A process for the preparation of 3,5-dibromo-o-aminobenzaldehyde

Abstract

The application discloses a preparation method of 3,5-dibromo-o-aminobenzaldehyde. Indigo is used as a starting material, a bromination reaction is first performed, and bromine atoms are introduced at specific positions (3,5-positions) of an indole ring to obtain brominated indigo; then, an oxidizing agent is used to open a 2,3-diketone structure of the indigo to directly obtain the target product 3,5-dibromo-o-aminobenzaldehyde. In the first step, the bromine atoms introduced as strong electron-withdrawing groups reduce the electron cloud density of the whole molecule through an induction effect, thereby effectively slowing down or changing the process of rearrangement migration in the second step of the oxidation opening ring, the tendency of generating o-aminobenzoic acid under the oxidation condition is inhibited, and the reaction is allowed to stay at the aldehyde stage; meanwhile, the presence of the bromine atoms can also regulate the regioselectivity of the oxidation opening ring, guide the opening ring direction to accurately generate the target ortho amino and aldehyde group structure, and the protection requirement of the amino and aldehyde group in the traditional route is avoided, and the synthesis steps are simplified.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, specifically to a method for preparing 3,5-dibromo-o-aminobenzaldehyde. Background Technology

[0002] 3,5-Dibromo-o-aminobenzaldehyde is a widely used pharmaceutical intermediate with extensive applications in drug synthesis. It is primarily used as a crucial intermediate in the synthesis of ambroxol hydrochloride, a promising new expectorant approved in many countries worldwide, with a large market demand and promising future. Ambroxol hydrochloride is an organic compound, a white to pale yellow crystalline powder, mainly used as an expectorant. It promotes the elimination of viscous secretions from the respiratory tract and reduces mucus retention, thus significantly promoting sputum expectoration. It is suitable for acute and chronic respiratory diseases accompanied by abnormal sputum secretion and poor expectoration function.

[0003] The following are some existing methods for synthesizing 3,5-dibromo-o-aminobenzaldehyde: Patent CN102399159A uses methyl anthranilate as a starting material and reduces it with sodium borohydride to obtain 3,5-dibromo-anthranilaldehyde. However, due to the high cost of the reducing agent and the harsh reaction conditions, this method is not suitable for large-scale industrial production.

[0004] Patent CN 118851924 A uses o-nitrobenzaldehyde as a starting material, which is reduced to o-aminobenzaldehyde via nitro reduction, and then brominated with a brominating agent to obtain the target product. This method has relatively high raw material costs and generates a large amount of solid waste from iron powder processing. Compared to the previous method, this method has readily available raw materials, milder reaction conditions, and produces a higher purity product, making it suitable for industrial-scale production. However, the above reaction has a low product yield, high cost, and some pollution. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention provides a method for preparing 3,5-dibromo-o-aminobenzaldehyde. Using indigo as a starting material, a bromination reaction is first performed to introduce bromine atoms at a specific position (3,5-position) of the indole ring, yielding bromo-o-indigo. Subsequently, an oxidizing agent is used to open the 2,3-diketone structure of indigo, directly obtaining the target product 3,5-dibromo-o-aminobenzaldehyde.

[0006] A method for preparing 3,5-dibromo-o-aminobenzaldehyde includes the following steps: Brominated indigo is obtained by bromination of indigo with a brominating agent. Brominated indigo is then oxidized with an oxidizing agent to give 3,5-dibromo-o-aminobenzaldehyde. The specific route is as follows: .

[0007] Existing methods for preparing 3,5-dibromo-o-aminobenzaldehyde mostly employ the direct bromination route of o-aminobenzaldehyde. However, this route has significant drawbacks: both the amino and aldehyde groups in the o-aminobenzaldehyde molecule are highly reactive groups, which are prone to side reactions under bromination conditions, such as oxidation of the amino group and bromination or cyclization of the aldehyde group. Therefore, protection and deprotection operations of the amino or aldehyde groups are usually required, resulting in lengthy steps and low overall yield. At the same time, the positioning effect and steric hindrance of the bromine atom are difficult to control precisely, resulting in poor regioselectivity and increasing the difficulty of separation and purification.

