CN115650851A - Preparation method of 2-fluoro-4-bromo-6-methyl benzoate - Google Patents
Preparation method of 2-fluoro-4-bromo-6-methyl benzoate Download PDFInfo
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- CN115650851A CN115650851A CN202211403775.4A CN202211403775A CN115650851A CN 115650851 A CN115650851 A CN 115650851A CN 202211403775 A CN202211403775 A CN 202211403775A CN 115650851 A CN115650851 A CN 115650851A
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Abstract
The invention discloses a preparation method of 2-fluoro-4-bromo-6-methyl benzoate, which comprises the following steps: (1) 2-fluoro-6-methylaniline is used as a starting material and reacts with N-bromosuccinimide to generate a compound III; (2) The compound III and sodium nitrite generate diazonium salt, and the compound III and the sodium nitrite generate a sandmeyer reaction under the conditions of potassium iodide and copper powder to generate a compound IV; (3) The compound IV and magnesium generate a Grignard reagent, and the Grignard reagent reacts under the condition of carbon dioxide to generate a compound V; (4) Carrying out methyl esterification on the compound V under the catalysis of concentrated sulfuric acid to generate a compound I; namely the methyl 2-fluoro-4-bromo-6-methylbenzoate. The preparation method has higher yield.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, in particular to a preparation method of 2-fluoro-4-bromo-6-methyl benzoate.
Background
2-fluoro-4-bromo-6-methylbenzoate is a key pharmaceutical intermediate, and WO2021/7477 discloses the following route for synthesizing 2-fluoro-4-bromo-6-methylbenzoate compound I:
in the synthesis method, 2-fluoro-4-bromo-6-methylbenzoic acid is used as a starting material in the process of synthesizing the 2-fluoro-4-bromo-6-methylbenzoic acid methyl ester compound I, and the material is very expensive and is not beneficial to cost control.
Disclosure of Invention
In view of the above problems in the prior art, the applicant of the present invention provides a method for preparing methyl 2-fluoro-4-bromo-6-methylbenzoate. The preparation method of the invention has low cost and is beneficial to industrialized production.
The technical scheme of the invention is as follows:
the first purpose of the invention is to provide a preparation method of 2-fluoro-4-bromo-6-methyl benzoate, which is carried out according to the following synthetic route:
the method comprises the following specific steps:
(1) 2-fluoro-6-methylaniline is used as a starting material and reacts with N-bromosuccinimide to generate a compound III;
(2) Diazo salt is generated by the compound III and sodium nitrite, and the compound IV is generated by the Sandmeyer reaction under the condition of potassium iodide and copper powder;
(3) The compound IV and magnesium generate a Grignard reagent, and the Grignard reagent reacts under the condition of carbon dioxide to generate a compound V;
(4) Carrying out methyl esterification on the compound V under the catalysis of concentrated sulfuric acid to generate a compound I; namely the methyl 2-fluoro-4-bromo-6-methylbenzoate.
In one embodiment of the present invention, in step (1), the reaction solvent is N, N-dimethylformamide; the mol ratio of the 2-fluoro-6-methylaniline to the N-bromosuccinimide is 1.1-1.3; the reaction conditions are as follows: the temperature is 10-30 ℃, and the reaction time is 1-3 h.
In one embodiment of the present invention, in the step (2), the molar ratio of the compound III to the sodium nitrite is 1.1 to 1.3; the diazotization reaction conditions are as follows: the temperature is 10-30 ℃, and the reaction time is 1-3 h.
In one embodiment of the present invention, the solvent in the diazotization reaction is concentrated sulfuric acid, and the mass concentration of the concentrated sulfuric acid is 98%.
In one embodiment of the present invention, in step (2), the molar ratio of potassium iodide to compound III is 1.1 to 1.3; the molar ratio of the copper powder to the compound III is 0.05; the conditions of the Sandemall reaction are as follows: the temperature is 10-30 ℃, and the reaction time is 1-3 h.
In one embodiment of the present invention, in step (3), the reaction solvent is one or more of tetrahydrofuran, diethyl ether, and methyl tetrahydrofuran; the molar ratio of the compound IV to magnesium and carbon dioxide is 1.0-1.2.
In one embodiment of the present invention, in the step (3), the conditions for reacting the compound IV with magnesium are: the temperature is 40-65 ℃, and the reaction time is 2-6 h.
In one embodiment of the present invention, in the step (3), the conditions for the reaction of the grignard reagent with carbon dioxide are: the temperature is 0-10 ℃, and the reaction time is 1-2 h.
