CN108929217B - Preparation method of 2-methyl-5-fluorobenzoic acid - Google Patents
Preparation method of 2-methyl-5-fluorobenzoic acid Download PDFInfo
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Abstract
The invention discloses a preparation method of 2-methyl-5-fluorobenzoic acid, which comprises the steps of reacting 2-X-4-fluorotoluene with magnesium chips to generate a Grignard reagent, and converting the Grignard reagent to obtain the 2-methyl-5-fluorobenzoic acid; wherein X is selected from chlorine, bromine or iodine.
Description
Technical Field
The invention relates to the field of pharmaceutical chemicals, and particularly relates to a preparation method of 2-methyl-5-fluorobenzoic acid.
Background
Ovarian cancer is one of the common malignant tumors of female reproductive organs, and the mortality rate of ovarian cancer accounts for the first position of various gynecological tumors, thereby causing serious threat to the life of women. The ovarian cancer treatment drug Rucaparib under investigation by Clovis Oncology, Inc. qualifies as a breakthrough drug by the FDA, which acts by inhibiting the poly (adenosine diphosphate ribose) polymerase (PARPs) enzymes, which can block the occurrence of certain genetic mutations that can spread the cancer systemically. FDA awarding Rucaparib breakthrough therapy drug labeling covers its use in treating BRCA mutant advanced ovarian cancer patients who have failed to receive second line therapy drugs. Methyl 2-methyl-3-nitro-5-fluorobenzoate is an important intermediate of Rucaparib anticancer drugs, and 2-methyl-5-fluorobenzoic acid can be used as a starting material for preparing the same.
Therefore, there is a strong need in the art to provide a method for obtaining 2-methyl-5-fluorobenzoic acid.
Disclosure of Invention
The invention aims to provide a preparation method of 2-methyl-5-fluorobenzoic acid, and then 2-methyl-3-nitro-5-fluorobenzoic acid methyl ester is obtained.
In a first aspect of the present invention, there is provided a process for the preparation of 2-methyl-5-fluorobenzoic acid, which comprises reacting 2-X-4-fluorotoluene with magnesium turnings to produce a grignard reagent, and converting the grignard reagent to obtain 2-methyl-5-fluorobenzoic acid; wherein X is selected from chlorine, bromine or iodine; the conversion is to react the obtained Grignard reagent with carbon dioxide and then mix the Grignard reagent with an acid solution to obtain the 2-methyl-5-fluorobenzoic acid.
In another preferred embodiment, the conversion is to mix the obtained grignard reagent and the acid solution, separate the mixture into layers, extract the mixture with an organic solvent 1 to obtain an organic phase, and directly remove the solvent to obtain the 2-methyl-5-fluorobenzoic acid.
In another preferred embodiment, the transformation comprises the steps of:
(a) mixing the obtained Grignard reagent and an acid solution, layering, and extracting by using an organic solvent 1 to obtain an organic phase;
(b) mixing and layering an organic phase, an organic solvent 2 and an alkali solution to obtain a water phase; and
(c) and mixing the water phase and the acid solution to obtain the 2-methyl-5-fluorobenzoic acid.
In another preferred example, the acid solution is an aqueous solution of inorganic acid, and the content of the inorganic acid in the solution is 10-15 v/v% based on the total volume of the solution; the alkali solution is an inorganic alkali aqueous solution, and the content of the inorganic alkali is 5-15 v/v% based on the total volume of the solution; the inorganic acid is selected from hydrochloric acid, sulfuric acid and phosphoric acid; the inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
In another preferred embodiment, the organic solvent 1 is selected from ethyl acetate, isopropyl acetate or n-butyl acetate; the organic solvent 2 is selected from toluene, dichloromethane, xylene or methyl tert-butyl ether.
In another preferred embodiment, the pH of the mixture is brought to 1-2 in steps (a) and (c) by mixing with an acid solution.
