CN115057768A - Synthetic method of 3, 5-dichloro-4-methoxybenzoic acid - Google Patents
Synthetic method of 3, 5-dichloro-4-methoxybenzoic acid Download PDFInfo
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- CN115057768A CN115057768A CN202210997689.4A CN202210997689A CN115057768A CN 115057768 A CN115057768 A CN 115057768A CN 202210997689 A CN202210997689 A CN 202210997689A CN 115057768 A CN115057768 A CN 115057768A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
- B01J27/02—Sulfur, selenium or tellurium; Compounds thereof
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0215—Sulfur-containing compounds
- B01J31/0225—Sulfur-containing compounds comprising sulfonic acid groups or the corresponding salts
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4277—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues
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Abstract
The invention belongs to the technical field of synthesis of pharmaceutical compounds, and discloses a method for synthesizing 3, 5-dichloro-4-methoxybenzoic acid, which comprises the following steps: adding 4-methoxybenzoic acid into an organic solvent, adding a chlorine source and concentrated sulfuric acid, and carrying out chlorination reaction at the reaction temperature of 80-100 ℃; after the reaction is finished, water is added for crystallization, separation and drying to obtain the 3, 5-dichloro-4-methoxybenzoic acid.
Description
Technical Field
The invention belongs to the technical field of synthesis of pharmaceutical compounds, and particularly relates to a synthesis method of 3, 5-dichloro-4-methoxybenzoic acid.
Background
The statements herein merely provide background information related to the present disclosure and may not necessarily constitute prior art.
The Dotinurad (dortinode) is a urate reabsorption inhibitor and can be used for targeting and inhibiting the activity of a urate reabsorption transporter (URAT 1). Uric acid reabsorption is inhibited and blood uric acid levels are reduced by a transporter (URAT 1) that selectively inhibits uric acid reabsorption in the kidney. Can be used for treating gout caused by hyperuricemia. The Dotinurad is generally prepared by taking 3, 5-dichloro-4-methoxybenzoic acid as a raw material, firstly carrying out amide condensation reaction with benzothiazoline, and then oxidizing and demethylating.
The existing preparation method of 3, 5-dichloro-4-methoxybenzoic acid is generally prepared from chromium trioxide, potassium chlorate and other substances, and when chromium trioxide is adopted for preparation, the product yield is low; when the potassium chlorate is adopted for preparation, great potential safety hazard is easily caused, impurities such as chloranil and the like are generated in the reaction, the purification is not easy, and the method is not suitable for industrial production.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide the synthetic method of the 3, 5-dichloro-4-methoxybenzoic acid, which has the advantages of simple and safe operation, mild reaction conditions, high yield, suitability for industrial production and the like.
In order to achieve the purpose, the invention is realized by the following technical scheme:
the invention provides a synthetic method of 3, 5-dichloro-4-methoxybenzoic acid, which comprises the following steps: adding 4-methoxybenzoic acid into an organic solvent, adding a chlorine source and an acid catalyst, and carrying out chlorination reaction at the reaction temperature of 90-100 ℃; after the reaction is finished, adding water for crystallization, separating and drying to obtain the 3, 5-dichloro-4-methoxybenzoic acid.
The beneficial effects of the invention are as follows:
the synthesis method can effectively avoid the use of dangerous reagents, has mild reaction conditions, cheap and easily obtained raw materials and higher yield, and is favorable for industrial production.
Detailed Description
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
A synthetic method of 3, 5-dichloro-4-methoxybenzoic acid comprises the following steps: adding 4-methoxybenzoic acid into an organic solvent, adding a chlorine source and an acid catalyst, and carrying out chlorination reaction at the reaction temperature of 80-100 ℃; after the reaction is finished, adding water for crystallization, separating and drying to obtain the 3, 5-dichloro-4-methoxybenzoic acid.
In some embodiments, the organic solvent is selected from acetic acid, acetonitrile, trifluoroacetic acid or acetone, preferably acetonitrile.
In some embodiments, the acid catalyst is selected from sulfuric acid, methanesulfonic acid or p-toluenesulfonic acid, preferably p-toluenesulfonic acid, and the molar ratio of 4-methoxybenzoic acid to p-toluenesulfonic acid is 1:0 to 1.5, preferably 1: 1.
In some embodiments, the chlorine source is N-chlorosuccinimide. The chlorine source is safe and stable, and is easy to be obtained industrially.
