CN109232259B - Preparation method of nitroacetophenone - Google Patents
Preparation method of nitroacetophenone Download PDFInfo
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- CN109232259B CN109232259B CN201811133588.2A CN201811133588A CN109232259B CN 109232259 B CN109232259 B CN 109232259B CN 201811133588 A CN201811133588 A CN 201811133588A CN 109232259 B CN109232259 B CN 109232259B
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
Abstract
The invention discloses a preparation method of nitroacetophenone, which takes nitrobenzoic acid as a raw material and obtains a target product through three steps of reactions of acyl chlorination, condensation and hydrolysis. The method has mild reaction conditions and simple post-treatment, avoids the problem of harsh nitration and oxidation reaction conditions in the traditional method, and has the advantages of small pollution, high yield and the like.
Description
Technical Field
The invention relates to the field of organic synthesis, and particularly relates to a preparation method of nitroacetophenone.
Background
Nitroacetophenone is an important intermediate in the field of organic synthesis and pharmaceutical synthesis, and is widely applied to o-nitroacetophenone, m-nitroacetophenone and p-nitroacetophenone. The o-nitroacetophenone is used for preparing a sensitizer and also used for preparing diabetes drugs such as linagliptin and the like; the m-nitroacetophenone can be prepared into m-aminoacetophenone through reduction, and the pharmaceutical industry is used for preparing epinephrine medicaments and the like; the p-nitroacetophenone is used for synthesizing broad-spectrum antibacterial antibiotic medicines such as chloramphenicol and synmycin, and is also used for synthesizing pesticides, dyes and spices.
At present, the synthesis methods of o-nitroacetophenone and p-nitroacetophenone mainly comprise two methods:
a. nitroethylbenzene oxidation. The method takes nitroethylbenzene as a raw material, and uses tert-butyl hydroperoxide (such as Xu, Q.et al. Asian Journal of Chemistry,2015,27(10),3555-3558.) to carry out oxidation to prepare the ortho-position or para-position nitroacetophenone under the action of a composite transition metal catalyst. The composite transition metal catalyst used in the method is often prepared in multiple steps, and the cost is too high.
b. Nitrobenzoyl chloride process. The method takes nitrobenzoic acid as a raw material, generates nitrobenzoyl chloride by acyl chlorination, and then reacts with diethyl malonate under the action of magnesium alkoxide to prepare ortho-position or para-position nitroacetophenone. The inventor conducts repeated experiments on the method for many times, and the actual yield is far lower than that reported in the literature.
The synthesis method of m-nitroacetophenone is mainly an acetophenone nitration method. The method uses acetophenone as a raw material, and uses sulfuric acid/nitric acid mixed acid to carry out nitration under the low temperature condition (generally-20 ℃ to-15 ℃) to prepare the m-nitroacetophenone (such as Blau, Lorena et al European Journal of Medicinal Chemistry,2013,67, 142-. In the nitration process of the method, a large excess of sulfuric acid and nitric acid is used, and meanwhile, ortho-position and para-position byproducts are generated, so that the problems of difficult separation, low product purity, serious three wastes and the like exist.
Disclosure of Invention
The invention aims to provide a preparation method of nitroacetophenone, which has the advantages of simple raw material, simple operation, mild conditions, high yield and little pollution.
