A process for the preparation of 2-methoxy-4-acetylamino-5-iodobenzoic acid methyl ester
By simplifying the preparation process, the preparation steps of methyl 2-methoxy-4-acetamido-5-iodobenzoate are shortened to three steps, the overall yield is increased to 70%, and the yield of iodination reaction is increased to 90%, which solves the problems of cumbersome steps and low yield in the existing technology.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- 苏州诚和医药化学有限公司
- Filing Date
- 2024-01-24
- Publication Date
- 2026-06-26
AI Technical Summary
The existing methods for preparing methyl 2-methoxy-4-acetamido-5-iodobenzoate are cumbersome and have low overall yields, especially the iodination reaction yield is insufficient.
A three-step preparation method is adopted, including the reaction of p-aminosalicylic acid with acetic anhydride to prepare 4-acetaminosalicylic acid, the reaction of 4-acetaminosalicylic acid with dimethyl sulfate to prepare methyl 2-methoxy-4-acetaminobenzoate, and finally the reaction with iodine or potassium iodate and an oxidizing agent to prepare methyl 2-methoxy-4-acetamino-5-iodobenzoate.
The reaction steps were shortened to three, the overall yield was increased to about 70%, and the yield of the iodination reaction was increased to over 90%.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of chemical product preparation technology, and in particular to a method for preparing methyl 2-methoxy-4-acetamido-5-iodobenzoate. Background Technology
[0002] Methyl 2-methoxy-4-acetamido-5-iodobenzoate is an important pharmaceutical intermediate. The preparation method of this compound is reported in William A. Hew Let T, Tomas De PAULIs, Chem. Pharm. Bull. 45(12) 2079--2084 (1997):
[0003]
[0004] The preparation method uses para-aminosalicylic acid as the starting material and obtains the target product through esterification, acetylation, iodination and methylation reactions. The yields of each reaction are 53%, 58%, 29% and 86%, respectively, with an overall yield of 7.6%.
[0005] Therefore, there is an urgent need for a method for preparing methyl 2-methoxy-4-acetamido-5-iodobenzoate. Summary of the Invention
[0006] The purpose of this invention is to address the shortcomings of the prior art by providing a method for preparing methyl 2-methoxy-4-acetamido-5-iodobenzoate.
[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows:
[0008] A method for preparing methyl 2-methoxy-4-acetamido-5-iodobenzoate is provided, comprising the following steps:
[0009] S1. 4-Acetaminosalicylic acid is prepared by reacting p-aminosalicylic acid with acetic anhydride;
[0010] S2. Methyl 2-methoxy-4-acetaminobenzoate is prepared by reacting the 4-acetaminosalicylic acid with dimethyl sulfate.
[0011] S3. Methyl 2-methoxy-4-acetaminobenzoate is prepared by reacting the methyl 2-methoxy-4-acetamino-5-iodobenzoate with iodine.
[0012] Preferably, the reaction between the p-aminosalicylic acid and the acetic anhydride comprises:
[0013] The para-aminosalicylic acid was stirred in a first solvent and cooled to 0℃-5℃. The acetic anhydride was slowly added dropwise, and the mixture was stirred and kept warm for 1-3 hours. The temperature was raised to room temperature and kept warm for 1-3 hours. The mixture was then filtered and dried to obtain the 4-acetaminosalicylic acid.
[0014] Preferably, the first solvent is water.
[0015] Preferably, the reaction between the 4-acetamidosalicylic acid and the dimethyl sulfate comprises:
[0016] The 4-acetaminosalicylic acid and the second catalyst were stirred in a second solvent, while the dimethyl sulfate was added dropwise. The mixture was heated to 30°C-40°C, stirred, and kept at that temperature for 10-14 hours. After crystallization, the mixture was filtered and dried to obtain the methyl 2-methoxy-4-acetaminobenzoate.
[0017] Preferably, the second solvent is acetone.
[0018] Preferably, the second catalyst is potassium carbonate.
[0019] Preferably, the reaction between the 4-acetamidosalicylic acid and the dimethyl sulfate further includes:
[0020] The dried methyl 2-methoxy-4-acetaminobenzoate was recrystallized.
