A method for preparing methyl o-iodobenzoate
By reacting methyl o-aminobenzoate with nitrososulfuric acid under acidic conditions, the problems of foam generation and large wastewater volume in the synthesis of methyl o-iodobenzoate were solved, and a high-purity, low-cost preparation method was achieved.
Patent Information
- Application Number
- CN202310983536.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-08-07
- Publication Date
- 2026-02-10
- Estimated Expiration
- 2043-08-07
AI Technical Summary
Existing methods for synthesizing methyl o-iodobenzoate suffer from problems such as excessive foam generation, large wastewater volume, high product salt content, and low purity.
Methyl o-aminobenzoate was produced by reacting methyl o-aminobenzoate with nitrosulosic acid under acidic conditions. Dilute sulfuric acid was used as the acidic condition, and the reaction temperature and time were controlled. Urea was added to quench excess nitrosulosic acid, and hexane was used for extraction during post-treatment.
This method enables the low-cost and environmentally friendly preparation of methyl o-iodobenzoate, with readily available raw materials, safe operation, high product purity, low salt content, and reduced wastewater generation.
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Figure BDA0004380207490000011 
Figure BDA0004380207490000021
Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for preparing methyl o-iodobenzoate. Background Technology
[0002] Montelukast sodium is a highly effective, low-toxicity, and safe anti-asthmatic, anti-inflammatory, and anti-allergic drug with broad application prospects. Compound A ((E)-2-[3-[3-[2-(7-chloro-2-quinolinyl)vinyl]phenyl]-3-oxopropyl]benzoate) is an important intermediate in the synthesis of montelukast sodium. Methyl o-iodobenzoate, as an ester organic compound, is an important organic synthesis intermediate, used as a pharmaceutical intermediate, pesticide intermediate, etc., and is also an important raw material for the preparation of compound A.
[0003]
[0004] Currently, one method for synthesizing methyl o-iodobenzoate involves reacting methyl o-aminobenzoate with potassium iodide in the presence of sodium nitrite and acid. However, this method uses sodium nitrite, which releases a large amount of nitrogen and easily generates excessive foam, making the reaction difficult to continue. It also produces a large amount of wastewater, and the resulting product has high salt content, low purity, and poor appearance. Therefore, it is necessary to develop a new method for synthesizing methyl o-iodobenzoate. Summary of the Invention
[0005] The purpose of this invention is to provide a method for preparing methyl o-iodobenzoate based on the prior art, wherein methyl o-aminobenzoate is used as a raw material and reacted with sodium iodide in the presence of nitrososulfuric acid to generate methyl o-iodobenzoate.
[0006] The technical solution of the present invention is as follows:
[0007] A method for preparing methyl o-iodobenzoate involves using methyl o-aminobenzoate as a raw material under acidic conditions, adding nitrososulfuric acid, and undergoing an iodination reaction to generate methyl o-iodobenzoate; the synthetic route is as follows:
[0008]
[0009] In a preferred embodiment, nitrososulfuric acid is used in solution with a mass concentration of 30 wt.% to 50 wt.%, which may be, but is not limited to, 35 wt.%, 40 wt.%, 45 wt.%, or 50 wt.%, with 40 wt.% being preferred.
[0010] The acidic conditions in this invention can be provided by sulfuric acid, preferably dilute sulfuric acid, more preferably dilute sulfuric acid with a mass concentration of 10-50%, and even more preferably dilute sulfuric acid with a mass concentration of 10-30%.
[0011] For the purposes of this invention, the molar ratio of methyl anthranilate to nitrososulfuric acid is 1:0.5-2.5, and may be, but is not limited to, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, and 1:2.5, preferably 1:0.8-1.5, and more preferably 1:1.1.
[0012] In a preferred embodiment, the molar ratio of methyl anthranilate to sodium iodide is 1:0.5-1.5, and may be, but is not limited to, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, and 1:1.5, preferably 1:0.8-1.2, and more preferably 1:1.
[0013] In this invention, the iodination reaction temperature is 28-65℃, preferably 30-65℃, more preferably 30-60℃, more preferably 35-55℃, and more preferably 40-50℃. The iodination reaction time is 0.5-20h, preferably 1-10h, and more preferably 1-5h.
[0014] In this invention, nitrososulfuric acid is added slowly under stirring, preferably at a temperature below 5°C. After the reaction is complete, excess nitrososulfuric acid can be quenched with urea to terminate the reaction; the amount of urea used can be adjusted according to the amount of nitrososulfuric acid used.
