Chemical synthesis method of 10, 11-dibromo-5H-dibenzo [b, f] aza-5-formyl chloride

Abstract

The invention provides a preparation method of a dihalo-substituted dibenzo [b, f] aza-5-formyl chloride compound, which is prepared from a compound II through dihalo substitution reaction. The method is reasonable in process, high in reaction yield and suitable for large-scale industrial production. In the reaction formula, R1 can be a halogen substituent such as bromine, chlorine or iodine, and R2 can be H, C1-C6 alkoxy and the like.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug synthesis, in particular to a chemical synthesis method of 10,11-dibromo-5H-dibenzo[b,f]azepine-5-carboxylic acid chloride. BACKGROUND

[0002] 10,11-dibromo-5H-dibenzo[b,f]azepine-5-carboxylic acid chloride 10,11-dibromo-5H-dibenzo[b,f]azepine-5-carboxylic acid chloride is a chemical intermediate, which has very wide application in the field of chemical industry and medicine synthesis. 10,11-dibromo-5H-dibenzo[b,f]azepine-5-carboxylic acid chloride is a chemical intermediate, which has very wide application in the field of chemical industry and medicine synthesis. The main synthesis route of the chemical synthesis method of 10,11-dibromo-5H-dibenzo[b,f]azepine-5-carboxylic acid chloride is described in the article entitled Synthesis of oxcarbazepine in Chinese Journal of Pharmaceuticals (2006), 37(7), 443-445. The synthesis route is as follows:

[0003]

[0004] The synthesis method uses bromine and raw material 5 to react through three stages to obtain product 8. Specifically, compound 5, chlorobenzene and benzoyl peroxide are added to a reaction bottle, and bromine is slowly added when heated to 140-150℃. After the formation of brown solid 7, it is dissolved in chloroform, and bromine and chloroform are slowly added under water bath control at 30℃ or below to prepare brown crystal 8. In this route, there are disadvantages such as long reaction steps, harsh conditions, many impurities of intermediates, difficult purification, low yield, etc., which are not conducive to quality control and cost control, and the yield of the obtained crude product is only 66.4%.

[0005] For a long time afterwards, the preparation of compound 8 has not been further improved and optimized. Therefore, it is necessary to have a competitive industrial production route of 10,11-dibromo-5H-dibenzo[b,f]azepine-5-carboxylic acid chloride. SUMMARY

[0006] The main purpose of the present application is to improve the prior art, shorten the three steps to one step, and provide a chemical synthesis method of 10,11-dibromo-5H-dibenzo[b,f]azepine-5-carboxylic acid chloride.

[0007] The inventors of the present application have unexpectedly found that the preparation of such compounds does not need to go through three steps of reaction, but only one step of reaction can be realized, which achieves a breakthrough technical effect.

[0008] ​​​In order to achieve the technical purpose of the present application, the technical scheme provided by the present application is as follows:

[0009] The present application provides a 10,11-dihalo-5H-dibenzo[b,f]azepine-5-carbonyl chloride compound in a first aspect. The present application provides a preparation method of a 10,11-dihalo-5H-dibenzo[b,f]azepine-5-carbonyl chloride compound.

[0010]

[0011] In the formula, R1 can be a halogen substituent such as bromine, chlorine or iodine, and R2 can be H or C1-C6 alkoxy.

[0012] Further, the present application provides a preparation method of a 10,11-dihalo-5H-dibenzo[b,f]azepine-5-carbonyl chloride compound. The present application provides a preparation method of a 10,11-dihalo-5H-dibenzo[b,f]azepine-5-carbonyl chloride compound. The present application provides a preparation method of a 10,11-dihalo-5H-dibenzo[b,f]azepine-5-carbonyl chloride compound. The present application provides a preparation method of a 10,11-dihalo-5H-dibenzo[b,f]azepine-5-carbonyl chloride compound.

[0013]

[0014] The present application provides a preparation method of a 10,11-dihalo-5H-dibenzo[b,f]azepine-5-carbonyl chloride compound. The present application provides a preparation method of a 10,11-dihalo-5H-dibenzo[b,f]azepine-5-carbonyl chloride compound. The present application provides a preparation method of a 10,11-dihalo-5H-dibenzo[b,f]azepine-5-carbonyl chloride compound. The present application provides a preparation method of a 10,11-dihalo-5H-dibenzo[b,f]azepine-5-carbonyl chloride compound.

[0015]

[0016] The reaction solvent can be chlorobenzene or dichlorobenzene.

[0017] Most preferably, the reaction solvent is chlorobenzene.

[0018] In the double halogen substitution reaction, the reaction temperature can be 70-110°C.

[0019] Most preferably, the reaction temperature is 85-100°C.

[0020] In the double halogen substitution reaction, the reaction steps are preferably as follows: first, the reaction solvent is added, then the temperature is raised, and finally the halogen compound is added.

[0021] In a preferred embodiment of the present application, the 5H-dibenzo[b,f]azepine-5-carbonyl chloride compound is added first, then the reaction solvent is added, and finally the halogen compound is added. -5-formyl chloride, after adding reaction solvent chlorobenzene, after warming, adding bromine compound, after reaction, 10,11-dibromo-5H-dibenzo[b,f]azepine is prepared -5-formyl chloride.

