Method for preparing carboxybenzaldehyde
By using phthalic anhydride and hydrazine hydrate as starting materials, combined with catalysts and solvents, o-carboxybenzaldehyde was prepared, solving the problems of high cost and environmental unfriendliness in existing technologies, and realizing the synthesis of high-purity o-carboxybenzaldehyde.
Patent Information
- Application Number
- CN202511634342.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-10
- Publication Date
- 2026-01-13
AI Technical Summary
The existing synthesis route for o-carboxybenzaldehyde has high starting material phthalide and high bromine toxicity, resulting in high production costs and environmental problems.
o-Carboxybenzaldehyde was prepared by using phthalic anhydride and hydrazine hydrate as starting materials through a three-step reaction. The catalyst was 4-dimethylaminopyridine, and the solvents were acetonitrile and methanol. The reaction was carried out in combination with strong acid salts. The reaction conditions were mild and the product had high chemical purity.
A low-cost and environmentally friendly synthesis of o-carboxybenzaldehyde was achieved, with the product achieving a chemical purity of 99.9%, meeting the quality requirements of the pharmaceutical industry.
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Figure CN121318693A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical chemical industry, and specifically relates to a method for preparing o-carboxybenzaldehyde, a key raw material for the synthesis of various drugs. Background Technology
[0002] o-Carboxybenzaldehyde is a key intermediate in the synthesis of butylphthalide, simethicone, olaparib, indobufen, hydralazine hydrochloride, etc.
[0003] The existing literature, "Organic Syntheses, 1943, vol. 23, p. 74," uses phthalide as a starting material, undergoing bromination to obtain 3-bromophthalide, followed by hydrolysis to yield o-carboxybenzaldehyde. This synthetic route is currently the primary method used industrially. The synthetic route is as follows: The main drawback of this route is that although the starting material phthalide is a basic chemical, it is still relatively expensive, and the brominating agent uses bromine, which is highly toxic. Summary of the Invention
[0004] To address the shortcomings of existing technologies, this invention provides a method for preparing o-carboxybenzaldehyde. Compared to known literature methods, this method uses phthalic anhydride and hydrazine hydrate, which are more inexpensive and readily available, as starting materials. The method involves a three-step reaction to obtain o-carboxybenzaldehyde with a chemical purity of over 99.9%, which meets the pharmaceutical industry's quality expectations for key intermediates.
[0005] To achieve the above objectives, the present invention provides the following technical solution: A method for preparing o-carboxybenzaldehyde includes the following steps: (1) Acylation reaction of phthalic anhydride compound II with hydrazine hydrate yields o-carboxybenzoylhydrazine compound III; (2) The o-carboxybenzoylhydrazide compound III obtained in the previous step was heated together with sodium sulfite to obtain the adduct compound IV of o-carboxybenzaldehyde and sodium bisulfite; (3) The product compound IV from the previous step was reacted with a strong acid to obtain compound I of o-carboxybenzaldehyde; The reaction flow chart is as follows: .
[0006] Furthermore, in step (1), a catalyst, 4-dimethylaminopyridine, is added during the acylation reaction.
[0007] Furthermore, acetonitrile is used as the reaction solvent in step (1).
[0008] Furthermore, in step (2), methanol is used as the reaction solvent.
[0009] Furthermore, in step (2), the molar ratio of sodium sulfite to o-carboxybenzoylhydrazine compound III is 1.2:1.
[0010] Furthermore, the strong acid used in step (3) is hydrochloric acid.
[0011] More specifically, the present invention relates to a method for preparing o-carboxybenzaldehyde, which adopts the following technical solution: A method for preparing o-carboxybenzaldehyde includes the following steps: (1) In the reactor, add acetonitrile, hydrazine hydrate, phthalic anhydride and 4-dimethylaminopyridine, start the stirring reaction, after the reaction is completed, add 4-dimethylaminopyridine and activated carbon again, stir to decolorize, add liquid alkali to the filtrate, adjust the pH to 11.0, cool and stir, filter, add the filter cake to water, add activated carbon and stir to decolorize, cool the filtrate, add hydrochloric acid dropwise under stirring at 0-5℃, adjust the pH to 5.0-7.0, filter, dry the filter cake under vacuum to obtain white powdered o-carboxybenzoyl hydrazine; (2) In a nitrogen atmosphere, o-carboxybenzoylhydrazine, sodium sulfite, methanol and water obtained in the previous step were added to the reaction flask, the temperature was raised to reflux, after the reaction was completed, the temperature was lowered, and the mixture was filtered to obtain a white solid powder. (3) Mix the off-white solid powder obtained in the previous step with water, add activated carbon, stir to decolorize, add hydrochloric acid to the filtrate, adjust the pH value to 1.0, cool, filter, dry, and obtain the target product o-carboxybenzaldehyde, which is a white crystalline powder.
[0012] Compared with existing literature reports on the synthesis methods of o-carboxybenzaldehyde, the main advantages of this invention are: The starting materials used in this application, phthalic anhydride and hydrazine hydrate, are more inexpensive and readily available than phthalide and bromine, which are reported in existing literature, offering a cost advantage for industrial production. The reaction conditions are mild, and the absence of bromine makes it more environmentally friendly. The o-carboxybenzaldehyde obtained using this method has a chemical purity of over 99.9%, meeting the pharmaceutical industry's quality expectations for key intermediates. Attached Figure Description
[0013] Figure 1 Example 3: HPLC chromatogram of the chemical purity of o-carboxybenzaldehyde (compound = I) prepared; Figure 2 : HNMR spectrum of o-carboxybenzaldehyde (compound I) prepared in Example 3. Detailed Implementation
[0014] The following detailed description of the present invention, through several specific examples, further illustrates the above-described contents of the invention. However, this should not be construed as limiting the scope of the invention to the following specific embodiments. All techniques experimented with based on the above-described contents of the present invention fall within the scope of the present invention.