In another preferred example, the method comprises the steps of:
(i) reacting 2-X-4-fluorotoluene with magnesium chips to generate a Grignard reagent;
(ii) reacting the Grignard reagent with carbon dioxide to obtain carboxylate; and
(iii) mixing the obtained carboxylate and an acid solution, layering, extracting by using an organic solvent 1 to obtain an organic phase, and removing the solvent to obtain 2-methyl-5-fluorobenzoic acid;
or comprises the following steps:
(1) reacting 2-X-4-fluorotoluene with magnesium chips to generate a Grignard reagent;
(2) reacting the Grignard reagent with carbon dioxide to obtain carboxylate;
(3) mixing the obtained carboxylate and an acid solution, layering, and extracting by using an organic solvent 1 to obtain an organic phase;
(4) mixing and layering an organic phase, an organic solvent 2 and an alkali solution to obtain a water phase; and
(5) and mixing the water phase and the acid solution to obtain the 2-methyl-5-fluorobenzoic acid.
In another preferred embodiment, the magnesium chips in step (i) or (1) are present in an amount of 1 to 3 times the molar amount; reacting at the reaction temperature of 20-85 ℃ in the step (i) or (1); the solvent used in step (i) or (1) is selected from one or more of the following: toluene, methyl tert-ether, diethyl ether, isopropyl ether, tetrahydrofuran and methyltetrahydrofuran.
In another preferred embodiment, the temperature of step (ii) or (2) is between-20 ℃ and 50 ℃; more preferably from 0 to 20 ℃.
In another preferred embodiment, the temperature of step (5) is between-10 ℃ and 40 ℃; more preferably from 0 to 10 ℃.
In a second aspect of the present invention, there is provided a process for preparing methyl 2-methyl-3-nitro-5-fluorobenzoate, which comprises the steps of:
(A) reacting the 2-methyl-5-fluorobenzoic acid prepared by the invention with dilute nitric acid, concentrated nitric acid or fuming nitric acid to obtain 2-methyl-3-nitro-5-fluorobenzoic acid; and
(B) reacting 2-methyl-3-nitro-5-fluorobenzoic acid with methanol to obtain 2-methyl-3-nitro-5-fluorobenzoic acid methyl ester.
In another preferred embodiment, the reaction solvent of step (a) is selected from one or two or more of the following: sulfuric acid, concentrated sulfuric acid, fuming sulfuric acid, acetic acid and dichloromethane.
In another preferred embodiment, the catalyst in step (B) is selected from one or two or more of the following: sulfuric acid, acetyl chloride, thionyl chloride and oxalyl chloride; the dosage of the catalyst is 0.1 to 2 times of the molar weight; the solvent used in the step (B) is one or more than two of the following solvents: toluene, dichloromethane and methanol; the reaction temperature of the step (B) is between 0 and 110 ℃.
Accordingly, the present invention provides a method for obtaining 2-methyl-5-fluorobenzoic acid.
Detailed Description
The inventors have extensively and intensively studied and found that 2-methyl-5-fluorobenzoic acid can be obtained by reacting an inexpensive raw material under mild conditions. On the basis of this, the present invention has been completed.
Preparation of 2-methyl-5-fluorobenzoic acid
The preparation method of the 2-methyl-5-fluorobenzoic acid provided by the invention comprises the following steps:
in the first step, a grignard reagent is obtained by 2-X-4-fluorotoluene (X ═ Cl, Br, I) and magnesium chips;
secondly, carboxyl is added to the Grignard reagent;
and thirdly, acidifying to obtain the 2-methyl-5-fluorobenzoic acid.
Mixing 2-X-4-fluorotoluene (X ═ Cl, Br, I) and a reaction solvent of magnesium chips in the first step, and reacting at a temperature of not more than 85 ℃ to obtain a grignard reagent; the reaction solvent is one or more of toluene, methyl tertiary ether, diethyl ether, isopropyl ether, tetrahydrofuran and methyl tetrahydrofuran.
In the first step, the reaction temperature is 25 to 85 ℃, preferably 25 to 55 ℃, more preferably 25 to 35 ℃. The amount of the solvent is not particularly required, so long as the reaction is not affected stably. Preferably, the solvent is used in an amount of 1 to 5 times by volume based on 2-X-4-fluorotoluene.