The technical scheme adopted by the invention for solving the technical problems is as follows:
a preparation method of nitroacetophenone comprises the following steps:
1) taking a compound of a formula I as a raw material, adding a first inert solvent and a catalyst, stirring and heating to 55-65 ℃, dropwise adding a chlorinating agent, heating to reflux reaction for 2-3 hours, and after finishing the acyl chlorination reaction, distilling out the excessive chlorinating agent and the inert solvent under reduced pressure to obtain a crude product of a compound of a formula II, wherein the crude product can be directly used for the next reaction;
2) adding inorganic salt, a second inert solvent, an alkaline reagent and malonic acid di-tert-butyl ester or malonic acid di-tert-amyl ester into a reaction bottle, fully stirring, dropwise adding a crude compound of the formula II, heating to 55-65 ℃, reacting for 1-2 hours, neutralizing with hydrochloric acid until the pH value is 5-6 after the condensation reaction is finished, separating an organic layer, sequentially washing with saturated sodium bicarbonate and saturated salt water, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound of the formula III;
3) adding the compound shown in the formula III into a mixed solution of water, organic acid and inorganic acid for reflux reaction for 2-3 hours, adjusting a sodium hydroxide solution to be neutral after the hydrolysis reaction is finished, extracting by using an organic solvent, and concentrating under reduced pressure to obtain a compound shown in the formula IV.
The invention takes nitrobenzoic acid as a raw material, and obtains a target product through three steps of reactions of acyl chlorination, condensation and hydrolysis. Excessive chlorinating agent is added in the step 1), which is beneficial to the full conversion of nitrobenzoic acid. The inert solvent is added, so that the reactants are fully contacted, the reaction rate is accelerated, and the reaction time is shortened; meanwhile, after the reaction is finished, the excessive chlorinating agent can be evaporated out, and the method can be recycled. The reaction rate can be obviously accelerated by adding a small amount of catalyst, and the cost is saved.
The addition of inorganic salt in the step 2) is beneficial to promoting the reaction, and the reaction is difficult if the inorganic salt is not available. Adding an alkaline reagent to facilitate the leaving of active hydrogen in the di-tert-butyl malonate or di-tert-amyl malonate; meanwhile, the hydrogen chloride generated in the reaction process can be absorbed, so that the condensation reaction is completely carried out.
The addition of the organic acid in the step 3) is beneficial to the full mixing and dissolving of reactants and the acceleration of the reaction rate. The control of the amount of the inorganic acid added is critical, and if the amount is large, the yield is lowered.
The technical basis of the invention is shown in the research of related chemical reactions, and the inventor finds that the compound with the structure as V can generate two products when being hydrolyzed under the acidic condition. When R is primary alkyl such as methyl, ethyl, propyl and the like, the generated product is mainly nitrobenzoic acid, and the target product nitroacetophenone is very little; when R is tertiary alkyl, the target product nitroacetophenone is dominant in the product.
Preferably, the compound of formula I is o-nitrobenzoic acid, m-nitrobenzoic acid or p-nitrobenzoic acid.
Preferably, the first inert solvent is one or two of toluene, benzene and xylene; the second inert solvent is ethyl acetate.
Preferably, the chlorinating agent is one or more of thionyl chloride, phosphorus trichloride, phosphorus pentachloride and triphosgene.
Preferably, the catalyst is one or more of N, N-dimethylformamide, triethylamine, N-dimethylaniline and pyridine.
Preferably, the inorganic salt is one or more of calcium chloride, calcium bromide and calcium iodide; the alkaline reagent is one or more of triethylamine, diisopropylethylamine, N-dimethylaniline, pyridine, picoline, sodium carbonate, potassium carbonate and calcium phosphate.
Preferably, the molar ratio of the compound of formula i to the chlorinating agent is 1: 1 to 2.
Preferably, the molar ratio of the compound of formula I to di-tert-butyl malonate or di-tert-amyl malonate is 1: 1 to 1.2.
Preferably, the amount of the catalyst is 4-6% of the mass of the chlorinating agent; the dosage of the inorganic salt is 20-30% of the mass of the crude product of the compound shown in the formula II; the mass ratio of the alkaline reagent to the chlorinating agent is 1: 1-2; the volume ratio of the water to the organic acid to the inorganic acid is 2-2.5: 1: 0.02-0.05.
The organic acid is selected from one or more of acetic acid, formic acid, propionic acid and methanesulfonic acid; the inorganic acid is selected from one or more of sulfuric acid, hydrochloric acid, phosphoric acid and perchloric acid.