[0008] This invention directly uses indigo as the starting material, first undergoing a bromination reaction to introduce a bromine atom at a specific position (3,5-position) of the indole ring, yielding bromoindigo. Subsequently, an oxidizing agent is used to open the 2,3-diketone structure of indigo, directly yielding the target product 3,5-dibromo-o-aminobenzaldehyde. The key to this route lies in the significant synergistic electronic effect between the bromination and oxidation reactions: the bromine atom introduced in the first step acts as a strong electron-withdrawing group, reducing the electron cloud density of the entire molecule (especially the C2-C3 bond) through an inductive effect. This effectively slows down or alters the rearrangement migration process in the second step of Baeyer-Villiger type oxidative ring opening, inhibiting the tendency to generate an-aminobenzoic acid under oxidative conditions, allowing the reaction to remain at the aldehyde stage. Simultaneously, the presence of the bromine atom can also regulate the regioselectivity of the oxidative ring opening, guiding the ring opening direction to precisely generate the target ortho-amino and aldehyde structures, achieving a synergistic design of "bromine-directed and bromine-controlled oxygen," avoiding the protection requirements of amino and aldehyde groups in traditional routes, and simplifying the synthetic steps.

[0009] Preferably, the brominating agent is at least one of N-bromosuccinimide (NBS), liquid bromine, and dibromohydantoin (DBH).

[0010] Preferably, the mass ratio of indigo to brominating agent is 1:2~3.

[0011] Preferably, the bromination reaction is carried out at a temperature of 20-60 °C for 4-8 h.

[0012] Preferably, the oxidant is at least one of manganese dioxide, sodium hypochlorite, and hydrogen peroxide.

[0013] Preferably, the mass ratio of the bromoindigo to the oxidant is 1:1 to 6.

[0014] Preferably, the oxidation reaction temperature is 30~90 °C and the reaction time is 3~10 h.

[0015] Preferably, after the oxidation is completed, the reaction system is filtered and the filtrate is collected. After rotary evaporation, a crude product is obtained. The crude product is recrystallized to obtain 3,5-dibromo-o-aminobenzaldehyde. The solvent for recrystallization is petroleum ether or n-heptane.

[0016] Preferably, during the oxidation process, when the oxidant is sodium hypochlorite or hydrogen peroxide, sodium bromide and 2,2,6,6-tetramethylpiperidine oxide (TEMPO) are also added.

[0017] More preferably, the molar ratio of the bromoinin, sodium bromide and 2,2,6,6-tetramethylpiperidine oxide is 1:0.1~0.2:0.4~0.6.

[0018] Preferably, the yield of the 3,5-dibromo-o-aminobenzaldehyde is ≥80% and the purity is ≥96%.

[0019] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention uses indigo as a starting material, first undergoing a bromination reaction to introduce a bromine atom at a specific position (3,5-position) of the indole ring, yielding bromoindigo. Subsequently, an oxidizing agent is used to open the 2,3-diketone structure of indigo, directly yielding the target product 3,5-dibromo-o-aminobenzaldehyde. A significant synergistic electronic effect exists between the bromination and oxidation reactions. By controlling the regioselectivity of the oxidation ring-opening by regulating the position of the bromine atom, the ring-opening direction is precisely guided to generate the target ortho-amino and aldehyde structures, avoiding the protection requirements of the amino and aldehyde groups in traditional routes and simplifying the synthetic steps. Attached Figure Description

[0020] Figure 1 The 1H NMR spectrum of 3,5-dibromo-o-aminobenzaldehyde.

[0021] Figure 2 HPLC test data for 3,5-dibromo-o-aminobenzaldehyde. Detailed Implementation

[0022] The present invention will be further described in detail below with reference to the embodiments, but the implementation of the present invention is not limited to the following embodiments.

[0023] All raw materials used in this invention are commercially available.