The first step can be followed by conventional methods (e.g., gas chromatography, etc.) to monitor the completion of the reaction. The reaction time depends on the reaction temperature, the solvent and the specific reactants, and the reaction can be completed within about 2 to 24 hours under the reaction conditions.
In one embodiment of the present invention, the second step is to introduce carbon dioxide gas at-20 ℃ to 50 ℃ after the reaction in the first step is completed until the intermediate substantially disappears; preferably at 0-20 ℃; more preferably from 0 to 10 ℃.
In an embodiment of the present invention, after the intermediate substantially disappears in the second step, the pH is adjusted to 1 to 2 by an acid solution, the organic phase is separated, the aqueous phase is extracted by an organic solvent 1, the organic phase is combined, the organic phase, the organic solvent 2 and an alkali solution are mixed, the aqueous phase is extracted by the organic solvent 2 after separation, the aqueous phase obtained after extraction is adjusted to pH 1 to 2 by an acid solution at-10 ℃ to 40 ℃, and 2-methyl-5-fluorobenzoic acid is obtained; preferably at 0-10 ℃.
The acid solution is an aqueous solution of inorganic acid, and the content of the inorganic acid is 10-15 v/v% based on the total volume of the solution; the inorganic acid is selected from hydrochloric acid, sulfuric acid or phosphoric acid.
The alkali solution is an inorganic alkali aqueous solution, and the content of the inorganic alkali is 5-15 v/v% based on the total volume of the solution; the inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
The organic solvent 1 is selected from ethyl acetate, isopropyl acetate or n-butyl acetate; the organic solvent 2 is selected from toluene, xylene, dichloromethane or methyl tert-butyl ether.
In an embodiment of the present invention, in the third step, the crude product is obtained by combining the organic phases obtained after the extraction with the organic solvent 1 and concentrating, and the crude product, the organic solvent 2 and the alkali solution are mixed and then subjected to the subsequent operation.
Preparation of methyl 2-methyl-3-nitro-5-fluorobenzoate
The 2-methyl-3-nitro-5-fluorobenzoic acid methyl ester provided by the invention is obtained by nitrifying 2-methyl-5-fluorobenzoic acid obtained by the method of the invention to obtain 2-methyl-3-nitro-5-fluorobenzoic acid, and esterifying 2-methyl-3-nitro-5-fluorobenzoic acid to obtain 2-methyl-3-nitro-5-fluorobenzoic acid methyl ester.
The nitration is carried out by reacting 2-methyl-5-fluorobenzoic acid with nitric acid to obtain 2-methyl-3-nitro-5-fluorobenzoic acid. The nitric acid can be dilute nitric acid, concentrated nitric acid, fuming nitric acid; fuming nitric acid is preferred. The amount thereof is 1.2 to 2.5 times the molar amount of 2-methyl-3-nitro-5-fluorobenzoic acid.
The nitration reaction is carried out in a solvent, and any solvent which does not adversely affect the reaction may be used, such as one or more of dilute sulfuric acid, concentrated sulfuric acid, fuming sulfuric acid, acetic acid, and methylene chloride. The amount of the solvent is not particularly limited as long as the stability of the reaction is not impaired, and it is preferably 4.0 to 8.0 times by volume as much as 2-methyl-5-fluorobenzoic acid.
The reaction temperature is not specially required, preferably 0-50 ℃, and under the preferred temperature, good reaction efficiency can be obtained, and the nitration reaction yield can reach more than 60%.
The completion of the reaction can be followed by conventional methods (e.g., thin layer chromatography, liquid chromatography, etc.). The reaction time depends on the reaction temperature, solvent and the particular reactants, and the reaction is generally completed in about 1 to 5 hours under the above-mentioned preferable conditions.
The esterification reaction is carried out by reacting 2-methyl-3-nitro-5-fluorobenzoic acid with methanol to obtain 2-methyl-3-nitro-5-fluorobenzoic acid methyl ester. The dosage of the methanol is 1.5 to 30 times of the molar weight of the 2-methyl-3-nitro-5-fluorobenzoic acid.