Preferably, the molar ratio of 4-methoxybenzoic acid to N-chlorosuccinimide is 1: 2.5-3.0.
It is further preferred that the molar ratio of 4-methoxybenzoic acid to N-chlorosuccinimide is 1: 2.8.
In some embodiments, the time for the chlorination reaction is 2 to 4 hours, preferably 2.5 to 3.5 hours.
Preferably, the temperature of the chlorination reaction is 90-95 ℃.
In some embodiments, after the reaction is finished, the reaction system is cooled to 40-60 ℃, and water is added for crystallization.
Preferably, the temperature for water addition crystallization is 50-55 ℃.
The present invention will be further described with reference to the following examples.
Example 1
The preparation method of the 3, 5-dichloro-4-methoxybenzoic acid comprises the following steps:
in a 250 mL three-necked flask, 4-methoxybenzoic acid (10.0 g, 65.7 mmol) was added at room temperature, followed by acetonitrile (100 mL) and N-chlorosuccinimide (24.6 g, 184.0 mmol), and the reaction was stirred at 95 ℃ for 3 hours after completion of the addition. Cooling to 55 ℃, adding water (100 mL) for crystallization, performing suction filtration, washing with 30% methanol water, and drying to obtain 9.2 g of 3, 5-dichloro-4-methoxybenzoic acid with the yield of 63.3%. 1 H NMR(DMSO; 400MHz) 13.55(s, 1H) 7.94(s, 2H) 3.89(s, 3H)。
Example 2
The preparation method of the 3, 5-dichloro-4-methoxybenzoic acid comprises the following steps:
in a 250 mL three-necked flask, 4-methoxybenzoic acid (10.0 g) was added at room temperature, followed by acetonitrile (100 mL), N-chlorosuccinimide (24.6 g) and p-toluenesulfonic acid (11.3 g), and the reaction was stirred at 95 ℃ for 3 hours after the addition. Cooling to 60 ℃, adding water (100 mL) for crystallization, performing suction filtration, washing with 30% methanol water, and drying to obtain 10.5 g of 3, 5-dichloro-4-methoxybenzoic acid with the yield of 72.3%.
Example 3
The preparation method of the 3, 5-dichloro-4-methoxybenzoic acid comprises the following steps:
in a 250 mL three-necked flask, 4-methoxybenzoic acid (10.0 g) was added at room temperature, followed by acetonitrile (100 mL), N-chlorosuccinimide (24.6 g) and p-toluenesulfonic acid (3.7 g), and the reaction was stirred at 94 ℃ for 3 hours after the addition. Cooling to 50 deg.C, adding water (100 mL), crystallizing, filtering, washing with 30% methanol water, and drying to obtain 9.6 g of 3, 5-dichloro-4-methoxybenzoic acid with yield of 66.1%.
Example 4
The preparation method of the 3, 5-dichloro-4-methoxybenzoic acid comprises the following steps:
in a 250 mL three-necked flask, 4-methoxybenzoic acid (10.0 g) was added at room temperature, followed by acetonitrile (100 mL), N-chlorosuccinimide (24.6 g) and p-toluenesulfonic acid (9.4 g), and the reaction was stirred at 90 ℃ for 3 hours after the addition. Cooling to 50 ℃, adding water (100 mL) for crystallization, performing suction filtration, washing with 30% methanol water, and drying to obtain 9.8 g of 3, 5-dichloro-4-methoxybenzoic acid with the yield of 67.4%.
Example 5
The preparation method of the 3, 5-dichloro-4-methoxybenzoic acid comprises the following steps:
in a 250 mL three-necked flask, 4-methoxybenzoic acid (10.0 g) was added at room temperature, followed by acetonitrile (100 mL), N-chlorosuccinimide (24.6 g) and p-toluenesulfonic acid (14.3 g), and the reaction was stirred at 85 ℃ for 3 hours after the addition. Cooling to 50 deg.C, adding water (100 mL), crystallizing, filtering, washing with 30% methanol water, and drying to obtain 9.9 g of 3, 5-dichloro-4-methoxybenzoic acid with yield of 68.1%.