In one embodiment of the present invention, in step (4), the solvent is methanol; the molar ratio of the compound V to concentrated sulfuric acid is 1.01-0.05; the reaction conditions are as follows: the temperature is 50-65 ℃, and the reaction time is 3-6 h.
In one embodiment of the present invention, in the step (4), the mass concentration of the concentrated sulfuric acid is 98%;
the beneficial technical effects of the invention are as follows:
the method takes the cheap 2-fluoro-6-methylaniline as the starting material, has low cost and easy treatment in the process of the total synthesis route, and the lowest yield in each step also reaches 85 percent, and the total yield also reaches about 71 percent; compared with the method of directly diazotizing and re-esterifying the upper cyano group by using 2-fluoro-4-bromo-6-methylaniline (compound II), the method avoids the use of highly toxic products such as sodium cyanide, cuprous cyanide and the like, is more environment-friendly and is more beneficial to industrial production.
Drawings
FIG. 1 shows the preparation of methyl 2-fluoro-4-bromo-6-methylbenzoate obtained in example 1 1 An H-NMR spectrum;
FIG. 2 is a gas chromatogram of methyl 2-fluoro-4-bromo-6-methylbenzoate obtained in example 1.
Detailed Description
The present invention will be described in detail with reference to the accompanying drawings and examples.
Example 1
A preparation method of methyl 2-fluoro-4-bromo-6-methylbenzoate comprises the following steps:
(1) Synthesis of Compound III
Adding 125g (1 mol) of 2-fluoro-6-methylaniline and 300ml of N, N-dimethylformamide into a reaction bottle, adding 194.7g (1.1 mol) of N-bromosuccinimide in batches, heating to 30 ℃ after the addition, stirring for 3 hours, and tracking the reaction by TLC until the 2-fluoro-6-methylaniline is completely reacted; water is added for quenching, filtration and drying, 192.9g of compound III is obtained, and the molar yield: 95 percent.
(2) Synthesis of Compound IV
Adding 300ml of 98% sulfuric acid into a reaction bottle, cooling to 30 ℃, adding 53.1g (0.77 mol) of sodium nitrite in batches, slowly adding 142.1g (0.7 mol) of compound III, stirring for 1 hour at the reaction temperature of 30 ℃, and performing TLC (thin layer chromatography) point plate tracking reaction until the compound III completely reacts to obtain a diazonium solution;
adding 500ml of water, 127.8g (0.77 mol) of potassium iodide and 2.24g (35 mmol) of copper powder into another reaction flask in sequence, controlling the temperature to be 30 ℃, pumping in the diazo liquid, controlling the reaction temperature to be 30 ℃, stirring for 3 hours, tracing the reaction by a TLC point plate until the diazo compound completely reacts, adding dichloroethane for layering, extracting the dichloroethane in a water layer, concentrating an organic layer, crystallizing methanol to obtain 182.4g of compound IV, and obtaining the molar yield: 83 percent.
(3) Synthesis of Compound V
Adding 1000ml of tetrahydrofuran and 14.4g (600 mmol) of magnesium into a reaction bottle, heating to 65 ℃, dissolving 157g (500 mmol) of compound IV in 300ml of tetrahydrofuran, slowly dripping, refluxing for 2 hours after dripping is finished until magnesium chips basically disappear, and tracking the reaction by GC until the compound IV completely reacts; cooling to 0 ℃, introducing 26.4g (600 mmol) of carbon dioxide, keeping the temperature and stirring for 2 hours at the temperature of 0 ℃, tracing the reaction by a TLC point plate until the reaction is complete, adding 1000ml of saturated ammonium chloride aqueous solution to quench the reaction, adding 1000ml of ethyl acetate to stratify, washing by saturated sodium chloride, drying and concentrating an organic layer, crystallizing by toluene to obtain 98.6g of a compound V, wherein the molar yield is as follows: 85 percent.
(4) Synthesis of Compound I
Adding 23.2g (0.1 mol) of compound V,100ml of methanol and 0.1g (1 mmol) of concentrated sulfuric acid into a reaction bottle, completely heating to 65 ℃, stirring for 6 hours, and tracking the reaction by TLC until the compound V is completely reacted; concentrating, adding water, pulping, filtering and drying the solid to obtain 24.6g of a compound I, wherein the molar yield is as follows: 100 percent.
FIG. 1 is a hydrogen spectrum of methyl 2-fluoro-4-bromo-6-methylbenzoate compound I, 1 H-NMR(400MHz,DMSO-d6)δ:7.55～7.53(m,1H，ArH),7.46(s,1H，ArH)，3.88(s,3H，OCH 3 ),2.33(s,3H，CH 3 )。
FIG. 2 is a gas chromatogram of methyl 2-fluoro-4-bromo-6-methylbenzoate compound I, and it can be seen that the purity of methyl 2-fluoro-4-bromo-6-methylbenzoate compound I is greater than 98%.
