CN114456074A - Preparation method of 2-hydroxy-3-nitroacetophenone - Google Patents
Preparation method of 2-hydroxy-3-nitroacetophenone Download PDFInfo
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- CN114456074A CN114456074A CN202210148259.5A CN202210148259A CN114456074A CN 114456074 A CN114456074 A CN 114456074A CN 202210148259 A CN202210148259 A CN 202210148259A CN 114456074 A CN114456074 A CN 114456074A
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- XQZGSPSZLMKODN-UHFFFAOYSA-N 1-(2-hydroxy-3-nitrophenyl)ethanone Chemical compound CC(=O)C1=CC=CC([N+]([O-])=O)=C1O XQZGSPSZLMKODN-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 17
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 230000021736 acetylation Effects 0.000 claims abstract description 5
- 238000006640 acetylation reaction Methods 0.000 claims abstract description 5
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- 238000003756 stirring Methods 0.000 claims description 42
- 238000001035 drying Methods 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 238000001914 filtration Methods 0.000 claims description 28
- 239000012074 organic phase Substances 0.000 claims description 20
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 238000001816 cooling Methods 0.000 claims description 15
- 238000000926 separation method Methods 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 239000007788 liquid Substances 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- WQOXQRCZOLPYPM-UHFFFAOYSA-N dimethyl disulfide Chemical compound CSSC WQOXQRCZOLPYPM-UHFFFAOYSA-N 0.000 claims description 8
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 6
- 229960001701 chloroform Drugs 0.000 claims description 6
- VCJMYUPGQJHHFU-UHFFFAOYSA-N iron(3+);trinitrate Chemical compound [Fe+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O VCJMYUPGQJHHFU-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000005457 ice water Substances 0.000 claims description 5
- 239000007868 Raney catalyst Substances 0.000 claims description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 4
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 4
- 239000012346 acetyl chloride Substances 0.000 claims description 4
- 230000000802 nitrating effect Effects 0.000 claims description 4
- 239000002244 precipitate Substances 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 3
- DDCYYCUMAFYDDU-UHFFFAOYSA-N methyl thiohypochlorite Chemical compound CSCl DDCYYCUMAFYDDU-UHFFFAOYSA-N 0.000 claims description 3
- 229910052750 molybdenum Inorganic materials 0.000 claims description 3
- 239000011733 molybdenum Substances 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 claims description 3
- 239000012414 tert-butyl nitrite Substances 0.000 claims description 3
- 230000011987 methylation Effects 0.000 claims description 2
- 238000007069 methylation reaction Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000006396 nitration reaction Methods 0.000 abstract description 3
- 238000006477 desulfuration reaction Methods 0.000 abstract 1
- 230000023556 desulfurization Effects 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- JECYUBVRTQDVAT-UHFFFAOYSA-N 2-acetylphenol Chemical compound CC(=O)C1=CC=CC=C1O JECYUBVRTQDVAT-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- CBCKQZAAMUWICA-UHFFFAOYSA-N 1,4-phenylenediamine Chemical compound NC1=CC=C(N)C=C1 CBCKQZAAMUWICA-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 102000003835 leukotriene receptors Human genes 0.000 description 1
- 108090000146 leukotriene receptors Proteins 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229960004583 pranlukast Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of 2-hydroxy-3-nitroacetophenone, in particular to a method for efficiently synthesizing 2-hydroxy-3-nitroacetophenone by four steps of methyl sulfide, nitration, acetylation and desulfurization by taking phenol as a raw material. The preparation method of the 2-hydroxy-3-nitroacetophenone provided by the invention is a preparation method which has the advantages of high yield, low cost, less three wastes, good product quality and suitability for industrialization.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a preparation method of 2-hydroxy-3-nitroacetophenone.