The reaction is carried out in a solvent, and any solvent which does not adversely affect the reaction, such as one or more of toluene, dichloromethane, and methanol, may be used. The amount of the solvent is not particularly limited as long as the stability of the reaction is not impaired, and it is preferably 2.0 to 8.0 times by volume as much as 2-methyl-3-nitro-5-fluorobenzoic acid.
The reaction temperature is not specially required, preferably 0-110 ℃, and good reaction efficiency can be obtained at the preferred temperature, and the esterification reaction yield can reach more than 80%.
The completion of the reaction can be followed by conventional methods (e.g., thin layer chromatography, liquid chromatography, etc.). The reaction time depends on the reaction temperature, solvent and the particular reactants, and the reaction is generally completed in about 2 to 8 hours under the above-mentioned preferred conditions.
The target product 2-methyl-3-nitro-5-fluorobenzoic acid methyl ester can be verified by methods such as melting point determination, liquid phase simplicity, nuclear magnetic resonance and the like.
The reaction of each step involved in the preparation method provided by the invention can be directly carried out the next step, but the intermediate product obtained by separating and purifying each step of reaction by adopting post-treatment modes such as extraction, suction filtration, washing, drying, concentration and the like is beneficial to improving the efficiency of the next step of reaction.
The features mentioned above with reference to the invention, or the features mentioned with reference to the embodiments, can be combined arbitrarily. All the features disclosed in this specification may be combined in any combination, and each feature disclosed in this specification may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the features disclosed are merely generic examples of equivalent or similar features.
The main advantages of the invention are:
1. the raw materials used by the method provided by the invention are cheap and easily available.
2. The method provided by the invention has the advantages of less side reaction, large production capacity, mild reaction conditions, low cost and easy industrial production.
3. The purity of the 2-methyl-3-nitro-5-fluorobenzoic acid methyl ester obtained by the preparation method provided by the invention can reach more than 99% after purification, and the total yield can reach more than 40%.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. All percentages, ratios, proportions, or parts are by weight unless otherwise specified. The weight volume percentage units in the present invention are well known to those skilled in the art and refer to, for example, the weight of solute in a 100ml solution. 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. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
Example 1
Preparation of 2-methyl-5-fluorobenzoic acid from 2-chloro-4-fluorotoluene
Adding 20g (0.83mol) of magnesium chips and 100ml of methyl tetrahydrofuran into a 1L four-neck bottle, adding 10g (0.07mol) of 2-chloro-4-fluorotoluene under the protection of nitrogen, stirring and heating until the reaction is initiated, successfully initiating at 55 ℃, greatly releasing heat, stopping stirring, stirring and heating until the temperature is stable, dissolving 90g (0.62mol) of the residual 2-chloro-4-fluorotoluene into 300ml of methyl tetrahydrofuran, slowly dropping into the reaction solution, and keeping the temperature under the reflux state. And (4) after 9h of dropwise addition, reacting for 2h, and detecting in a gas phase to complete the reaction. Cooling to 0-10 deg.C, and introducing clean carbon dioxide gas until the intermediate is substantially disappeared. A 12% hydrochloric acid solution was added dropwise until the pH was 1-2. The layers are separated, the water phase is extracted for 1 time by using 200ml of ethyl acetate, the organic phases are combined and concentrated to dryness, and a crude product is obtained. Toluene (200 ml) was added. 320g of 10% aqueous sodium hydroxide solution, stirring until clear, standing for layering, and extracting the aqueous phase with 200ml of toluene for 1 time. The organic phase was discarded and the aqueous phase was adjusted to pH 1-2 with 12% hydrochloric acid at 0-10 ℃. A large amount of white solid precipitated. Filtering, rinsing the filter cake with water, pumping, and drying the filter cake at 50 ℃. 80.4g of crude product are obtained, HPLC 90%. The yield of the product is 67.9 percent. The crude product can be directly reacted in the next step.