Example 2
A preparation method of methyl 2-fluoro-4-bromo-6-methylbenzoate comprises the following steps:
(1) Synthesis of Compound III
Adding 125g (1 mol) of 2-fluoro-6-methylaniline and 300mlN, N-dimethylformamide into a reaction bottle, adding 212.4g (1.2 mol) of N-bromosuccinimide in batches, heating to 20 ℃, stirring for 2 hours after the addition is finished, and tracking the reaction by TLC until the 2-fluoro-6-methylaniline is completely reacted; water is added for quenching, filtering and drying to obtain 194.9g of compound III, and the molar yield: 96 percent.
(2) Synthesis of Compound IV
Adding 300ml of 98% sulfuric acid into a reaction bottle, cooling to 20 ℃, adding 58g (0.84 mol) of sodium nitrite in batches, slowly adding 142.1g (0.7 mol) of compound III, controlling the reaction temperature to 20 ℃, stirring for 2 hours, and performing TLC (thin layer chromatography) point plate tracking reaction until the compound III completely reacts to obtain a diazo liquid;
adding 500ml of water, 139.4g (0.84 mol) of potassium iodide and 2.24g (35 mmol) of copper powder into another reaction flask in sequence, pumping the diazo liquid at the controlled temperature of 20 ℃, stirring for 2 hours at the controlled reaction temperature of 20 ℃, tracing the reaction by a TLC point plate until the diazo compound is completely reacted, adding dichloroethane for layering, extracting the dichloroethane in a water layer, concentrating an organic layer, crystallizing methanol to obtain 186.8g of compound IV, and obtaining the molar yield: 85 percent.
(3) Synthesis of Compound V
Adding 1000ml of tetrahydrofuran and 13.2g (550 mmol) of magnesium into a reaction bottle, heating to 50 ℃, dissolving 157g (500 mmol) of compound IV in 300ml of tetrahydrofuran, slowly dripping, stirring for 4 hours at 50 ℃ until magnesium chips basically disappear, and carrying out GC tracking reaction until the compound IV completely reacts; cooling to-5 ℃, introducing 33g (750 mmol) of carbon dioxide, keeping the temperature and stirring for 1.5 hours at the temperature of-5 ℃, tracing the reaction by a TLC point plate until the reaction is complete, adding 1000ml of saturated ammonium chloride aqueous solution to quench the reaction, adding 1000ml of ethyl acetate to stratify, washing by saturated sodium chloride, drying and concentrating an organic layer, crystallizing by toluene to obtain 100.9g of a compound V, wherein the molar yield is as follows: 87 percent.
(4) Synthesis of Compound I
Adding 23.2g (0.1 mol) of compound V,100ml of methanol and 0.3g (3 mmol) of concentrated sulfuric acid into a reaction bottle, heating to 55 ℃, stirring for 4 hours, and tracking the reaction by TLC until the compound V is completely reacted; concentrating, adding water, pulping, filtering and drying the solid to obtain 24.1g of a compound I, wherein the molar yield is as follows: 98 percent.
Example 3
A preparation method of 2-fluoro-4-bromo-6-methyl benzoate comprises the following steps:
(1) Synthesis of Compound III
Adding 125g (1 mol) of 2-fluoro-6-methylaniline and 300mlN, N-dimethylformamide into a reaction bottle, adding 230.1g (1.3 mol) of N-bromosuccinimide in batches, cooling to 10 ℃, stirring for 1 hour, and tracking the reaction by TLC until the 2-fluoro-6-methylaniline is completely reacted; adding water to quench, filtering and drying to obtain 194.9g of a compound III, wherein the molar yield is as follows: 96 percent.
(2) Synthesis of Compound IV
Adding 300ml of 98% sulfuric acid into a reaction bottle, cooling to 10 ℃, adding 62.8g (0.91 mol) of sodium nitrite in batches, then slowly adding 142.1g (0.7 mol) of compound III, controlling the reaction temperature to 10 ℃, stirring for 3 hours, and tracking the reaction by a TLC (thin layer chromatography) spot plate until the compound III completely reacts to prepare a diazonium solution;
taking another reaction flask, adding 500ml water, 151g (0.91 mol) potassium iodide and 2.24g (35 mmol) copper powder in sequence, controlling the temperature to be 10 ℃, pumping the diazo liquid, controlling the reaction temperature to be 10 ℃, stirring for 1 hour, tracing the reaction by a TLC point plate until the diazo compound is completely reacted, adding dichloroethane for layering, extracting the dichloroethane in a water layer, concentrating an organic layer, crystallizing methanol to obtain 186.8g of compound IV, and obtaining molar yield: 85 percent.