Example 6
The preparation method of the 3, 5-dichloro-4-methoxybenzoic acid comprises the following steps:
in a 250 mL three-necked flask, 4-methoxybenzoic acid (10.0 g) was added at room temperature, followed by acetic acid (100 mL), N-chlorosuccinimide (24.6 g) and p-toluenesulfonic acid (11.3 g), and the reaction was stirred at 95 ℃ for 3 hours after the addition. Cooling to 50 ℃, adding water (100 mL) for crystallization, performing suction filtration, washing with 30% methanol water, and drying to obtain 8.7 g of 3, 5-dichloro-4-methoxybenzoic acid with the yield of 59.9%.
Example 7
The preparation method of the 3, 5-dichloro-4-methoxybenzoic acid comprises the following steps:
in a 250 mL three-necked flask, 4-methoxybenzoic acid (10.0 g) was added at room temperature, followed by trifluoroacetic acid (100 mL), N-chlorosuccinimide (24.6 g) and p-toluenesulfonic acid (11.3 g), and the reaction was stirred at 95 ℃ for 3 hours after the addition. Cooling to 50 deg.C, adding water (100 mL), crystallizing, filtering, washing with 30% methanol water, and drying to obtain 8.9 g of 3, 5-dichloro-4-methoxybenzoic acid with yield of 61.3%.
Example 8
The difference from example 7 is that: trifluoroacetic acid was replaced with acetic acid, and the other parameters were the same as in example 7. The yield of the prepared 3, 5-dichloro-4-methoxybenzoic acid was 56.1%.
Example 9
The difference from example 7 is that: trifluoroacetic acid was replaced with acetone, and the other parameters were the same as in example 7. The yield of the prepared 3, 5-dichloro-4-methoxybenzoic acid was 53.2%.
Example 10
The difference from example 7 is that: p-toluenesulfonic acid (11.3 g) was replaced with 6.6 g of sulfuric acid, the other parameters being the same as in example 7. The yield of the prepared 3, 5-dichloro-4-methoxybenzoic acid was 55.4%.
Example 11
The difference from example 7 is that: p-toluenesulfonic acid (11.3 g) was replaced with methanesulfonic acid 6.3 g, and the other parameters were the same as in example 7. The yield of the prepared 3, 5-dichloro-4-methoxybenzoic acid was 56.1%.
Example 12
The difference from example 7 is that: 4-Methoxybenzoic acid (10.0 g) and N-chlorosuccinimide (24.6 g) were replaced with 4-methoxybenzoic acid (10.0 g) and N-chlorosuccinimide (21.9 g), and the other parameters were the same as in example 7. The yield of the prepared 3, 5-dichloro-4-methoxybenzoic acid was 55.3%.
Example 13
The difference from example 7 is that: 4-Methoxybenzoic acid (10.0 g) and N-chlorosuccinimide (24.6 g) were replaced with 4-methoxybenzoic acid (10.0 g) and N-chlorosuccinimide (26.3 g), and the other parameters were the same as in example 7. The yield of the 3, 5-dichloro-4-methoxybenzoic acid obtained was 61.1%.
Example 14
The difference from example 7 is that: the stirring reaction time was changed from 3 hours to 4 hours, and other parameters were the same as in example 7. The yield of the 3, 5-dichloro-4-methoxybenzoic acid obtained was 61.5%.
Example 15
The difference from example 7 is that: the stirring reaction time was changed from 3 hours to 2 hours, and other parameters were the same as in example 7. The yield of the prepared 3, 5-dichloro-4-methoxybenzoic acid was 55.3%.
Example 16
The difference from example 7 is that: the "temperature rise to 95 ℃ after the end of addition" was replaced with "temperature rise to 90 ℃ after the end of addition", and the other parameters were the same as in example 7. The yield of the prepared 3, 5-dichloro-4-methoxybenzoic acid was 57.6%.
Example 17
The difference from example 7 is that: the "temperature increased to 95 ℃ after the end of addition" was replaced with "temperature increased to 93 ℃ after the end of addition", and the other parameters were the same as in example 7. The yield of the prepared 3, 5-dichloro-4-methoxybenzoic acid is 60.2%.
Example 18
The difference from example 7 is that: the "temperature rise to 95 ℃ after the end of addition" was replaced with "temperature rise to 80 ℃ after the end of addition", and the other parameters were the same as in example 7. The yield of the prepared 3, 5-dichloro-4-methoxybenzoic acid was 49.3%.
Example 19
The difference from example 7 is that: the "temperature increased to 95 ℃ after the end of addition" was replaced with "temperature increased to 100 ℃ after the end of addition", and the other parameters were the same as in example 7. The yield of the prepared 3, 5-dichloro-4-methoxybenzoic acid was 51.2%.
