-butoxide, potassium tert-butoxide, potassium phosphate, potassium carbonate, potassium hydroxide; the organic solvent is DMF, DMSO, dioxane, toluene, methanol, ethanol, isopropanol, tert-butanol or tetrahydrofuran.

7. A method for preparing a compound of formula B, characterized in that: Including nucleophilic addition reaction, reduction reaction and coupling reaction steps, The coupling reaction is carried out in the presence of a metal catalyst and a bidentate phosphine ligand, wherein the metal catalyst is palladium acetate or iodide; the bidentate phosphine ligand is P(t-Bu)3, JosiPhos, Binap or XantPhos; the base in the nucleophilic addition reaction is potassium phosphate.

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