1H-NMR CDCl3 2.50(S,3H),7.26-7.34(m，2H),7.51-7.54(d，1H),13.09(S,1H)。LC-MS(MH-):153.1
Example 2
Preparation of 2-methyl-5-fluorobenzoic acid from 2-bromo-4-fluorotoluene
Adding 20g (0.83mol) of magnesium chips and 100ml of tetrahydrofuran into a 1L four-mouth bottle, adding 6g (0.032mol) of 2-bromo-4-fluorotoluene under the protection of nitrogen, stirring and heating until the reaction is initiated, wherein the reaction is initiated at 25 ℃, the initiation is successful, releasing heat to reflux, cooling the mixture to 25 ℃ in an ice water bath, dissolving 124g (0.66mol) of the rest 2-bromo-4-fluorotoluene in 300ml of tetrahydrofuran, and slowly dropping the solution into the reaction solution at 25-35 ℃. After the dropwise addition is finished for 2h, the reaction is carried out for 2h, and the gas phase detection is carried out to complete the reaction. Cooling to 0-10 deg.C, and introducing clean carbon dioxide gas until the intermediate is substantially disappeared. A 12% hydrochloric acid solution was added dropwise until the pH was 1-2. The layers are separated, the water phase is extracted for 1 time by using 200ml of ethyl acetate, the organic phases are combined and concentrated to dryness, and a crude product is obtained. Toluene (200 ml) was added. 320g of 10% aqueous sodium hydroxide solution, stirring until clear, standing for layering, and extracting the aqueous phase with 200ml of toluene for 1 time. The organic phase was discarded and the aqueous phase was adjusted to pH 1-2 with 12% hydrochloric acid at 0-10 ℃. A large amount of white solid precipitated. Filtering, rinsing the filter cake with water, pumping, and drying the filter cake at 50 ℃. 85g of crude product are obtained, HPLC 95%. The yield of the product is 75.8 percent. The crude product can be directly reacted in the next step.
1H-NMR CDCl3 2.50(S,3H),7.26-7.34(m，2H),7.51-7.54(d，1H),13.09(S,1H)。LC-MS(MH-):153.1
Example 3
Preparation of 2-methyl-5-fluorobenzoic acid from 2-iodo-4-fluorotoluene
Adding 20g (0.83mol) of magnesium chips and 100ml of methyl tert-ether into a 1L four-neck flask, adding 6g (0.025mol) of 2-iodo-4-fluorotoluene under the protection of nitrogen, stirring at room temperature to initiate successfully, releasing heat to about 50 ℃, cooling to 25 ℃ in an ice water bath, dissolving 157g (0.665mol) of the rest 2-iodo-4-fluorotoluene into 300ml of methyl tert-ether, and slowly dropping into the reaction solution at 25-35 ℃. After the dropwise addition is finished for 2h, the reaction is carried out for 2h, and the gas phase detection is carried out to complete the reaction. Cooling to 0-10 deg.C, and introducing clean carbon dioxide gas until the intermediate is substantially disappeared. A 12% hydrochloric acid solution was added dropwise until the pH was 1-2. The layers are separated, the water phase is extracted for 1 time by using 200ml of ethyl acetate, the organic phases are combined and concentrated to dryness, and a crude product is obtained. Toluene (200 ml) was added. 320g of 10% aqueous sodium hydroxide solution, stirring until clear, standing for layering, and extracting the aqueous phase with 200ml of toluene for 1 time. The organic phase was discarded and the aqueous phase was adjusted to pH 1-2 with 12% hydrochloric acid at 0-10 ℃. A large amount of white solid precipitated. Filtering, rinsing the filter cake with water, pumping, and drying the filter cake at 50 ℃. Crude 90g was obtained, 96% by HPLC. The yield of the product is 81 percent. The crude product can be directly reacted in the next step.