Background
The 2-hydroxy-3-nitroacetophenone is the starting material of the leukotriene receptor antagonist-pranlukast, and the main synthetic route is as follows:
the method comprises the following steps:
in the Journal of Medicinal Chemistry (Journal of Medicinal Chemistry, Mark Cushman, 1994, vol.37, # 20, p.3353-3362), o-hydroxyacetophenone is used as a raw material and the target product is obtained by nitration. The method has extremely poor selectivity, the yield is only 33 percent, and the paranitrated product is generated in an approximately equal amount; the separation of the two nitro isomers is difficult and does not meet the requirement of environmental protection.
The method 2 comprises the following steps:
in the method disclosed in US4977162, 1-phenyl-2-hydroxyacetophenone is used as a raw material, and the target product is obtained after nitration. The method has poor yield selectivity, and the yield is 30% after the preparative chromatographic separation; the raw materials are expensive, and the industrial significance is not great.
Disclosure of Invention
Aiming at the problems, the invention discloses a preparation method of 2-hydroxy-3-nitroacetophenone, and particularly relates to a preparation method of 2-hydroxy-3-nitroacetophenone, which takes p-phenylenediamine as a raw material and is efficiently synthesized through four steps of protection, acylation, cyclization and deprotection.
The reaction equation is as follows:
the technical scheme for solving the technical problems is as follows: a preparation method of 2-hydroxy-3-nitroacetophenone comprises the following steps:
(1) adding a solvent I into a reaction bottle, adding 1.0mol of phenol and 0.5-1.6mol of a catalyst I under stirring, adding 1.1-1.5mol of a methylation reagent under the condition of keeping the temperature at 20-60 ℃, reacting completely after adding, concentrating under reduced pressure to dryness, adding ethyl acetate and water, stirring, standing for liquid separation, drying an organic phase, then refluxing and decoloring by using activated carbon, concentrating a filtrate to dryness, recrystallizing by using toluene, filtering and drying to obtain an intermediate I;
(2) adding a solvent II into a reaction bottle, adding 0.74-0.86mol of an intermediate I under stirring, adding 0.82-1.3mol of a nitrating reagent under the condition of controlling the temperature to be 0-60 ℃, reacting completely after the addition is finished, concentrating under reduced pressure, adding water, extracting with ethyl acetate, drying an organic phase, concentrating and crystallizing, filtering and drying to obtain an intermediate II;
(3) adding a solvent III into a reaction bottle, adding 0.63-0.70mol of an intermediate II and 1.1-1.6mol of anhydrous aluminum trichloride under stirring, dropwise adding 0.7-0.9mol of an acetylation reagent under the condition of controlling the temperature to be 0-40 ℃, stirring for reaction till completion, heating to 60-70 ℃ for reaction, cooling to room temperature, slowly pouring into ice water, stirring, standing for liquid separation, drying an organic phase, concentrating to dryness, recrystallizing with acetone, filtering and drying to obtain an intermediate III;
(4) adding a solvent IV into a reaction bottle, adding 0.53-0.61mol of an intermediate III and 1.6-3.0mol of a catalyst II under stirring, heating to 50-80 ℃ to react completely, cooling and filtering, concentrating the filtrate to dryness, adding ethyl acetate and water, stirring, standing for liquid separation, drying the organic phase, adding activated carbon for reflux and decoloration, concentrating to a large amount of precipitates, cooling and crystallizing, filtering and drying to obtain the 2-hydroxy-3-nitroacetophenone.
In the step (1), the methyl sulfide reagent is one of chlorothiomethane and dimethyl disulfide.
In the step (1), the catalyst I is one of N-methylmorpholine, cupric diacetate and anhydrous aluminum trichloride.
In the step (1), the solvent I is one of dichloromethane, tetrahydrofuran and trichloromethane.
In the step (2), the solvent II is one of ethanol, acetic acid and acetonitrile.
The nitrating reagent in the step (2) is one of ferric nitrate, nitric acid and tert-butyl nitrite.
In the step (3), the solvent III is one of dichloroethane, chloroform and o-dichlorobenzene.
And (3) the acetylation reagent is one of acetyl chloride and acetic anhydride.
In the step (4), the solvent IV is one of methanol, ethanol and tetrahydrofuran.
In the step (4), the catalyst II is one of W2 type Raney nickel and molybdenum hexacarbonyl.