[0021] Preferably, the reaction of the methyl 2-methoxy-4-acetaminobenzoate with the iodine comprises:
[0022] The methyl 2-methoxy-4-acetaminobenzoate was heated to 20°C-30°C in a third solvent, and the iodine and the third catalyst were added. The mixture was heated and kept at that temperature for 4-6 hours, and then post-treated to obtain the methyl 2-methoxy-4-acetamino-5-iodobenzoate.
[0023] Preferably, the reaction of the methyl 2-methoxy-4-acetaminobenzoate with the iodine comprises:
[0024] The methyl 2-methoxy-4-acetaminobenzoate was heated to 20°C-30°C in a third solvent, and the iodine, potassium iodate, and third catalyst were added. The mixture was heated and kept at this temperature for 4-6 hours, and then post-treated to obtain the methyl 2-methoxy-4-acetamino-5-iodobenzoate.
[0025] Preferably, the third solvent is methanol or acetic acid.
[0026] Preferably, the third catalyst is sulfuric acid, hydrogen peroxide, or chloramine T.
[0027] The present invention adopts the above technical solution and has the following technical effects compared with the prior art:
[0028] Compared with the prior art, the preparation method of the present invention shortens the reaction steps to three steps and achieves a total yield of about 70%; at the same time, it increases the yield of the iodination reaction from 29% to over 90%. Detailed Implementation
[0029] The specific embodiments of the present invention will be described in detail below.
[0030] Unless otherwise defined, the technical or scientific terms used in the claims and description shall have the ordinary meaning as understood by one of ordinary skill in the art to which this invention pertains.
[0031] The word "comprising" or similar terms used in the specification and claims of this patent application mean that the objects preceding "comprising" include the objects listed after "comprising" or their equivalents, and do not exclude other objects.
[0032] The numerical values mentioned in this invention include all values increasing one unit at a time from low to high, assuming that there is at least a two-unit interval between any lower and higher value. For example, if it is said that a component quantity or a physical quantity is better from 1 to 100, 10 to 90, and 20 to 80, it means that values such as 5 to 95, 14 to 76, 23 to 67, 32 to 58, and 41 to 49 are clearly listed in this specification; for values less than 1, 0.0001, 0.001, 0.01, or 0.1 are considered to be a suitable unit. The foregoing examples are for illustrative purposes only; in practice, all combinations of values between the lowest and highest listed values are considered to be clearly listed in this specification in a similar manner.
[0033] Iodinated aromatic compounds have unique advantages in organic synthesis. Iodization of aromatic compounds can be broadly classified into two categories: indirect iodization, such as through the Sandmeyer reaction, and direct iodization, which involves reacting elemental iodine or iodine-containing compounds with aromatic compounds under specific conditions. Direct iodization has become a rapidly developing method in recent years due to its fewer reaction steps, milder conditions, better selectivity, and higher yield. However, directly iodizing aromatic compounds by reacting elemental iodine and / or iodine-containing compounds with aromatic compounds under specific conditions is difficult because iodine is a relatively inert electrophilic reagent and is difficult to directly iodize on the aromatic ring; an oxidizing agent is often required. Commonly used oxidizing agents include hydrogen peroxide, sodium chlorate, and chloramine-T, but their conversion rates are not ideal. The iodine / potassium iodate / inorganic acid system disclosed in this invention achieves a conversion rate of over 90%, with mild reaction conditions, low oxidizing agent usage, and high iodine atom utilization.
[0034] Example 1
[0035] This embodiment provides a method for preparing methyl 2-methoxy-4-acetamido-5-iodobenzoate, the steps of which include:
[0036]
[0037] S1. Add 50.0 g (326.5 mmol) of para-aminosalicylic acid to 350 mL of water, stir and cool to 0℃-5℃, slowly add 50 g (489.8 mmol) of acetic anhydride, stir and keep warm at 0℃-5℃ for 2 hours, raise to room temperature and keep warm for 2 hours, filter and dry under vacuum at 50℃ to obtain 60 g of grayish-white solid, which is 4-acetaminosalicylic acid, with a yield of 94.2%.