1H-NMR CDCl3 2.50(S,3H),7.26-7.34(m，2H),7.51-7.54(d，1H),13.09(S,1H)。LC-MS(MH-):153.1
Example 4
Preparation of 2-methyl-3-nitro-5-fluorobenzoic acid
30g (0.195mol) of 2-methyl-5-fluorobenzoic acid was added to 120ml of concentrated sulfuric acid, and the temperature was raised to 30 ℃ to 40 ℃ with stirring. 24.5g (0.39mol) of concentrated nitric acid is added dropwise, and the temperature is controlled at 30-40 ℃. After the dropping, the reaction was carried out for 2 hours, the reaction was stopped after the raw materials had substantially disappeared, and the reaction solution was poured into ice water. Filtering, rinsing the filter cake with water, and pumping to dry. The wet product was dried at 50 ℃ to give 28g, HPLC 95%. The pure yield is 66.5%.
1H-NMR DMSO 2.45(S,3H),7.83-7.85(d，1H),8.02-8.04(d，1H),13.78(S,1H)。LC-MS(MH-):198.1
Example 5
Preparation of 2-methyl-3-nitro-5-fluorobenzoic acid
30g (0.195mol) of 2-methyl-5-fluorobenzoic acid was added to 150ml of acetic acid, and the temperature was raised to 40 ℃ to 50 ℃ with stirring. 24.5g (0.39mol) of fuming nitric acid is added dropwise, and the temperature is controlled to be 40-50 ℃. After the dropping, the reaction was stopped after 3 hours when the raw materials were almost disappeared, and the reaction solution was poured into ice water. Filtering, rinsing the filter cake with water, and pumping to dry. The wet product was dried at 50 ℃ to yield 35g, HPLC 96%. Yield 84% pure.
1H-NMR DMSO 2.45(S,3H),7.83-7.85(d，1H),8.02-8.04(d，1H),13.78(S,1H)。LC-MS(MH-):198.1
Example 6
Preparation of 2-methyl-3-nitro-5-fluorobenzoic acid
30g (0.195mol) of 2-methyl-5-fluorobenzoic acid was added to a mixture of 30ml of concentrated sulfuric acid and 150ml of dichloromethane, and the mixture was heated to 30 ℃ to 40 ℃ with stirring. 24.5g (0.39mol) of fuming nitric acid is added dropwise, and the temperature is controlled at 30-40 ℃. After the dropping, the reaction was stopped after 3 hours when the raw materials were almost disappeared, and the reaction solution was poured into ice water. Filtering, rinsing the filter cake with water, and pumping to dry. The wet product was dried at 50 ℃ to give 30g, HPLC 94%. The purity yield is 70.5%.
1H-NMR DMSO 2.45(S,3H),7.83-7.85(d，1H),8.02-8.04(d，1H),13.78(S,1H)。LC-MS(MH-):198.1
Example 7
Preparation of methyl 2-methyl-3-nitro-5-fluorobenzoate
3g (15.1mmol) of 2-methyl-3-nitro-5-fluorobenzoic acid is added into 30ml of methanol, 0.3g of concentrated sulfuric acid (98%) is added dropwise with stirring, then the mixture is refluxed for 8 hours, the reaction is stopped, and sodium bicarbonate aqueous solution is added to adjust the pH to about 7. Concentrating methanol, adding dichloromethane 30ml, washing with water for 2 times, washing with saturated salt water for 1 time, concentrating the organic phase to obtain crude product, recrystallizing with methanol for 2 times 10ml to obtain 2.4g product with HPLC above 99%. The yield thereof was found to be 74.8%.
1H-NMR DMSO 2.43(S,3H),3.88(S，3H),7.85-7.87(d，1H),8.07-8.09(d,1H)。LC-MS(MH+):214.1
Example 8
Preparation of methyl 2-methyl-3-nitro-5-fluorobenzoate
58g (0.291mol) of 2-methyl-3-nitro-5-fluorobenzoic acid is added into 300ml of methanol, stirred, and added with 41.6g (0.35mol) of thionyl chloride dropwise at 0-10 ℃, so that obvious heat release is realized, and the temperature is controlled below 20 ℃. After dripping, heating to reflux, reacting for 7h, basically eliminating the raw materials, stopping the reaction, cooling to 25 ℃ under stirring, separating out a large amount of solids, filtering, rinsing the filter cake with 60ml of methanol, draining, recrystallizing the filter cake with 150ml of methanol to obtain a wet product, and drying to obtain 45g of the product. HPLC is more than 99%. The yield thereof was found to be 72.6%.