The preparation method of the 2-hydroxy-3-nitroacetophenone has the advantages that: (1) the process is simple; (2) the three wastes are less; (3) the cost is low and the yield is high; (4) the product quality is good.
Detailed Description
The present invention is further illustrated by the following specific examples.
Example 1
A preparation method of 2-hydroxy-3-nitroacetophenone specifically comprises the following steps:
(1) adding 700ml of dichloromethane into a reaction bottle, adding 94.1g of phenol and 161.6g of N-methylmorpholine under stirring, keeping the temperature at 20-30 ℃, slowly dropwise adding 123.8g of chlorothiomethane, stirring for 10 hours after the addition is finished, concentrating under reduced pressure to dryness, adding 800ml of ethyl acetate and 300ml of water, stirring, standing for liquid separation, drying an organic phase by anhydrous sodium sulfate, refluxing and decoloring by activated carbon, filtering, concentrating a filtrate to dryness, recrystallizing by 250ml of toluene, filtering and drying to obtain 120.1g of an intermediate I, a reddish solid, wherein the yield is 85.7%.
(2) Adding 1100ml of ethanol into a reaction bottle, adding 120.1g of intermediate I while stirring, adding 266.1g of ferric nitrate in batches under the condition of controlling the temperature to be 50-60 ℃, reacting for 14 hours after the addition is finished, concentrating under reduced pressure to about 300ml, adding 200ml of water, extracting with 1200ml of ethyl acetate, drying an organic phase, concentrating, crystallizing, filtering and drying to obtain intermediate II, 128.3g of light yellow solid, and the yield of 80.9%.
(3) Adding 600ml of dichloroethane into a reaction bottle, adding 128.3g of intermediate II and 148.9g of anhydrous aluminum trichloride under stirring, dropwise adding 54.9g of acetyl chloride under the condition of controlling the temperature to be 0-10 ℃, stirring for reacting for 2 hours, heating to 60-70 ℃, reacting for 6 hours, cooling to room temperature, slowly pouring into 500ml of ice water, stirring, standing for liquid separation, drying the organic phase, concentrating to dryness, recrystallizing by 300ml of acetone, filtering and drying to obtain intermediate III, 132.9g of off-white powder, and the yield of 84.4%.
(4) Adding 600ml of methanol into a reaction bottle, adding 132.9g of intermediate III and 176.1g of W2 type Raney nickel under stirring, heating to 50-60 ℃ for reaction for 14 hours, cooling and filtering, concentrating the filtrate to dryness, adding 600ml of ethyl acetate and water, stirring, standing for liquid separation, drying the organic phase, adding activated carbon for reflux decoloring, concentrating to precipitate in a large amount, cooling for crystallization, filtering and drying to obtain 2-hydroxy-3-nitroacetophenone, 95.7g of white solid, high yield and high purity90.3%，MP=86-88℃。1H NMR (400 MHz, CDCl3) δ 13.1 (s, 1H), 8.2 (dd, J = 8.1,1.7Hz ,1H), 8.07 (dd, J = 8.1,1.7 Hz ,1H), 7.06(t, J = 8.1 Hz ,1H),2.74 (s, 3H).
Example 2
A preparation method of 2-hydroxy-3-nitroacetophenone specifically comprises the following steps:
(1) adding 900ml of tetrahydrofuran into a reaction bottle, adding 94.1g of phenol and 90.6g of copper diacetate under stirring, slowly dropwise adding 103.6g of dimethyl disulfide under the condition of keeping the temperature at 50-60 ℃, stirring for reacting for 24 hours after the addition is finished, concentrating under reduced pressure to dryness, adding 800ml of ethyl acetate and 300ml of water, stirring, standing for liquid separation, drying an organic phase by anhydrous sodium sulfate, refluxing and decoloring by using activated carbon, filtering, concentrating a filtrate to dryness, recrystallizing by using 250ml of toluene, filtering and drying to obtain 110.1g of an intermediate I, a reddish solid, wherein the yield is 78.5%.