[0024] Example 1 The specific route is as follows: (1) Preparation of indigo Take a 3000 mL three-necked flask, add 411.5 g of sodium sulfate, 960 g of water, and 57.60 g of trichloroacetaldehyde. Heat to 65 °C and stir. After the system is dissolved, add 30 g of aniline and maintain the temperature while stirring for 1 h. After 1 h, slowly add 65.3 g of 36% hydrochloric acid dropwise. After the addition is complete, maintain the temperature and continue stirring for 1 h. Add 112 g of hydroxylamine hydrochloride and maintain the temperature while stirring for 4 h. Then heat to 100 °C and reflux with stirring for 8 h. TLC reaction monitoring showed that the reaction was complete. After the reaction was complete, continue stirring and allow to cool naturally to 40 °C. Then transfer the three-necked flask to a cold trap and continue stirring and cooling to 0 °C. Filter and dry the obtained solid for later use. Put the obtained solid into a 1000 mL three-necked flask, add 150 g of petroleum ether and stir. Add 100 mL of sulfuric acid and reflux at 60 °C with stirring for 1 h. TLC monitoring showed that the reaction was complete. The mixture was then stirred and cooled at 0 °C, and 500 mL of water was added dropwise. After the addition was complete, the mixture was stirred at 0 °C for another 30 min to crystallize. The crystals were filtered to obtain 43.53 g of indigo (yield of 91.84%). The solid was dried in a forced-air drying oven at 75 °C for later use.

[0025] (2) Preparation of bromoindigo 43 g of indigo was added to a 500 mL three-necked flask, dissolved in 200 g of water, and 95 g of liquid bromine was added. The reaction was carried out at 20 °C for 4 h. The reaction was monitored by TLC until completion. After filtration, 87.63 g of bromoindigo was obtained, with a yield of 97.69%.

[0026] (3) Preparation of 3,5-dibromo-o-aminobenzaldehyde 15 g of bromoindigo was added to a 250 mL three-necked flask, along with 100 mL of dichloroethane. The mixture was heated to 60 °C and stirred until dissolved. After dissolution, 0.54 g of sodium bromide, 4 g of Tempo, and 84 g of sodium hypochlorite aqueous solution (available chlorine mass ratio 13%~16%) were added. The mixture was stirred at 60 °C and the reaction was completed after 8 h of TLC monitoring. The product was filtered, and the filtrate was retained. The organic solvent was then removed by rotary evaporation to obtain the crude product. Petroleum ether was added, and the crude product was heated to dissolve. After cooling and crystallization, 11.32 g of the target product, 3,5-dibromo-o-aminobenzaldehyde, was obtained, with a yield of 83.1% and a purity of 96.4%.

[0027] Example 2 (1) Preparation of indigo: Same as in Example 1.

[0028] (2) Preparation of bromoindigo 10 g of indigo was added to a 250 mL three-necked flask and dissolved in 100 mL of dichloroethane. 24.20 g of N-bromosuccinimide and 2-3 drops of 98% concentrated sulfuric acid were added. The reaction was carried out at 40 °C for 4 h. The reaction was monitored by TLC and found to be incomplete. The temperature was raised to 60 °C and the reaction was continued for another 4 h until the reaction was complete. 100 mL of water was added to wash away impurities. The organic layer was separated and 10 g of anhydrous sodium sulfate was added to the organic layer to remove water. After rotary evaporation of the organic solvent, 19.88 g of bromosuccinimide was obtained, with a yield of 95.30%.

[0029] (3) Preparation of 3,5-dibromo-o-aminobenzaldehyde 15 g of bromoindigo was added to a 250 mL three-necked flask, along with 100 mL of dichloroethane. The mixture was heated to 60 °C and stirred until dissolved. After dissolution, 0.53 g of sodium bromide, 3.8 g of Tempo, and 18.50 g of hydrogen peroxide (with an effective hydrogen peroxide content of 36% by mass) were added. The mixture was stirred at 35 °C and the reaction was completed after 3 h of TLC monitoring. The product was filtered, and the filtrate was retained. The organic solvent was then removed by rotary evaporation to obtain the crude product. Petroleum ether was added, and the crude product was heated to dissolve. After cooling and crystallization, 11.20 g of the target product, 3,5-dibromo-o-aminobenzaldehyde, was obtained, with a yield of 82.2% and a purity of 96.10%.