[0015] Example 1 Synthesis of o-carboxybenzoylhydrazide: In a reaction flask, add 300 mL of acetonitrile, 62.6 g (1.0 mol) of hydrazine hydrate (80% purity), 148.1 g (1.0 mol) of phthalic anhydride, and 0.6 g (0.005 mol) of 4-dimethylaminopyridine. Start stirring and react at 20-25°C for 1 hour. Add another 0.6 g (0.005 mol) of 4-dimethylaminopyridine and 5 g of activated carbon, stir for 1 hour, filter out the activated carbon, and add 146 g of [unspecified ingredient] dropwise to the filtrate. (1.1 mol) 32% liquid alkali was added, the pH was adjusted to 11.0, the temperature was lowered to 0-5℃, and the mixture was stirred for 0.5 hours. The mixture was then filtered, and the filter cake was added to 540 mL of water. The mixture was stirred and heated to 35℃, at which point most of the solid dissolved. 5 g of activated carbon was added and stirred for decolorization for 0.5 hours. The activated carbon was then filtered off, and the filtrate was cooled. 10% hydrochloric acid was added dropwise at 0-5℃ with stirring to adjust the pH to 5.0-7.0. Stirring was continued for 0.5 hours, and the mixture was filtered. The filter cake was dried under vacuum to obtain 165.7 g of white powder, with a yield of 92%. Example 2: Synthesis of the addition salt of o-carboxybenzaldehyde and sodium bisulfite: In a nitrogen atmosphere, 90 g (0.5 mol) of o-carboxybenzoyl hydrazine obtained in Example 1, 75.6 g (0.6 mol) of sodium sulfite, 600 mL of methanol, and 120 mL of water were added to the reaction flask. The mixture was heated to reflux for 5 hours, cooled to 10-15 °C, and filtered to obtain a white powder.
[0016] Experimental Example 3 Synthesis of o-carboxybenzaldehyde Mix the filter cake obtained in the previous step with 300 ml of water, add 4 g of activated carbon, stir at 60°C for 0.5 hours to decolorize, filter out the activated carbon, add 10% hydrochloric acid dropwise to the filtrate at 55-60°C to adjust the pH to 1.0, slowly cool to 10-15°C, filter, dry to obtain 54.1 g of white crystalline powder, yield 72%, purity 99.98%.
[0017] The HNMR spectrum is attached. Figure 2 , 1H-NMR (DMSO-d6), δ: 8.19 (d, 1H), 7.78-7.85 (m, 2H), 7.65-7.70 (m, 2H), 6.69 (d, 1H). According to the H-NMR spectrum, o-carboxybenzaldehyde is in a closed ring state in DMSO. .
[0018] Experimental methods: HPLC detection method .
Claims
1. A method for preparing o-carboxybenzaldehyde, characterized in that... Includes the following steps: (1) Acylation reaction of phthalic anhydride compound II with hydrazine hydrate yields o-carboxybenzoylhydrazine compound III; The o-carboxybenzoylhydrazide compound III obtained in the previous step was reacted with sodium sulfite upon heating to obtain o-carboxybenzaldehyde. Compound IV, an adduct of sodium bisulfite; The product compound IV from the previous step was reacted with a strong acid to obtain compound I, o-carboxybenzaldehyde; The reaction flow chart is as follows: 。 2. The method for preparing o-carboxybenzaldehyde according to claim 1, characterized in that... In step (1) During the acylation reaction, a catalyst, 4-dimethylaminopyridine, is added.
3. The method for preparing o-carboxybenzaldehyde according to claim 1, characterized in that... In step (1) Acetonitrile was used as the reaction solvent.
4. The method for preparing o-carboxybenzaldehyde according to claim 1, characterized in that... In step (2) Methanol was used as the reaction solvent.
5. The method for preparing o-carboxybenzaldehyde according to claim 1, characterized in that... In step (2) The molar ratio of sodium sulfite to compound III (o-carboxybenzoyl hydrazine) is 1.2:
1.
6. The method for preparing o-carboxybenzaldehyde according to claim 1, characterized in that... In step (3) The strong acid used is hydrochloric acid.
7. A method for preparing o-carboxybenzaldehyde, characterized in that... Includes the following steps: (1) In the reactor, add acetonitrile, hydrazine hydrate, phthalic anhydride and 4-dimethylaminopyridine, start the stirring reaction, after the reaction is completed, add 4-dimethylaminopyridine and activated carbon again, stir to decolorize, add liquid alkali to the filtrate, adjust the pH to 11.0, cool and stir, filter, add the filter cake to water, add activated carbon and stir to decolorize, cool the filtrate, add hydrochloric acid dropwise under stirring at 0-5℃, adjust the pH to 5.0-7.0, filter, dry the filter cake under vacuum to obtain white powdered o-carboxybenzoyl hydrazine; (2) In a nitrogen atmosphere, o-carboxybenzoylhydrazine, sodium sulfite, methanol and water obtained in the previous step were added to the reaction flask, the temperature was raised to reflux, after the reaction was completed, the temperature was lowered, and the mixture was filtered to obtain a white solid powder. (3) Mix the off-white solid powder obtained in the previous step with water, add activated carbon, stir to decolorize, add hydrochloric acid to the filtrate, adjust the pH value to 1.0, cool, filter, dry, and obtain the target product o-carboxybenzaldehyde, which is a white crystalline powder.