1H-NMR DMSO 2.43(S,3H),3.88(S，3H),7.85-7.87(d，1H),8.07-8.09(d,1H)。LC-MS(MH+):214.1
Example 9
Preparation of methyl 2-methyl-3-nitro-5-fluorobenzoate
Adding 30g (0.151mol) of 2-methyl-3-nitro-5-fluorobenzoic acid and 10g (0.31mol) of methanol into 150ml of toluene solution, stirring and heating to reflux, dropwise adding 18g (0.227mol) of thionyl chloride after refluxing, discharging hydrochloric acid gas, and after finishing dripping, carrying out reflux reaction for 2 hours, wherein the raw materials basically disappear, and the reaction solution turns turbid and becomes clear. The reaction was stopped, the solvent was concentrated to give crude product, which was recrystallized 2 times 100ml with methanol to give 28g of product, HPLC 99% above, yield 87.2%.
1H-NMR DMSO 2.43(S,3H),3.88(S，3H),7.85-7.87(d，1H),8.07-8.09(d,1H)。LC-MS(MH+):214.1
The foregoing is merely a preferred embodiment of the invention and is not intended to limit the scope of the invention, which is defined by the claims appended hereto, and any other technical entity or method that is encompassed by the claims as broadly defined herein, or equivalent variations thereof, is contemplated as being encompassed by the claims.
Claims (14)
1. A method for preparing methyl 2-methyl-3-nitro-5-fluorobenzoate, which is characterized by comprising the following steps:
(A) reacting 2-X-4-fluorotoluene with magnesium chips to generate a Grignard reagent, reacting the Grignard reagent with carbon dioxide, and mixing with an acid solution to obtain 2-methyl-5-fluorobenzoic acid; reacting the 2-methyl-5-fluorobenzoic acid with dilute nitric acid, concentrated nitric acid or fuming nitric acid to obtain 2-methyl-3-nitro-5-fluorobenzoic acid; wherein X is selected from chlorine, bromine or iodine;
(B) reacting 2-methyl-3-nitro-5-fluorobenzoic acid with methanol to obtain 2-methyl-3-nitro-5-fluorobenzoic acid methyl ester.
2. The process of claim 1 wherein the reaction solvent in the reaction with dilute, concentrated or fuming nitric acid of step (a) is selected from one or more of the following: sulfuric acid, concentrated sulfuric acid, fuming sulfuric acid, acetic acid and dichloromethane.
3. The process of claim 1, wherein the catalyst for the reaction of step (B) is selected from one or more of the following: sulfuric acid, acetyl chloride, thionyl chloride and oxalyl chloride; the dosage of the catalyst is 0.1 to 2 times of the molar weight; the solvent used in the reaction in the step (B) is one or more than two of the following solvents: toluene, dichloromethane and methanol; the reaction temperature of the step (B) is between 0 and 110 ℃.
4. The preparation method according to claim 1, wherein the conversion is carried out by mixing the obtained grignard reagent with an acid solution, layering, extracting with an organic solvent 1 to obtain an organic phase, and directly removing the solvent to obtain 2-methyl-5-fluorobenzoic acid; or comprises the following steps:
(a) mixing the obtained Grignard reagent and an acid solution, layering, and extracting by using an organic solvent 1 to obtain an organic phase;
(b) mixing and layering an organic phase, an organic solvent 2 and an alkali solution to obtain a water phase;
(c) and mixing the water phase and the acid solution to obtain the 2-methyl-5-fluorobenzoic acid.
5. The method according to claim 4, wherein the acid solution is an aqueous solution of an inorganic acid, and the content of the inorganic acid is 10 to 15 v/v% based on the total volume of the solution; the alkali solution is an inorganic alkali aqueous solution, and the content of the inorganic alkali is 5-15 v/v% based on the total volume of the solution.