[0030] Example 3 (1) Preparation of indigo: Same as in Example 1.

[0031] (2) Preparation of bromoindigo 10 g of indigo was added to a 250 mL three-necked flask and dissolved in 100 mL of dichloroethane. 21.40 g of dibromohydantoin and 2-3 drops of 98% concentrated sulfuric acid were added. The reaction was carried out at 40 °C for 4 h. The reaction was monitored by TLC and found to be incomplete. The temperature was raised to 60 °C and the reaction was continued for another 3 h until the reaction was complete. 100 mL of water was added to wash away impurities. The organic layer was separated and 10 g of anhydrous sodium sulfate was added to the organic layer to remove water. After rotary evaporation of the organic solvent, 20.05 g of bromoindigo was obtained, with a yield of 96.10%.

[0032] (3) Preparation of 3,5-dibromo-o-aminobenzaldehyde 15 g of bromoindigo was added to a 250 mL three-necked flask, along with 100 mL of dichloroethane. The mixture was heated to 60 °C and stirred until dissolved. After dissolution, 17 g of manganese dioxide was added, and the reaction was stirred at 60 °C. The reaction was monitored by TLC for 10 h until it was complete. The product was filtered, and the filtrate was retained. The organic solvent was then removed by rotary evaporation of the filtrate to obtain the crude product. Petroleum ether was added, and the crude product was heated to dissolve. After cooling and crystallization, 10.97 g of the target product, 3,5-dibromo-o-aminobenzaldehyde, was obtained, with a yield of 80.5% and a purity of 96.3%.

[0033] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing 3,5-dibromo-o-aminobenzaldehyde, characterized in that, Includes the following steps: Brominated indigo is obtained by bromination of indigo with a brominating agent. Brominated indigo is then oxidized with an oxidizing agent to give 3,5-dibromo-o-aminobenzaldehyde. The specific route is as follows: 。 2. The method for preparing 3,5-dibromo-o-aminobenzaldehyde according to claim 1, characterized in that, The brominating agent is at least one of N-bromosuccinimide, liquid bromine, and dibromohydantoin.

3. The method for preparing 3,5-dibromo-o-aminobenzaldehyde according to claim 1, characterized in that, The mass ratio of indigo to brominating agent is 1:1~2.

4. The method for preparing 3,5-dibromo-o-aminobenzaldehyde according to claim 1, characterized in that, The bromination reaction is carried out at a temperature of 20-60 °C for 4-8 h.

5. The method for preparing 3,5-dibromo-o-aminobenzaldehyde according to claim 1, characterized in that, The oxidant is at least one of manganese dioxide, sodium hypochlorite, and hydrogen peroxide.

6. The method for preparing 3,5-dibromo-o-aminobenzaldehyde according to claim 1, characterized in that, The mass ratio of the bromoindigo to the oxidizing agent is 1:1~6.

7. The method for preparing 3,5-dibromo-o-aminobenzaldehyde according to claim 1, characterized in that, The oxidation reaction temperature is 30~90 ℃, and the reaction time is 3~10 h.

8. The method for preparing 3,5-dibromo-o-aminobenzaldehyde according to claim 1, characterized in that, After the oxidation is completed, the reaction system is filtered and the filtrate is collected. After rotary evaporation, a crude product is obtained. The crude product is recrystallized to obtain 3,5-dibromo-o-aminobenzaldehyde. The solvent for recrystallization is petroleum ether or n-heptane.

9. The method for preparing 3,5-dibromo-o-aminobenzaldehyde according to claim 1, characterized in that, In the oxidation process, when the oxidant is sodium hypochlorite or hydrogen peroxide, sodium bromide and 2,2,6,6-tetramethylpiperidine oxide are also added.

10. The method for preparing 3,5-dibromo-o-aminobenzaldehyde according to claim 1, characterized in that, The yield of the 3,5-dibromo-o-aminobenzaldehyde is ≥80%; the purity is ≥96%.

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