(3) Synthesis of Compound V
Adding 1000ml of tetrahydrofuran and 12g (500 mmol) of magnesium into a reaction bottle, heating to 40 ℃, dissolving 157g (500 mmol) of compound IV in 300ml of tetrahydrofuran, slowly dripping, stirring for 6 hours at 40 ℃ until magnesium chips basically disappear, and carrying out GC tracking reaction until the compound IV completely reacts; cooling to-10 ℃, introducing 44g (1 mol) of carbon dioxide, keeping the temperature and stirring for 1 hour at-10 ℃, tracing the reaction by a TLC point plate until the reaction is complete, adding 1000ml of saturated ammonium chloride aqueous solution to quench the reaction, adding 1000ml of ethyl acetate to stratify, washing by saturated sodium chloride, drying and concentrating an organic layer, crystallizing by toluene to obtain 100.9g of a compound V, wherein the molar yield is as follows: 87 percent.
(4) Synthesis of Compound I
Adding 23.2g (0.1 mol) of compound V,100ml of methanol and 0.5g (5 mmol) of concentrated sulfuric acid into a reaction bottle, completely heating to 50 ℃, stirring for 3 hours, and tracking the reaction by TLC until the compound V is completely reacted; concentrating, adding water, pulping, filtering and drying the solid to obtain 24.1g of a compound I, wherein the molar yield is as follows: 98 percent.
Claims (10)
1. A preparation method of 2-fluoro-4-bromo-6-methyl benzoate is characterized by comprising the following synthetic routes:
the method comprises the following specific steps:
(1) 2-fluoro-6-methylaniline is used as a starting material and reacts with N-bromosuccinimide to generate a compound III;
(2) Diazo salt is generated by the compound III and sodium nitrite, and the compound IV is generated by the Sandmeyer reaction under the condition of potassium iodide and copper powder;
(3) The compound IV and magnesium generate a Grignard reagent, and the Grignard reagent reacts under the condition of carbon dioxide to generate a compound V;
(4) Carrying out methyl esterification on the compound V under the catalysis of concentrated sulfuric acid to generate a compound I; namely the methyl 2-fluoro-4-bromo-6-methylbenzoate.
2. The method according to claim 1, wherein in the step (1), the reaction solvent is N, N-dimethylformamide; the mol ratio of the 2-fluoro-6-methylaniline to the N-bromosuccinimide is 1.1-1.3; the reaction conditions are as follows: the temperature is 10-30 ℃, and the reaction time is 1-3 h.
3. The preparation method according to claim 1, wherein in the step (2), the molar ratio of the compound III to the sodium nitrite is 1; the diazotization reaction conditions are as follows: the temperature is 10-30 ℃, and the reaction time is 1-3 h.
4. The preparation method according to claim 3, wherein in the step (2), the solvent for the diazotization reaction is concentrated sulfuric acid, and the mass concentration of the concentrated sulfuric acid is 98%.
5. The process according to claim 1, wherein in the step (2), the molar ratio of potassium iodide to the compound III is 1.1 to 1.3; the molar ratio of the copper powder to the compound III is 0.05; the conditions of the Sandemall reaction are as follows: the temperature is 10-30 ℃, and the reaction time is 1-3 h.
6. The preparation method according to claim 1, wherein in the step (3), the reaction solvent is one or more of tetrahydrofuran, diethyl ether and methyl tetrahydrofuran; the molar ratio of the compound IV to magnesium and carbon dioxide is 1.0-1.2.
7. The method according to claim 1, wherein in the step (3), the conditions for reacting the compound IV with magnesium are as follows: the temperature is 40-65 ℃, and the reaction time is 2-6 h.
8. The method according to claim 1, wherein in the step (3), the conditions for reacting the Grignard reagent with carbon dioxide are as follows: the temperature is 0-10 ℃, and the reaction time is 1-2 h.
9. The method according to claim 1, wherein in the step (4), the solvent is methanol; the molar ratio of the compound V to concentrated sulfuric acid is 1.01-0.05; the reaction conditions are as follows: the temperature is 50-65 ℃, and the reaction time is 3-6 h.
10. The production method according to claim 9, wherein in the step (4), the concentrated sulfuric acid has a mass concentration of 98%.
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