6. The method of claim 5, wherein the inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid; the inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
7. The process according to claim 4, wherein the organic solvent 1 is selected from ethyl acetate, isopropyl acetate or n-butyl acetate; the organic solvent 2 is selected from toluene, dichloromethane, xylene or methyl tert-butyl ether.
8. The method of claim 4, wherein the mixing with the acid solution in steps (a) and (c) is carried out to a pH of 1 to 2.
9. The method of any one of claims 1 to 8, wherein the method comprises the steps of:
(i) reacting 2-X-4-fluorotoluene with magnesium chips to generate a Grignard reagent;
(ii) reacting the Grignard reagent with carbon dioxide to obtain carboxylate;
(iii) mixing the obtained carboxylate and an acid solution, layering, extracting by using an organic solvent 1 to obtain an organic phase, and removing the solvent to obtain 2-methyl-5-fluorobenzoic acid;
(iv) reacting the 2-methyl-5-fluorobenzoic acid with dilute nitric acid, concentrated nitric acid or fuming nitric acid to obtain 2-methyl-3-nitro-5-fluorobenzoic acid;
(v) reacting 2-methyl-3-nitro-5-fluorobenzoic acid with methanol to obtain 2-methyl-3-nitro-5-fluorobenzoic acid methyl ester; or
(1) Reacting 2-X-4-fluorotoluene with magnesium chips to generate a Grignard reagent;
(2) reacting the Grignard reagent with carbon dioxide to obtain carboxylate;
(3) mixing the obtained carboxylate and an acid solution, layering, and extracting by using an organic solvent 1 to obtain an organic phase;
(4) mixing and layering an organic phase, an organic solvent 2 and an alkali solution to obtain a water phase;
(5) mixing the water phase and the acid solution to obtain 2-methyl-5-fluorobenzoic acid;
(6) reacting the 2-methyl-5-fluorobenzoic acid with dilute nitric acid, concentrated nitric acid or fuming nitric acid to obtain 2-methyl-3-nitro-5-fluorobenzoic acid;
(7) reacting 2-methyl-3-nitro-5-fluorobenzoic acid with methanol to obtain 2-methyl-3-nitro-5-fluorobenzoic acid methyl ester.
10. The method according to claim 9, wherein the magnesium chips in the step (i) or (1) are contained in an amount of 1 to 3 times by mol; reacting at the reaction temperature of 20-85 ℃ in the step (i) or (1); the solvent used in step (i) or (1) is selected from one or more of the following: toluene, methyl tert-ether, diethyl ether, isopropyl ether, tetrahydrofuran and methyltetrahydrofuran.
11. The method of claim 9, wherein the temperature of step (ii) or (2) is between-20 ℃ and 50 ℃.
12. The method of claim 9, wherein the temperature of step (ii) or (2) is between 0 ℃ and 20 ℃.
13. The method of claim 9, wherein the temperature of step (5) is between-10 ℃ and 40 ℃.
14. The method of claim 9, wherein the temperature of step (5) is between 0 ℃ and 10 ℃.
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| CN1232018A (en) * | 1998-03-09 | 1999-10-20 | 罗姆和哈斯公司 | Process for synthesizing benzoic acids |
| CN1358708A (en) * | 2001-12-13 | 2002-07-17 | 中国科学院上海有机化学研究所 | Method for synthesizing 2,3,4-trifluoro phenyl formic acid |
| CN101381301A (en) * | 2007-09-06 | 2009-03-11 | 华东理工大学 | Preparation method of 4-chloro-2,5-difluorobenzoic acid |
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| CN1358708A (en) * | 2001-12-13 | 2002-07-17 | 中国科学院上海有机化学研究所 | Method for synthesizing 2,3,4-trifluoro phenyl formic acid |
| CN101381301A (en) * | 2007-09-06 | 2009-03-11 | 华东理工大学 | Preparation method of 4-chloro-2,5-difluorobenzoic acid |
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