The invention has the beneficial effects that: the method avoids the use of expensive composite transition metal catalysts or mixed acid of sulfuric acid/nitric acid and the like, has high production safety factor, less three wastes, high yield (75-85 percent) and low cost. In addition, the method has wide applicability, and the o-nitroacetophenone, the m-nitroacetophenone and the p-nitroacetophenone can be prepared.
Detailed Description
The technical solution of the present invention will be further specifically described below by way of specific examples.
In the present invention, the raw materials and equipment used are commercially available or commonly used in the art, unless otherwise specified. The methods in the following examples are conventional in the art unless otherwise specified.
Example 1
1) Adding 16.7g (0.1mol) of o-nitrobenzoic acid, 1ml of DMF (dimethyl formamide) and 100ml of toluene into a reaction bottle provided with a drying tube and a tail gas absorption device, stirring and heating to 60 ℃, dropwise adding 17.8g (0.15mol) of thionyl chloride, heating to reflux reaction for about 2-3h after dropwise adding, discharging no obvious bubbles in the tail gas absorption device, cooling to room temperature, and distilling out excessive thionyl chloride and toluene under reduced pressure to obtain a light yellow oily substance which is directly used for the next reaction;
2) adding 21.6g (0.1mol) of di-tert-butyl malonate, 5g of anhydrous calcium chloride, 100ml of ethyl acetate and 20ml of triethylamine into a reaction bottle, fully stirring, dropwise adding the yellowish oily substance in the previous step, heating to 60 ℃ for reaction for about 1-2h, detecting by TLC (thin layer chromatography) to finish the reaction, cooling, adjusting the pH to 5-6 with hydrochloric acid, separating an organic phase, washing with saturated sodium bicarbonate and saturated salt twice in sequence, drying with anhydrous sodium sulfate, and concentrating to obtain a yellow oily substance;
3) heating the yellow oily substance, 100ml of water, 40ml of acetic acid and 2ml of sulfuric acid to reflux for about 2-3h, detecting by TLC after the reaction is finished, cooling to room temperature, adjusting the solution of sodium hydroxide to be neutral, extracting by ethyl acetate, washing an organic layer twice by using saturated salt solution, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 13.3g of yellow oily liquid with the yield of 80.5%.
Example 2
1) Adding 16.7g (0.1mol) of p-nitrobenzoic acid, 1ml of DMF (dimethyl formamide) and 100ml of toluene into a reaction bottle provided with a drying tube and a tail gas absorption device, stirring and heating to 60 ℃, dropwise adding 17.8g (0.15mol) of thionyl chloride, heating to reflux reaction for about 2-3h after dropwise adding, discharging no obvious bubbles in the tail gas absorption device, cooling to room temperature, and distilling out excessive thionyl chloride and toluene under reduced pressure to obtain a light yellow oily substance which is directly used for the next reaction;
2) adding 21.6g (0.1mol) of di-tert-butyl malonate, 5g of anhydrous calcium chloride, 100ml of ethyl acetate and 20ml of triethylamine into a reaction bottle, fully stirring, dropwise adding the yellowish oily substance in the previous step, heating to 60 ℃ for reaction for about 1-2h, detecting by TLC (thin layer chromatography) to finish the reaction, cooling, adjusting the pH to 5-6 with hydrochloric acid, separating an organic phase, washing with saturated sodium bicarbonate and saturated salt twice in sequence, drying with anhydrous sodium sulfate, and concentrating to obtain a yellow oily substance;
3) heating the yellow oily substance, 100ml of water, 40ml of acetic acid and 2ml of sulfuric acid to reflux for about 2-3h, detecting by TLC after the reaction is finished, cooling to room temperature, adjusting the solution of sodium hydroxide to be neutral, extracting by ethyl acetate, washing an organic layer twice by using saturated salt solution, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 13.6g of yellow oily liquid with the yield of 82.3%.