[0038] S2. Add 100g (512.8mmol) of the 4-acetaminosalicylic acid and 240g (1739.1mmol) of potassium carbonate to 500mL of acetone. Add 250g (1984.1mmol) of dimethyl sulfate dropwise while stirring. Heat to 30℃-40℃, stir and keep warm for 12 hours. Transfer to cold water, stir to precipitate crystals, filter and dry at 50℃ to obtain 102.5g of methyl 2-methoxy-4-acetaminobenzoate (HPLC purity 98.72%), yield 89.9%. Recrystallize from 300mL of ethyl acetate to obtain 93.6g of methyl 2-methoxy-4-acetaminobenzoate (HPLC purity 99.78%).
[0039] S3. Add 100g (448.4mmol) of the methyl 2-methoxy-4-acetaminobenzoate to 300g of methanol. Add 67g of iodine and 22g of potassium iodate at 20℃-30℃, and slowly add 20g of sulfuric acid. Heat to 30℃-35℃ and keep warm for 5 hours. Add sodium bicarbonate solution to neutralize the pH to 6-7. Add a small amount of sodium sulfite until the liquid color disappears. Concentrate under negative pressure to recover methanol until no liquid is dispensed. Add 800mL of water and stir thoroughly for 2 hours. Cool to below 5℃ and keep warm for 1 hour. Filter to obtain 180g of methyl 2-methoxy-4-acetamino-5-iodobenzoate (wet). Dry at 60℃ for 15 hours to obtain 150g of methyl 2-methoxy-4-acetamino-5-iodobenzoate (dry, HPLC purity 99.7%), with a yield of 95.8%.
[0040] Example 2
[0041] This embodiment provides a method for preparing methyl 2-methoxy-4-acetamido-5-iodobenzoate, the steps of which include:
[0042] S1. Add 50.0 g (326.5 mmol) of para-aminosalicylic acid to 350 mL of water, stir and cool to 0℃-5℃, slowly add 50 g (489.8 mmol) of acetic anhydride, stir and keep warm at 0℃-5℃ for 2 hours, raise to room temperature and keep warm for 2 hours, filter and dry under vacuum at 50℃ to obtain 60 g of grayish-white solid, which is 4-acetaminosalicylic acid, with a yield of 94.2%.
[0043] S2. Add 100g (512.8mmol) of the 4-acetaminosalicylic acid and 240g (1739.1mmol) of potassium carbonate to 500mL of acetone. Add 250g (1984.1mmol) of dimethyl sulfate dropwise while stirring. Heat to 30℃-40℃, stir and keep warm for 12 hours. Transfer to cold water, stir to precipitate crystals, filter and dry at 50℃ to obtain 102.5g of methyl 2-methoxy-4-acetaminobenzoate (HPLC purity 98.72%), yield 89.9%. Recrystallize from 300mL of ethyl acetate to obtain 93.6g of methyl 2-methoxy-4-acetaminobenzoate (HPLC purity 99.78%).
[0044] S3. Add 100g (448.4mmol) of the methyl 2-methoxy-4-acetaminobenzoate to 300g of acetic acid. Add 67g of iodine and 22g of potassium iodate at 20℃-30℃, and slowly add 20g of sulfuric acid dropwise. Heat to 30℃-35℃ and maintain this temperature for 5 hours. Pour the solution into a sodium sulfite solution and stir for 2 hours. A white to yellowish-white turbid liquid will form. Cool to below 5℃ and maintain this temperature for 1 hour. Filter to obtain 180g of 2- Methyl 2-methoxy-4-acetamido-5-iodobenzoate (wet, containing impurities) was added to 800g of water, stirred at room temperature for 1 hour, cooled to below 5°C and kept at that temperature for 1 hour, filtered, and 170g of methyl 2-methoxy-4-acetamido-5-iodobenzoate (wet) was obtained. The methyl 2-methoxy-4-acetamido-5-iodobenzoate was dried at 60°C for 15 hours to obtain 140g of methyl 2-methoxy-4-acetamido-5-iodobenzoate (dry, HPLC purity 99.6%), with a yield of 89.4%.