[0022] In the above reaction steps of the present application, after adding the solvent, the reaction can be in a partially dissolved or completely dissolved state.

[0023] The present application provides 10,11-dibromo-5H-dibenzo[b,f]azepine The chemical synthesis method of -5-formyl chloride has significant technical advantages and breakthroughs. The breakthrough mainly lies in that the dihalogen substitution reaction is realized in one step. In the prior art, three steps of monohalogen substitution, elimination reaction, and dihalogen substitution are required. The present application directly omits the two steps of monohalogen substitution and elimination reaction, which has a substantial breakthrough in the reaction steps and has substantial characteristics and significant further. The technical advantage lies in the significant increase in yield (26-30 percentage points higher than the prior art), which is significantly higher than the method using three steps. The process route is short, suitable for large-scale industrial production, and has great implementation value and social and economic benefits. DETAILED DESCRIPTION

[0024] In order to further understand the present application, the chemical synthesis method of 10,11-dibromo-5H-dibenzo[b,f]azepine -5-formyl chloride provided by the present application will be described in detail below. It should be understood that these examples are only for further detailed description of the features of the present application, and are not a limitation on the scope of the present application or the scope of the claims of the present application.

[0025] #imgpt23#

[0026] Example 1:

[0027] In a 500 mL four-necked reaction bottle, II-1 (90.0 g) was added, chlorobenzene (322.5 g) was added, and the temperature was raised to 100°C. Bromine (128.4 g) was added dropwise, and the dropwise addition was completed in 5-6 h. The reaction was continued for 2-3 h. The reaction was completed. Concentrated to dryness under reduced pressure, add water 300 ml, filter, wash with appropriate amount of water, and dry to obtain I-2 (139.2 g, yield 95.9%).

[0028] Example 2:

[0029] In a 500 mL four-necked flask, II-1 (90.0 g) was added, chlorobenzene (322.5 g) was added, and the temperature was raised to 100°C. Bromine (128.4 g) was added dropwise, and the dropwise addition was completed in 5-6 h. The reaction was continued for 2-3 h. The reaction was completed. The bromine / chlorobenzene (150-160 g) was distilled off under reduced pressure. The vacuum was released, and the temperature was cooled to 10-30°C. The reaction was maintained for 1 h. Filtration was performed, and the filtrate was washed with an appropriate amount of methanol. I-2 (127.4 g, yield 85.9%) was obtained.

[0030] Example 3:

[0031] In a 500 mL four-necked flask, II-1 (90.0 g) was added, chlorobenzene (322.5 g) was added, and the temperature was raised to 100°C. Bromine (128.4 g) was added dropwise, and the dropwise addition was completed in 5-6 h. The reaction was continued for 2-3 h. The reaction was completed. The bromine / chlorobenzene (150-160 g) was distilled off under reduced pressure. The vacuum was released, and the temperature was cooled to 10-30°C. The reaction was maintained for 1 h. Filtration was performed, and the filtrate was washed with an appropriate amount of methanol. I-2 (127.4 g, yield 85.9%) was obtained.

Claims

1. A 5H-dihalosubstituted dibenzo[b,f]aza A method for preparing 5-formyl chloride compounds, characterized in that, Prepared from compound II by a dihalogen substitution reaction, wherein R1 is a halogen substitution group, and R2 is H or C1-C6 alkoxy.

2. The production method according to claim 1, characterized by, 5H-dibenzo[b,f]azepine - 5-formyl chloride and a halogen compound to prepare 10,11-dihalo-5H- dibenzo[b,f]azepine by a dihalogen substitution reaction - 5-formyl chloride, whose reaction formula is: wherein X is halogen.

3. The production method according to claim 1, characterized by, 5H-dibenzo[b,f]azepine - 5-formyl chloride and bromine compound are subjected to a dibromination reaction to prepare 10,11-dibromo-5H-dibenzo[b,f]azepine - 5-formyl chloride, whose reaction formula is:

4. The method of claim 1, 2 or 3, wherein The reaction solvent is chlorobenzene or dichlorobenzene.

5. The method of claim 1, 2 or 3, wherein The reaction temperature is 70-110°C.

6. The method of claim 1, 2 or 3, wherein, The reaction steps include first adding the reaction solvent, then heating and adding the halogen compound.

7. A 10,11-dibromo-5H-dibenzo[b,f]azepine - Process for the preparation of 5-formyl chloride, characterized in that, 5H-dibenzo[b,f]azepine - 5-formyl chloride, after adding reaction solvent chlorobenzene, after warming, adding bromine compound, after reaction, obtaining 10,11-dibromo-5H-dibenzo[b,f]azepine - 5-formyl chloride.

8. The preparation method according to claim 7, characterized in that, The reaction temperature is 85-100°C.

9. The production method according to claim 7 or 8, characterized by, After adding the reaction solvent, the reaction is in a partially dissolved or completely dissolved state.

10. The method of manufacture according to any one of claims 1 to 9, characterized in that, The yield of the product prepared is greater than 85%.

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