Example 3
1) Adding 16.7g (0.1mol) of m-nitrobenzoic acid, 1ml of DMF (dimethyl formamide) and 100ml of toluene into a reaction bottle provided with a drying tube and a tail gas absorption device, stirring and heating to 60 ℃, dropwise adding 17.8g (0.15mol) of thionyl chloride, heating to reflux reaction for about 2-3h after dropwise adding, discharging no obvious bubbles in the tail gas absorption device, cooling to room temperature, and distilling out excessive thionyl chloride and toluene under reduced pressure to obtain a light yellow oily substance which is directly used for the next reaction;
2) adding 21.6g (0.1mol) of di-tert-butyl malonate, 5g of anhydrous calcium chloride, 100ml of ethyl acetate and 20ml of triethylamine into a reaction bottle, fully stirring, dropwise adding the yellowish oily substance in the previous step, heating to 60 ℃ for reaction for about 1-2h, detecting by TLC (thin layer chromatography) to finish the reaction, cooling, adjusting the pH to 5-6 with hydrochloric acid, separating an organic phase, washing with saturated sodium bicarbonate and saturated salt twice in sequence, drying with anhydrous sodium sulfate, and concentrating to obtain a yellow oily substance;
3) heating the yellow oily substance, 100ml of water, 40ml of acetic acid and 2ml of sulfuric acid to reflux for about 2-3h, detecting by TLC after the reaction is finished, cooling to room temperature, adjusting the solution of sodium hydroxide to be neutral, extracting by ethyl acetate, washing an organic layer twice by using saturated salt solution, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 12.6g of yellow oily liquid with the yield of 76.3%.
The scope of the invention can be adjusted within the following ranges:
1) taking a compound of a formula I as a raw material, adding a first inert solvent and a catalyst, stirring and heating to 55-65 ℃, dropwise adding a chlorinating agent, heating to reflux reaction for 2-3 hours, and after finishing the acyl chlorination reaction, distilling out the excessive chlorinating agent and the inert solvent under reduced pressure to obtain a crude product of a compound of a formula II, wherein the crude product can be directly used for the next reaction; the compound of formula I is o-nitrobenzoic acid, m-nitrobenzoic acid or p-nitrobenzoic acid.
2) Adding inorganic salt, a second inert solvent, an alkaline reagent and malonic acid di-tert-butyl ester or malonic acid di-tert-amyl ester into a reaction bottle, fully stirring, dropwise adding a crude compound of the formula II, heating to 55-65 ℃, reacting for 1-2 hours, neutralizing with hydrochloric acid until the pH value is 5-6 after the condensation reaction is finished, separating an organic layer, sequentially washing with saturated sodium bicarbonate and saturated salt water, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the compound of the formula III.
3) Adding the compound shown in the formula III into a mixed solution of water, organic acid and inorganic acid for reflux reaction for 2-3 hours, adjusting a sodium hydroxide solution to be neutral after the hydrolysis reaction is finished, extracting by using an organic solvent, and concentrating under reduced pressure to obtain a compound shown in the formula IV.
Wherein, the first inert solvent is one or two of toluene, benzene and xylene; the second inert solvent is ethyl acetate. The chlorinating agent is one or more of thionyl chloride, phosphorus trichloride, phosphorus pentachloride and triphosgene. The catalyst is one or more of N, N-dimethylformamide, triethylamine, N-dimethylaniline and pyridine. The inorganic salt is one or more of calcium chloride, calcium bromide and calcium iodide; the alkaline reagent is one or more of triethylamine, diisopropylethylamine, N-dimethylaniline, pyridine, picoline, sodium carbonate, potassium carbonate and calcium phosphate. The molar ratio of the compound of the formula I to the chlorinating agent is 1: 1 to 2. The molar ratio of the compound shown in the formula I to the di-tert-butyl malonate or di-tert-amyl malonate is 1: 1 to 1.2. The dosage of the catalyst is 4-6% of the mass of the chlorinating agent; the dosage of the inorganic salt is 20-30% of the mass of the crude product of the compound shown in the formula II; the mass ratio of the alkaline reagent to the chlorinating agent is 1: 1-2; the volume ratio of the water to the organic acid to the inorganic acid is 2-2.5: 1: 0.02-0.05. The organic acid is selected from one or more of acetic acid, formic acid, propionic acid and methanesulfonic acid; the inorganic acid is selected from one or more of sulfuric acid, hydrochloric acid, phosphoric acid and perchloric acid.