[0045] Example 3
[0046] This embodiment provides a method for preparing methyl 2-methoxy-4-acetamido-5-iodobenzoate, the steps of which include:
[0047] S1. Add 50.0 g (326.5 mmol) of para-aminosalicylic acid to 350 mL of water, stir and cool to 0℃-5℃, slowly add 50 g (489.8 mmol) of acetic anhydride, stir and keep warm at 0℃-5℃ for 2 hours, raise to room temperature and keep warm for 2 hours, filter and dry under vacuum at 50℃ to obtain 60 g of grayish-white solid, which is 4-acetaminosalicylic acid, with a yield of 94.2%.
[0048] S2. Add 100g (512.8mmol) of the 4-acetaminosalicylic acid and 240g (1739.1mmol) of potassium carbonate to 500mL of acetone. Add 250g (1984.1mmol) of dimethyl sulfate dropwise while stirring. Heat to 30℃-40℃, stir and keep warm for 12 hours. Transfer to cold water, stir to precipitate crystals, filter and dry at 50℃ to obtain 102.5g of methyl 2-methoxy-4-acetaminobenzoate (HPLC purity 98.72%), yield 89.9%. Recrystallize from 300mL of ethyl acetate to obtain 93.6g of methyl 2-methoxy-4-acetaminobenzoate (HPLC purity 99.78%).
[0049] S3. Add 100g (448.4mmol) of the methyl 2-methoxy-4-acetaminobenzoate to 300g of acetic acid. Add 67g of iodine and chloramine T at 20℃-30℃. Heat to 30℃-35℃ and maintain the temperature for 5 hours. Pour into a sodium sulfite solution and stir for 2 hours. A white to yellowish-white turbid liquid is formed. Cool to below 5℃ and maintain the temperature for 1 hour. Filter to obtain 200g of 2-methoxy-4-acetaminobenzoate. Methyl amino-5-iodobenzoate (wet, containing impurities) was added to 800g of water, stirred at room temperature for 1 hour, cooled to below 5°C and kept at that temperature for 1 hour, filtered, and 160g of methyl 2-methoxy-4-acetamido-5-iodobenzoate (wet) was obtained. It was dried at 60°C for 15 hours to obtain 126g of methyl 2-methoxy-4-acetamido-5-iodobenzoate (dry, HPLC purity 99.5%), with a yield of 80.5%.
[0050] Example 4
[0051] This embodiment provides a method for preparing methyl 2-methoxy-4-acetamido-5-iodobenzoate, the steps of which include:
[0052] S1. Add 50.0 g (326.5 mmol) of para-aminosalicylic acid to 350 mL of water, stir and cool to 0℃-5℃, slowly add 50 g (489.8 mmol) of acetic anhydride, stir and keep warm at 0℃-5℃ for 2 hours, raise to room temperature and keep warm for 2 hours, filter and dry under vacuum at 50℃ to obtain 60 g of grayish-white solid, which is 4-acetaminosalicylic acid, with a yield of 94.2%.
[0053] S2. Add 100g (512.8mmol) of the 4-acetaminosalicylic acid and 240g (1739.1mmol) of potassium carbonate to 500mL of acetone. Add 250g (1984.1mmol) of dimethyl sulfate dropwise while stirring. Heat to 30℃-40℃, stir and keep warm for 12 hours. Transfer to cold water, stir to precipitate crystals, filter and dry at 50℃ to obtain 102.5g of methyl 2-methoxy-4-acetaminobenzoate (HPLC purity 98.72%), yield 89.9%. Recrystallize from 300mL of ethyl acetate to obtain 93.6g of methyl 2-methoxy-4-acetaminobenzoate (HPLC purity 99.78%).
[0054] S3. Add 100g (448.4mmol) of the methyl 2-methoxy-4-acetaminobenzoate to 300g of acetic acid, add 67g of iodine at 20℃-30℃, and slowly add 60g of 30% hydrogen peroxide dropwise. Raise the temperature to 50℃-55℃ and keep it at that temperature for 5 hours. TLC analysis shows that the reaction is about 20%.