[0015] In a preferred embodiment, a method for preparing methyl o-iodobenzoate includes the following steps:
[0016] (1) Methyl anthranilate was added to sulfuric acid to obtain solution A;
[0017] (2) Slowly add nitrososulfuric acid to the solution in the above solution preparation step to obtain solution B;
[0018] (3) Quickly add the above solution B to the iodide solution and react under controlled temperature to obtain solution C;
[0019] (4) Quenching reaction of the solution C;
[0020] (5) The quenched solution is subjected to a post-processing step to obtain the target product.
[0021] In a preferred embodiment, in step (1), methyl anthranilate is added to a 10-20% H2SO4 solution, stirred until dissolved, and cooled to below 10°C, preferably below 5°C.
[0022] In a preferred embodiment, 35-45 wt.% of nitrososulfuric acid is slowly added to the solution in step (1) in step (2) to obtain a diazonium solution.
[0023] In a preferred embodiment, in step 3, the above-mentioned diazo solution is rapidly added to a 10-20% sodium iodide solution, and the reaction is carried out at a controlled temperature for 1-5 hours.
[0024] In a preferred embodiment, the reaction temperature is 30-60℃, which may be, but is not limited to, 30℃, 35℃, 40℃, 45℃, 50℃, 55℃, or 60℃, but is preferably 45℃.
[0025] In a preferred embodiment, in step 4, stirring is required after quenching for 5-15 minutes, preferably 10 minutes.
[0026] In a preferred embodiment, in step 5, the separated aqueous layer is extracted twice with n-hexane.
[0027] The advantages of using the technical solution of this invention are as follows:
[0028] This invention provides a method for preparing methyl o-iodobenzoate. The raw material, methyl o-aminobenzoate, is widely available and inexpensive. The reagents used in the entire preparation process are readily available, resulting in low production costs and minimal toxicity. The reaction conditions are mild, the operation is simple, the operation is highly safe, and the post-treatment is simple, without generating large amounts of wastewater, which is beneficial to environmental protection. The prepared product has low salt content and high purity. Detailed Implementation
[0029] The preparation method of p-aminobenzonitrile in this invention will be clearly and completely described below with reference to specific embodiments. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.
[0030] Example 1
[0031] A method for preparing methyl o-iodobenzoate, comprising the following steps:
[0032] At room temperature, methyl anthranilate (0.1 mol, 15.1 g) was added to 17% H₂SO₄ solution (0.5 mol, 288.2 g), stirred until dissolved, and cooled to 5°C. 40 wt.% nitrososulfuric acid (0.11 mol, 34.9 g) was slowly added at 0-5°C, and stirred for 20-30 min to obtain a diazonium solution. This diazonium solution was then rapidly added to 13% sodium iodide solution (0.1 mol, 115.3 g), and the temperature was raised to 45°C and maintained for 3 h. After the reaction was complete, urea (0.01 mol, 0.6 g) was added to quench excess nitrososulfuric acid, and the mixture was stirred for 10 min. The organic layer was separated, and the aqueous layer was extracted twice with n-hexane, dissolved, and combined with the previously separated organic phases. The mixture was filtered, dried, and rotary evaporated to obtain methyl anthranilate with a purity of 96.57% and a yield of 99.5%.
[0033] Examples 2-9
[0034] Following the preparation method and reaction conditions disclosed in Example 1, with only some reaction conditions changed, Examples 2-9 and Comparative Examples 1-4 were constructed, as shown in Table 1.
[0035] Table 1 shows the reaction parameters and experimental results in the examples.
[0036] experiment 1 / 1 concentration / % Ratio 2 Reaction temperature / °C Total yield / % Product purity / % Example 1 1:1.1 40 1:1 45 99.5 96.57 Example 2 1:0.5 95.2 95.85 Example 3 1:2.5 97.6 94.33 Example 4 30 94.3 93.52 Example 5 50 98.1 94.56 Example 6 1:0.5 92.5 96.55 Example 7 1:1.5 97.9 94.85 Example 8 30 96.8 95.94 Example 9 60 95.4 96.50 Comparative Example 1 1:0.3 72.2 96.12 Comparative Example 2 1:2.8 80.3 90.25 Comparative Example 3 20 81.5 94.51 Comparative Example 4 55 73.4 92.53
[0037] Note 1: Blank spaces in the table indicate that the parameter is the same as in Example 1;
[0038] 2. "Ratio 1" in Table 1 represents the molar ratio of methyl anthranilate to nitrososulfuric acid.
