Preparation method of 2-amino-4, 5-dimethoxybenzaldehyde
By using sodium bisulfite to protect the aldehyde group, nitration and reduction reaction methods in the synthesis of 2-amino-4,5-dimethoxybenzaldehyde, the problem of veraricaldehyde sensitivity to light and heat and the problem of waste acid and three wastes is solved, and a high yield and low by-product synthesis process is achieved.
Patent Information
- Application Number
- CN202411873852.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-19
- Publication Date
- 2025-03-28
AI Technical Summary
The existing synthesis methods of 2-amino-4,5-dimethoxybenzaldehyde have the problem of verarialis sensitivity to light and heat, resulting in a low synthesis yield, and the use of nitrate nitration reaction will produce a large amount of waste acid and three waste.
Veraraldehyde is used as raw material, and the aldehyde group protection is carried out through sodium bisulfite, followed by nitration and reduction reaction, and finally sodium bisulfite is removed under alkaline conditions to form 2-amino-4,5-dimethoxybenzaldehyde. The method includes the following steps: A. Aldehyde group protection to form intermediate 1; B. Nitration reaction to form intermediate 2; C. Reduction reaction to form intermediate 3; D. Generate the final product under alkaline conditions.
It improves the synthetic yield, reduces the occurrence of side reactions, avoids the generation of waste acid and three wastes, and achieves a safer and more economical process route.
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Abstract
Description
Technical Field
[0001] The invention relates to a method for preparing 2-amino-4,5-dimethoxybenzaldehyde, and belongs to the technical field of pharmaceutical intermediate preparation. Background Art
[0002] 2-Amino-4,5-dimethoxybenzaldehyde (CAS No: 22608-87-3) is an important chemical intermediate. It is widely used in medicine, fragrance, pesticide and chemical fields.
[0003] For this product, after literature search of existing technologies, there are mainly the following methods for synthesizing the target product.
[0004] The literature [European Journal of Organic Chemistry, 2021, 2021, 1553; Tetrahedron Letters, 2015, 56, 3954; Synlett, 2020, 31, 1177; Bulletin of the Korean Chemical Society, 2013, 34, 2480; European Journal of Medicinal Chemistry, 2017, 127, 413; Synthetic Communications, 2014, 44, 346] reported that 2-amino-4,5-dimethoxybenzaldehyde was synthesized from veratraldehyde (3,4-dimethoxybenzaldehyde) through nitration and reduction reactions. The reaction formula is as follows:
[0005]
[0006] In the method provided in the above document, since veratraldehyde is sensitive to light and heat, if the reaction is not carried out under light-proof conditions or the temperature exceeds the decomposition temperature (about 50° C.), the yield of synthesizing 6-nitrovatraldehyde is usually 75-85%, with about 15-20% by-products; and when nitric acid is used for nitration reaction, a large amount of waste acid is produced.
[0007] The literature [Chemistry-A European Journal, 2012, 18, 5530; Organic and Biomolecular Chemistry, 2016, 14, 8966] reported that 2-amino-4,5-dimethoxybenzaldehyde was synthesized by oxidation or reduction reaction using (2-amino-4,5-dimethoxyphenyl)methanol or 2-amino-4,5-dimethoxybenzoic acid as raw materials. The reaction formula is as follows:
[0008]
[0009] In the methods provided in the above documents, a large amount of reducing agent or oxidizing agent is used, which will produce a large amount of three wastes.
[0010] Therefore, it is necessary to conduct in-depth research on the synthesis route of 2-amino-4,5-dimethoxybenzaldehyde to provide a better, simple, safe, stable and economical process route with readily available raw materials. Summary of the invention
[0011] The technical problem to be solved by the present invention is to provide a preparation method of 2-amino-4,5-dimethoxybenzaldehyde. The method provided by the present invention uses veratraldehyde as a raw material, performs aldehyde group protection by sodium bisulfite, then performs nitration and reduction reactions, and finally removes sodium bisulfite under alkaline conditions to generate 2-amino-4,5-dimethoxybenzaldehyde.
