Chemical synthesis method for 10,11-dibromo-5h-dibenzo[b,f]azepine-5-carbonyl chloride

Abstract

The present invention provides a preparation method for a dihalogen-substituted dibenzo[b,f]azepine-5-carbonyl chloride compound that is prepared from compound II by means of a dihalogen substitution reaction. The method of the present invention has a reasonable process and a high reaction yield, and is suitable for large-scale industrial production. The reaction formula is as follows: wherein, R1 may be a halogen substituent such as bromine, chlorine, or iodine, and R2 may be H, C1-C6 alkoxy, etc.

Description

A chemical synthesis method for 10,11-dibromo-5H-dibenzo[b,f]aza-5-formyl chloride

[0001] This application, filed on May 27, 2024, with application number 202410660449.4 and entitled "A 10,11-dibromo-5H-dibenzo[b,f]aza" azirmonophosphate, is entitled to be filed with the Chinese Patent Office. Priority is claimed in the Chinese patent application for “Chemical Synthesis Method of 5-Formyl Chloride”, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to the field of pharmaceutical synthesis technology, and in particular to a dihalosubstituted dibenzo[b,f]azapyridine. Chemical synthesis method of 5-formyl chloride. Background Technology

[0003] Dihalosubstituted dibenzo[b,f]aza -5-Formyl chloride, such as 10,11-dibromo-5H-dibenzo[b,f]aza 5-Formyl chloride is a chemical intermediate with wide applications in chemical and pharmaceutical synthesis. Currently, 10,11-dibromo-5H-dibenzo[b,f]azapyridine... The main synthetic route of 5-formyl chloride is described in the Chinese Journal of Pharmaceutical Industry (2006), 37(7), 443-445, entitled "Synthesis of Oxcarbazepine", which describes the synthesis of 10,11-dibromo-5H-dibenzo[b,f]aza A synthetic method for 5-formyl chloride is shown below:

[0004] This synthetic method uses bromine to react with starting material 5 in three stages to obtain product 8. Specifically, compound 5, chlorobenzene, and benzoyl peroxide are added to a reaction flask, and bromine is slowly added dropwise while heating to 140–150°C. After the formation of brown solid 7, it is dissolved in chloroform, and bromine and chloroform are slowly added dropwise in a water bath at a controlled temperature below 30°C to prepare brown crystals 8. This route has disadvantages such as long reaction steps, harsh conditions, many intermediate impurities, difficulty in purification, and low yield, which are not conducive to quality control and cost control. The yield of the crude product is only 66.4%.

[0005] For a long time afterward, the preparation of compound 8 did not receive further improvement or optimization. Therefore, it is necessary to develop a competitively advantageous dihalosubstituted dibenzo[b,f]azapyridine. Industrial production route for 5-formyl chloride.

[0006] Summary of the Invention

[0007] The main objective of this invention is to address the aforementioned problems and shortcomings by improving upon existing technology, reducing the process from three steps to one, and providing a 10,11-dibromo-5H-dibenzo[b,f]azapyridine. Chemical synthesis method of 5-formyl chloride.

[0008] The inventors of this application made an unexpected discovery that the preparation of this type of compound does not require three steps of reaction, but can be achieved in just one step, resulting in a breakthrough in technical performance.

[0009] To achieve the technical objective of this invention, the technical solution provided by this invention is as follows:

[0010] The first aspect of this invention provides dihalosubstituted dibenzo[b,f]aza The preparation method of the 5-formyl chloride compound involves the preparation of compound II via a dihalogen substitution reaction.

[0011] In this context, R1 can be a halogenated group such as bromine, chlorine, or iodine, and R2 can be H, C1-C6 alkoxy, etc.

[0012] Furthermore, the present invention provides a 10,11-dihalo-5H-dibenzo[b,f]aza- The preparation method of 5-formyl chloride compounds includes the following reaction steps: 5H-dibenzo[b,f]aza The reaction of 5-formyl chloride with halogen compounds via a dihalogen substitution reaction yields 10,11-dihalo-5H-dibenzo[b,f]azapyridine. 5-Formyl chloride. Its reaction formula is:

[0013] Most preferably, the present invention provides a 10,11-dibromo-5H-dibenzo[b,f]aza- The preparation method of 5-formyl chloride compounds includes the following reaction steps: 5H-dibenzo[b,f]aza 10,11-dibromo-5H-dibenzo[b,f]azazines were prepared by dibromosubstitution of 5-formyl chloride with bromine compounds. 5-Formyl chloride. Its reaction formula is:

[0014] The reaction solvent can be chlorobenzene or dichlorobenzene;

[0015] The most preferred reaction solvent is chlorobenzene.