The above-described embodiments are only preferred embodiments of the present invention, and are not intended to limit the present invention in any way, and other variations and modifications may be made without departing from the spirit of the invention as set forth in the claims.
Claims (6)
1. The preparation method of nitroacetophenone is characterized by comprising the following steps:
1) taking a compound of a formula I as a raw material, adding a first inert solvent and a catalyst, stirring and heating to 55-65 ℃, dropwise adding a chlorinating agent, heating to reflux reaction for 2-3 hours, and after finishing the acyl chlorination reaction, distilling out the excessive chlorinating agent and the inert solvent under reduced pressure to obtain a crude product of a compound of a formula II, wherein the crude product can be directly used for the next reaction;
2) adding inorganic salt, a second inert solvent, an alkaline reagent and di-tert-butyl malonate or di-tert-amyl malonate into a reaction bottle, fully stirring, dropwise adding a crude product of the compound shown in the formula II, heating to 55-65 ℃, reacting for 1-2 hours, neutralizing with hydrochloric acid until the pH is =5-6 after the condensation reaction is finished, separating an organic layer, sequentially washing with saturated sodium bicarbonate and saturated salt water, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound shown in the formula III;
3) adding the compound shown in the formula III into a mixed solution of water, organic acid and inorganic acid for reflux reaction for 2-3 hours, adjusting a sodium hydroxide solution to be neutral after the hydrolysis reaction is finished, extracting by using an organic solvent, and concentrating under reduced pressure to obtain a compound shown in the formula IV;
the inorganic salt is one or more of calcium chloride, calcium bromide and calcium iodide; the alkaline reagent is one or more of triethylamine, diisopropylethylamine, N-dimethylaniline, pyridine, picoline, sodium carbonate, potassium carbonate and calcium phosphate;
the molar ratio of the compound of the formula I to the chlorinating agent is 1: 1-2; the molar ratio of the compound shown in the formula I to the di-tert-butyl malonate or di-tert-amyl malonate is 1: 1 to 1.2; the dosage of the catalyst is 4-6% of the mass of the chlorinating agent; the dosage of the inorganic salt is 20-30% of the mass of the crude product of the compound shown in the formula II; the mass ratio of the alkaline reagent to the chlorinating agent is 1: 1-2; the volume ratio of the water to the organic acid to the inorganic acid is 2-2.5: 1: 0.02-0.05.
2. The method for preparing nitroacetophenone according to claim 1, wherein: the compound of the formula I is o-nitrobenzoic acid, m-nitrobenzoic acid or p-nitrobenzoic acid.
3. The method for preparing nitroacetophenone according to claim 1, wherein: the first inert solvent is one or two of methylbenzene, benzene and dimethylbenzene; the second inert solvent is ethyl acetate.
4. The method for preparing nitroacetophenone according to claim 1, wherein: the chlorinating agent is one or more of thionyl chloride, phosphorus trichloride, phosphorus pentachloride and triphosgene.
5. The method for preparing nitroacetophenone according to claim 1, wherein: the catalyst is one or more of N, N-dimethylformamide, triethylamine, N-dimethylaniline and pyridine.
6. The method for preparing nitroacetophenone according to claim 1, wherein: the organic acid is selected from one or more of acetic acid, formic acid, propionic acid and methanesulfonic acid; the inorganic acid is selected from one or more of sulfuric acid, hydrochloric acid, phosphoric acid and perchloric acid.
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