Example 20
The difference from example 7 is that: "Cool to 50 ℃ and add water (100 mL) for crystallization" was replaced by "Cool to 55 ℃ and add water (100 mL) for crystallization", and the other parameters were the same as in example 7. The yield of the 3, 5-dichloro-4-methoxybenzoic acid obtained was 61.4%.
Example 21
The difference from example 7 is that: "Cool to 50 ℃ and add water (100 mL) for crystallization" was replaced by "Cool to 53 ℃ and add water (100 mL) for crystallization", and the other parameters were the same as in example 7. The yield of the 3, 5-dichloro-4-methoxybenzoic acid obtained was 61.3%.
Example 22
The difference from example 7 is that: "lower to 50 ℃ and add water (100 mL) for crystallization" was replaced by "lower to 40 ℃ and add water (100 mL) for crystallization", and the other parameters were the same as in example 7. The yield of the prepared 3, 5-dichloro-4-methoxybenzoic acid was 56.2%.
Example 23
The difference from example 7 is that: the "50 ℃ lowering and water (100 mL) addition for crystallization" was replaced by "60 ℃ lowering and water (100 mL) addition for crystallization", and the other parameters were the same as in example 7. The yield of the prepared 3, 5-dichloro-4-methoxybenzoic acid was 58.9%.
Comparative example 1
The difference from example 2 is that: the organic solvent acetonitrile was replaced with ethyl acetate. The yield of 3, 5-dichloro-4-methoxybenzoic acid was 36.1%.
Comparative example 2
The difference from example 2 is that: the acid catalyst was replaced with acetic acid. The yield of 3, 5-dichloro-4-methoxybenzoic acid was 61.2%.
Comparative example 3
The difference from example 2 is that: the chlorine source N-chlorosuccinimide was replaced with sulfuryl chloride. The yield of 3, 5-dichloro-4-methoxybenzoic acid was 0.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A synthetic method of 3, 5-dichloro-4-methoxybenzoic acid is characterized by comprising the following steps: the method comprises the following steps: adding 4-methoxybenzoic acid into an organic solvent, adding a chlorine source and an acid catalyst, and carrying out chlorination reaction at the reaction temperature of 80-100 ℃; after the reaction is finished, adding water for crystallization, separating and drying to obtain the 3, 5-dichloro-4-methoxybenzoic acid.
2. The method for synthesizing 3, 5-dichloro-4-methoxybenzoic acid according to claim 1, characterized in that: the organic solvent is selected from acetic acid, acetonitrile, trifluoroacetic acid or acetone.
3. The method for synthesizing 3, 5-dichloro-4-methoxybenzoic acid according to claim 2, characterized in that: the organic solvent is acetonitrile.
4. The method for synthesizing 3, 5-dichloro-4-methoxybenzoic acid according to claim 1, characterized in that: the acid catalyst is selected from sulfuric acid, methanesulfonic acid or p-toluenesulfonic acid, preferably p-toluenesulfonic acid, and the molar ratio of 4-methoxybenzoic acid to p-toluenesulfonic acid is 1: 0-1.5.
5. The method for synthesizing 3, 5-dichloro-4-methoxybenzoic acid according to claim 1, characterized in that: the chlorine source is N-chlorosuccinimide.
6. The method for synthesizing 3, 5-dichloro-4-methoxybenzoic acid according to claim 5, characterized in that: the mol ratio of the 4-methoxybenzoic acid to the N-chlorosuccinimide is 1: 2.5-3.0.
7. The method of synthesizing 3, 5-dichloro-4-methoxybenzoic acid according to claim 6, characterized in that: the molar ratio of the 4-methoxybenzoic acid to the N-chlorosuccinimide is 1: 2.8.
8. The method for synthesizing 3, 5-dichloro-4-methoxybenzoic acid according to claim 1, characterized in that: the time of the chlorination reaction is 2-4 h; carrying out chlorination reaction at the temperature of 90-95 ℃.
9. The method for synthesizing 3, 5-dichloro-4-methoxybenzoic acid according to claim 1, characterized in that: after the reaction is finished, cooling the reaction system to 40-60 ℃, and adding water for crystallization.
10. The method for synthesizing 3, 5-dichloro-4-methoxybenzoic acid according to claim 9, which comprises the following steps: cooling the reaction system to 50-55 ℃, and adding water for crystallization.
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