[0016] In the aforementioned dihalogen substitution reaction, the reaction temperature can be 70-110℃.

[0017] The optimal reaction temperature is 85-100℃.

[0018] In the aforementioned dihalogen substitution reaction, the preferred reaction steps are to first add the reaction solvent, then raise the temperature, and finally add the halogen compound.

[0019] A preferred embodiment of the present invention is: adding 5H-dibenzo[b,f]aza -5-Formyl chloride, with the addition of chlorobenzene as a reaction solvent, followed by heating and the addition of a bromine compound, yields 10,11-dibromo-5H-dibenzo[b,f]azapyridine. -5-formyl chloride.

[0020] In the reaction steps described above in this invention, after the addition of a solvent, the reaction can be in a state of partial or complete dissolution.

[0021] The 10,11-dibromo-5H-dibenzo[b,f]aza-based product provided by this invention The chemical synthesis method of -5-formyl chloride possesses significant technical advantages and breakthroughs. The breakthrough primarily lies in achieving the dihalogen substitution reaction in a single step. Existing technologies require three steps: monohalogen substitution, elimination reaction, and dihalogen substitution. This invention directly omits the monohalogen substitution and elimination steps, representing a substantial breakthrough in reaction procedures and demonstrating significant advancements. The technical advantages are reflected in a significant increase in yield (26-30 percentage points higher than existing technologies), significantly exceeding the yield of the three-step method. The process route is shorter, suitable for large-scale industrial production, and possesses considerable implementation value and socio-economic benefits. Detailed Implementation

[0022] To further understand the present invention, the following examples illustrate a 10,11-dibromo-5H-dibenzo[b,f]azapyridine provided by the present invention. The chemical synthesis method of 5-formyl chloride is described in detail. It should be understood that these examples are described only to further illustrate the features of the invention and are not intended to limit the scope of the invention or the scope of the claims.

[0023] Example 1:

[0024] Add 90.0 g of II-1 and 322.5 g of chlorobenzene to a 500 mL four-necked reaction flask. Heat to 100 °C and add 128.4 g of bromine dropwise over 5–6 hours. Continue stirring and maintaining the temperature for 2–3 hours. The reaction is then complete. Concentrate to dryness under reduced pressure, add 300 mL of water, filter, rinse with a suitable amount of water, and dry to obtain 139.2 g of I-2 (yield 95.9%).

[0025] Example 2:

[0026] Add 90.0 g of II-1 and 322.5 g of chlorobenzene to a 500 mL four-necked reaction flask. Heat to 100 °C and add 128.4 g of bromine dropwise over 5–6 hours. Continue stirring and maintaining the temperature for 2–3 hours. The reaction is then complete. Distill under reduced pressure to remove 150–160 g of bromine / chlorobenzene. Remove the vacuum, cool to 10–30 °C, maintain the temperature for 1 hour, filter, and wash with an appropriate amount of methanol to obtain I-2 (127.4 g, yield 85.9%).

[0027] Example 3:

[0028] Add 90.0 g of II-1 and 60 g of chlorobenzene to a clean 500 mL four-necked flask, stir, heat to 85 °C, and keep warm for 15 minutes to dissolve. After complete dissolution, add 62.4 g of bromine dropwise. After the addition is complete, continue to keep warm. After the warming is complete, add 150 g of chlorobenzene, heat, and add 54 g of bromine dropwise. After the addition is complete, continue to keep warm to react. After the reaction is complete, concentrate under reduced pressure to dryness, add 300 mL of methanol, keep warm at 0–5 °C for 1 hour, filter, rinse with an appropriate amount of water, and dry to obtain I-2 (137.5 g, yield 92.7%).

Claims

1. A 5H-dihalosubstituted dibenzo[b,f]aza A method for preparing 5-formyl chloride compounds, characterized in that, from compound II via a dihalogen substitution reaction, wherein R1 is a halogen substituent 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 halogen compound by dihalogen substitution reaction to prepare 10,11-dihalo-5H-dibenzo[b,f]azepine - 5-formyl chloride, the reaction formula is: wherein X is halogen.

3. The preparation method according to claim 1, characterized in that, 5H-dibenzo[b,f]azepine - 5-formyl chloride and bromine compound by dibromine substitution reaction to prepare 10,11-dibromo-5H-dibenzo[b,f]azepine - 5-formyl chloride, its reaction formula is:

4. The production method according to claim 1, 2 or 3, characterized by, 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, addition of reaction solvent chlorobenzene, after warming, addition of bromine compound, preparation by reaction to obtain 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 obtained is greater than 85%.

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