[0055] Example 5
[0056] This embodiment provides a method for preparing methyl 2-methoxy-4-acetamido-5-iodobenzoate, the steps of which include:
[0057] S1. Add 50.0 g (326.5 mmol) of para-aminosalicylic acid to 350 mL of water, stir and cool to 0℃-5℃, slowly add 50 g (489.8 mmol) of acetic anhydride, stir and keep warm at 0℃-5℃ for 2 hours, raise to room temperature and keep warm for 2 hours, filter and dry under vacuum at 50℃ to obtain 60 g of grayish-white solid, which is 4-acetaminosalicylic acid, with a yield of 94.2%.
[0058] S2. Add 100g (512.8mmol) of the 4-acetaminosalicylic acid and 240g (1739.1mmol) of potassium carbonate to 500mL of acetone. Add 250g (1984.1mmol) of dimethyl sulfate dropwise while stirring. Heat to 30℃-40℃, stir and keep warm for 12 hours. Transfer to cold water, stir to precipitate crystals, filter and dry at 50℃ to obtain 102.5g of methyl 2-methoxy-4-acetaminobenzoate (HPLC purity 98.72%), yield 89.9%. Recrystallize from 300mL of ethyl acetate to obtain 93.6g of methyl 2-methoxy-4-acetaminobenzoate (HPLC purity 99.78%).
[0059] S3. Add 100g (448.4mmol) of the methyl 2-methoxy-4-acetaminobenzoate to 300g of acetic acid, add 67g of iodine at 20℃-30℃, raise the temperature to about 65℃ and keep it at that temperature for 5 hours; TLC monitoring analysis showed no reaction.
[0060] In summary, compared with the prior art, the preparation method of the present invention shortens the reaction steps to three steps and achieves a total yield of about 70%; at the same time, it increases the yield of the iodination reaction from 29% to over 90%.
[0061] The above description is merely a preferred embodiment of the present invention and does not limit the implementation and protection scope of the present invention. Those skilled in the art should realize that any equivalent substitutions and obvious changes made based on the content of this specification should be included within the protection scope of the present invention.
Claims
1. A method for preparing methyl 2-methoxy-4-acetamido-5-iodobenzoate, characterized in that the step... include: S1. 4-Acetaminosalicylic acid is prepared by reacting para-aminosalicylic acid with acetic anhydride: the para-aminosalicylic acid is stirred in a first solvent and cooled to 0℃-5℃, the acetic anhydride is slowly added dropwise, stirred and kept warm for 1-3 hours, the temperature is raised to room temperature and kept warm for 1-3 hours, and the 4-acetaminosalicylic acid is obtained by filtration and drying. S2. Methyl 2-methoxy-4-acetaminobenzoate is prepared by reacting the 4-acetaminosalicylic acid with dimethyl sulfate: the 4-acetaminosalicylic acid and the second catalyst are stirred in a second solvent, while the dimethyl sulfate is added dropwise. The mixture is heated to 30℃-40℃, stirred, and kept at that temperature for 10-14 hours. After crystallization, the mixture is filtered and dried to obtain methyl 2-methoxy-4-acetaminobenzoate. S3. Methyl 2-methoxy-4-acetaminobenzoate is prepared by reacting the methyl 2-methoxy-4-acetaminobenzoate with iodine: The methyl 2-methoxy-4-acetaminobenzoate is heated to 20°C-30°C in a third solvent, the iodine, potassium iodate, and the third catalyst are added, the temperature is raised and maintained for 4-6 hours, and the methyl 2-methoxy-4-acetamino-5-iodobenzoate is obtained after post-treatment. The third solvent is methanol, and the third catalyst is sulfuric acid.
2. The preparation method according to claim 1, characterized in that, The first solvent is water; or The second solvent is acetone; or The second catalyst is potassium carbonate.
3. The preparation method according to claim 1, characterized in that, The reaction between the 4-acetylaminosalicylic acid and the dimethyl sulfate further includes: The dried methyl 2-methoxy-4-acetaminobenzoate was recrystallized.