[0039] 3. The “concentration” in Table 1 represents the mass concentration of nitrososulfuric acid;
[0040] 4. “Ratio 2” in Table 1 represents the molar ratio of methyl anthranilate to sodium iodide.
[0041] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications may still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions may be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.
Claims
1. A method for preparing methyl o-iodobenzoate, characterized in that, Includes the following steps: At room temperature, 0.1 mol of methyl o-aminobenzoate was added to 0.5 mol of 17% H2SO4 solution and stirred until dissolved. The solution was then cooled to 5°C. 0.11 mol of 40 wt.% nitrososulfuric acid was slowly added at 0-5°C and stirred for 20-30 min to obtain a diazonium solution. The diazonium solution was then rapidly added to 0.1 mol of 13% sodium iodide solution and heated to 45°C for 3 h. After the reaction was completed, 0.01 mol of urea was added to quench the excess nitrososulfuric acid and stirred for 10 min. The organic layer was separated, and the aqueous layer was extracted twice with n-hexane. The aqueous layer was then combined with the previously separated organic phases, filtered, dried, and rotary evaporated to obtain methyl o-iodobenzoate with a purity of 96.57% and a yield of 99.5%.
2. A method for preparing methyl o-iodobenzoate, characterized in that, Includes the following steps: At room temperature, 0.1 mol of methyl o-aminobenzoate was added to 0.5 mol of 17% H2SO4 solution and stirred until dissolved. The solution was then cooled to 5°C. 0.05 mol of 40 wt.% nitrososulfuric acid was slowly added at 0-5°C and stirred for 20-30 min to obtain a diazonium solution. The diazonium solution was then rapidly added to 0.1 mol of 13% sodium iodide solution and heated to 45°C for 3 h. After the reaction was completed, 0.01 mol of urea was added to quench the excess nitrososulfuric acid and stirred for 10 min. The organic layer was separated, and the aqueous layer was extracted twice with n-hexane. The aqueous layer was then combined with the previously separated organic phases, filtered, dried, and rotary evaporated to obtain methyl o-iodobenzoate with a purity of 95.85% and a yield of 95.2%.
3. A method for preparing methyl o-iodobenzoate, characterized in that, Includes the following steps: At room temperature, 0.1 mol of methyl o-aminobenzoate was added to 0.5 mol of 17% H2SO4 solution and stirred until dissolved. The solution was then cooled to 5°C. 0.25 mol of 40 wt.% nitrososulfuric acid was slowly added at 0-5°C and stirred for 20-30 min to obtain a diazonium solution. The diazonium solution was then rapidly added to 0.1 mol of 13% sodium iodide solution and heated to 45°C for 3 h. After the reaction was completed, 0.01 mol of urea was added to quench the excess nitrososulfuric acid and stirred for 10 min. The organic layer was separated, and the aqueous layer was extracted twice with n-hexane. The aqueous layer was then combined with the previously separated organic phases, filtered, dried, and rotary evaporated to obtain methyl o-iodobenzoate with a purity of 94.33% and a yield of 97.6%.
4. A method for preparing methyl o-iodobenzoate, characterized in that, Includes the following steps: At room temperature, 0.1 mol of methyl o-aminobenzoate was added to 0.5 mol of 17% H2SO4 solution and stirred until dissolved. The solution was then cooled to 5°C. At 0-5°C, 0.11 mol of 30 wt.% nitrososulfuric acid was slowly added and stirred for 20-30 min to obtain a diazonium solution. The diazonium solution was then rapidly added to 0.1 mol of 13% sodium iodide solution and heated to 45°C for 3 h. After the reaction was completed, 0.01 mol of urea was added to quench the excess nitrososulfuric acid and stirred for 10 min. The organic layer was separated, and the aqueous layer was extracted twice with n-hexane. The aqueous layer was then combined with the previously separated organic phases, filtered, dried, and rotary evaporated to obtain methyl o-iodobenzoate with a purity of 93.52% and a yield of 94.3%.