[0012] The objective of the present invention is achieved through the following technical solutions, and the reaction equation is expressed as follows:
[0013]
[0014] The steps include:
[0015] A. Veratraldehyde is used as a raw material, reacted in the presence of sodium bisulfite solution at elevated temperature to generate intermediate 1;
[0016] B. Mixing the intermediate 1, ferric nitrate nonahydrate and a catalyst in trifluoroethanol to generate the intermediate 2;
[0017] C. Mixing intermediate 2 with iron powder in dioxane, adding hydrazine hydrate under reflux conditions to generate intermediate 3;
[0018] D. Mix intermediate 3 and sodium carbonate solution in 2-methyltetrahydrofuran to generate 2-amino-4,5-dimethoxybenzaldehyde.
[0019] Preferably, in the above step A, the temperature is raised to 30-40°C.
[0020] Preferably, in the above step A, the molar ratio of veratraldehyde to sodium bisulfite is 1:1-1.1.
[0021] Preferably, in the above step B, the catalyst is trifluoroacetic acid.
[0022] Preferably, in the above step B, the molar ratio of the intermediate 1, ferric nitrate 9hydrate and the catalyst is 1:1-1.1:0.01-0.05.
[0023] Preferably, in the above step C, the molar ratio of the intermediate 2, iron powder and hydrazine hydrate (80%) is 1:0.1-0.2:4-5.
[0024] Preferably, in the above step D, the molar ratio of the intermediate 3 to sodium carbonate is 1:2-3
[0025] Beneficial effects of the present invention:
[0026] A. The present invention develops a simple and practical synthesis route, which protects the aldehyde group by sodium bisulfite, followed by nitration reaction, with high yield, greatly reducing the side reactions of the aldehyde group caused by light and heat. At the same time, iron nitrate is used for nitration reaction, avoiding the generation of waste acid.
[0027] B. Using iron powder and hydrazine hydrate to reduce nitro groups avoids precious metal catalysts, reduces costs, has high reaction yields, and is highly operable. Specific embodiments
[0028] Although the present invention has been described in detail by way of preferred embodiments, the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, a person of ordinary skill in the art may make various equivalent modifications or substitutions to the embodiments of the present invention, and these modifications or substitutions shall be within the scope of the present invention. Any person of ordinary skill in the art may easily think of changes or substitutions within the technical scope disclosed by the present invention, and these shall be within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be subject to the scope of protection described in the claims.
[0029] Example 1
[0030] Under nitrogen protection and light-proof conditions, 16.6 g (0.1 mol) of veratraldehyde and 43.7 g of sodium bisulfite solution (25%) were mixed in a reaction flask, heated to 30-40°C, reacted for 1 hour, cooled to room temperature, added with 200 mL of ethanol, and then cooled to 0°C. Solids precipitated and were filtered. The filter cake was washed with n-hexane and dried to obtain intermediate 1, 26.5 g, with a yield of 98% and a HPLC purity of 99.3%. 1 HNMR(400MHz,D2O):7.16(d,1H),7.06(d,1H),6.98(d,1H),5.38(s,1H),3.81-3.78(d,6H).
[0031] Example 2
[0032] Under nitrogen protection, intermediate 1 (13.5 g, 0.05 mol), ferric nitrate nonahydrate 21.2 g (0.053 mol) and trifluoroacetic acid 0.17 g (1.5 mmol) were mixed in 200 mL of trifluoroethanol, reacted at room temperature for 6 hours, concentrated, and the crude product was slurried with 100 mL of ethanol / water (v / v=2 / 1) and filtered to obtain intermediate 2, 15 g, with a yield of 95% and a HPLC purity of 99.1%. 1 HNMR (400MHz, D2O): 7.76 (d, 1H), 7.33 (d, 1H), 5.88 (s, 1H), 3.92-3.83 (d, 6H). This reaction requires trifluoroacetic acid to initiate, and the reaction does not occur without the addition of trifluoroacetic acid.