5. A method for preparing methyl o-iodobenzoate, characterized in that, Includes the following steps: At room temperature, 0.1 mol of methyl o-aminobenzoate was added to 0.5 mol of 17% H2SO4 solution and stirred until dissolved. The solution was then cooled to 5°C. 0.11 mol of 50 wt.% nitrososulfuric acid was slowly added at 0-5°C and stirred for 20-30 min to obtain a diazonium solution. The diazonium solution was then rapidly added to 0.1 mol of 13% sodium iodide solution and heated to 45°C for 3 h. After the reaction was completed, 0.01 mol of urea was added to quench excess nitrososulfuric acid and stirred for 10 min. The organic layer was separated, and the aqueous layer was extracted twice with n-hexane. The aqueous layer was then combined with the previously separated organic phases, filtered, dried, and rotary evaporated to obtain methyl o-iodobenzoate with a purity of 94.56% and a yield of 98.1%.
6. A method for preparing methyl o-iodobenzoate, characterized in that, Includes the following steps: At room temperature, 0.1 mol of methyl o-aminobenzoate was added to 0.5 mol of 17% H2SO4 solution and stirred until dissolved. The solution was then cooled to 5°C. 0.11 mol of 40 wt.% nitrososulfuric acid was slowly added at 0-5°C and stirred for 20-30 min to obtain a diazonium solution. The diazonium solution was then rapidly added to 0.05 mol of 13% sodium iodide solution and heated to 45°C for 3 h. After the reaction was completed, 0.01 mol of urea was added to quench the excess nitrososulfuric acid and stirred for 10 min. The organic layer was separated, and the aqueous layer was extracted twice with n-hexane. The aqueous layer was then combined with the previously separated organic phases, filtered, dried, and rotary evaporated to obtain methyl o-iodobenzoate with a purity of 96.55% and a yield of 92.5%.
7. A method for preparing methyl o-iodobenzoate, characterized in that, Includes the following steps: At room temperature, 0.1 mol of methyl o-aminobenzoate was added to 0.5 mol of 17% H2SO4 solution and stirred until dissolved. The solution was then cooled to 5°C. 0.11 mol of 40 wt.% nitrososulfuric acid was slowly added at 0-5°C and stirred for 20-30 min to obtain a diazonium solution. The diazonium solution was then rapidly added to 0.15 mol of 13% sodium iodide solution and heated to 45°C for 3 h. After the reaction was completed, 0.01 mol of urea was added to quench the excess nitrososulfuric acid and stirred for 10 min. The organic layer was separated, and the aqueous layer was extracted twice with n-hexane. The aqueous layer was then combined with the previously separated organic phases, filtered, dried, and rotary evaporated to obtain methyl o-iodobenzoate with a purity of 94.85% and a yield of 97.9%.
8. A method for preparing methyl o-iodobenzoate, characterized in that, Includes the following steps: At room temperature, 0.1 mol of methyl o-aminobenzoate was added to 0.5 mol of 17% H2SO4 solution and stirred until dissolved. The solution was then cooled to 5°C. 0.11 mol of 40 wt.% nitrososulfuric acid was slowly added at 0-5°C and stirred for 20-30 min to obtain a diazonium solution. The diazonium solution was then rapidly added to 0.1 mol of 13% sodium iodide solution and heated to 30°C for 3 h. After the reaction was completed, 0.01 mol of urea was added to quench the excess nitrososulfuric acid and stirred for 10 min. The organic layer was separated, and the aqueous layer was extracted twice with n-hexane. The aqueous layer was then combined with the previously separated organic phases, filtered, dried, and rotary evaporated to obtain methyl o-iodobenzoate with a purity of 95.94% and a yield of 96.8%.
9. A method for preparing methyl o-iodobenzoate, characterized in that, Includes the following steps: At room temperature, 0.1 mol of methyl o-aminobenzoate was added to 0.5 mol of 17% H2SO4 solution and stirred until dissolved. The solution was then cooled to 5°C. 0.11 mol of 40 wt.% nitrososulfuric acid was slowly added at 0-5°C and stirred for 20-30 min to obtain a diazonium solution. The diazonium solution was then rapidly added to 0.1 mol of 13% sodium iodide solution and heated to 60°C for 3 h. After the reaction was completed, 0.01 mol of urea was added to quench the excess nitrososulfuric acid and stirred for 10 min. The organic layer was separated, and the aqueous layer was extracted twice with n-hexane. The aqueous layer was then combined with the previously separated organic phases, filtered, dried, and rotary evaporated to obtain methyl o-iodobenzoate with a purity of 96.50% and a yield of 95.4%.