[0033] Example 3
[0034] Under nitrogen protection, intermediate 2 (15.8 g, 0.05 mol) and iron powder 0.42 g (7.5 mmol) were mixed in 250 mL of dioxane. Under reflux conditions, 14.1 g of hydrazine hydrate (80%) was slowly added dropwise. After the addition was complete, the reaction was refluxed for 1.5 hours, cooled to room temperature, concentrated, and the crude product was recrystallized with dioxane and water and filtered to generate intermediate 3, 13.3 g, with a yield of 93% and a HPLC purity of 98.8%.
[0035] Example 4
[0036] Under nitrogen protection, intermediate 3 (28.5 g, 0.1 mol) and 130 g of sodium carbonate (20%) solution were mixed in 300 mL of 2-methyltetrahydrofuran, stirred at room temperature, reacted for 1 hour, separated, the aqueous layer was extracted twice with 100 mL of 2-methyltetrahydrofuran, the organic layers were combined, the organic layers were washed twice with 100 mL of saturated brine, and the organic layers were concentrated to generate 2-amino-4,5-dimethoxybenzaldehyde, 17.4 g, yield 96%, HPLC purity 99.0%. 1 HNMR (400MHz, CDCl3): 9.72 (s, 1H), 6.89 (s, 1H), 6.13 (s, 1H), 6.09-6.03 (s, 2H), 3.89 (s, 3H), 3.84 (s, 3H).
[0037] Although the present invention has been described in detail by way of preferred embodiments, the protection scope of the present invention is not limited thereto, and any technician familiar with the technical field, within the technical scope disclosed by the present invention, who makes equivalent substitutions or changes according to the technical scheme and inventive concept of the present invention, should be covered by the protection scope of the present invention.
Claims
1. A method for preparing 2-amino-4,5-dimethoxybenzaldehyde, characterized in that: The steps include: A. Veratraldehyde is used as a raw material, reacted in the presence of sodium bisulfite solution at elevated temperature to generate intermediate 1; B. Mixing the intermediate 1, ferric nitrate nonahydrate and a catalyst in trifluoroethanol to generate the intermediate 2; C. Mixing intermediate 2 with iron powder in dioxane, adding hydrazine hydrate under reflux conditions to generate intermediate 3; D. Mix intermediate 3 and sodium carbonate solution in 2-methyltetrahydrofuran to generate 2-amino-4,5-dimethoxybenzaldehyde.
2. The method for preparing 2-amino-4,5-dimethoxybenzaldehyde according to claim 1, characterized in that: In the above step A, the temperature is raised to 30-40°C.
3. The method for preparing 2-amino-4,5-dimethoxybenzaldehyde according to claim 1, characterized in that: In the above step A, the molar ratio of veratraldehyde to sodium bisulfite is 1:1-1.
1.
4. The method for preparing 2-amino-4,5-dimethoxybenzaldehyde according to claim 1, characterized in that: In the above step B, the catalyst is trifluoroacetic acid.
5. The method for preparing 2-amino-4,5-dimethoxybenzaldehyde according to claim 1, characterized in that: In the above step B, the molar ratio of the intermediate 1, ferric nitrate nonahydrate and the catalyst is 1:1-1.1:0.01-0.
05.
6. The method for preparing 2-amino-4,5-dimethoxybenzaldehyde according to claim 1, characterized in that: In the above step C, the molar ratio of the intermediate 2, iron powder and hydrazine hydrate (80%) is 1:0.1-0.2:4-5.
7. The method for preparing 2-amino-4,5-dimethoxybenzaldehyde according to claim 1, characterized in that: In the above step D, the molar ratio of the intermediate 3 to sodium carbonate is 1:2-3.