(2) Adding 800ml of acetic acid into a reaction bottle, adding 110.1g of intermediate I under stirring, dropwise adding 86.1g of nitric acid with the mass concentration of 60% under the condition of controlling the temperature to be 0-10 ℃, reacting for 4 hours after the addition is finished, concentrating under reduced pressure to about 300ml, adding 200ml of water, extracting with 1200ml of ethyl acetate, drying an organic phase, concentrating and crystallizing, filtering and drying to obtain intermediate II, 127.9g of light yellow solid, and the yield is 87.9%.
(3) Adding 800ml of chloroform into a reaction bottle, adding 127.9g of intermediate II and 186.9g of anhydrous aluminum trichloride under stirring, dropwise adding 62.8g of acetyl chloride under the condition of controlling the temperature to be 10-20 ℃, stirring for reacting for 2 hours, heating to 60-70 ℃, reacting for 4 hours, cooling to room temperature, slowly pouring into 500ml of ice water, stirring, standing for liquid separation, drying organic phase, concentrating to dryness, recrystallizing by 300ml of acetone, filtering and drying to obtain intermediate III, 137.8g of off-white powder, wherein the yield is 86.5%.
(4) Adding 800ml of ethanol into a reaction bottle, adding 137.8g of intermediate III and 139.2g of W2 Raney nickel under stirring, heating to 70-80 ℃ for reaction for 24 hours, cooling and filtering, concentrating the filtrate to dryness, adding 600ml of ethyl acetate and water, stirring, standing for liquid separation, drying the organic phase, adding activated carbon for reflux decolorization, concentrating to a large amount of precipitate, cooling for crystallization, filtering and drying to obtain 94.2g of 2-hydroxy-3-nitroacetophenone, wherein the white solid is 94.2g, and the yield is 84.9%.
Example 3
(1) 1100ml of trichloromethane is added into a reaction bottle, 94.1g of phenol and 146.8g of anhydrous aluminum trichloride are added under the stirring condition, 141.3g of dimethyl disulfide is slowly dripped under the condition of keeping the temperature at 40-50 ℃, the stirring reaction is carried out for 6 hours after the addition, the reduced pressure concentration is carried out till the mixture is dry, 800ml of ethyl acetate and 300ml of water are added, the mixture is stirred, kept still and separated, an organic phase is dried by anhydrous sodium sulfate, then reflux decoloration is carried out by active carbon, the filtration is carried out, the filtrate is concentrated till the dryness, 250ml of toluene is used for recrystallization, the filtration and the drying are carried out, thus obtaining 103.9g of an intermediate I, a white-like solid, and the yield is 74.1%.
(2) Adding 600ml of acetonitrile into a reaction bottle, adding 103.9g of intermediate I while stirring, dropwise adding 133.9g of tert-butyl nitrite under the condition of controlling the temperature to be 30-40 ℃, reacting for 48 hours after the addition, concentrating under reduced pressure to about 300ml, adding 200ml of water, extracting with 1200ml of ethyl acetate, drying an organic phase, concentrating and crystallizing, filtering and drying to obtain intermediate II, 117.6g of light yellow solid and 85.4% of yield.
(3) Adding 1100ml of o-dichlorobenzene into a reaction bottle, adding 117.6g of intermediate II and 213.6g of anhydrous aluminum trichloride under stirring, dropwise adding 91.8g of acetic anhydride under the condition of controlling the temperature to be 30-40 ℃, stirring for reacting for 6 hours, heating to 60-70 ℃, reacting for 4 hours, cooling to room temperature, slowly pouring into 500ml of ice water, stirring, standing for liquid separation, drying organic phase, concentrating to dryness, recrystallizing by 300ml of acetone, filtering and drying to obtain intermediate III, wherein the yield is 83.7 percent.
(4) Adding 1500ml of tetrahydrofuran into a reaction bottle, adding 120.8g of intermediate III and 422.4g of molybdenum hexacarbonyl under stirring, heating to 60-70 ℃ for reaction for 72 hours, cooling and filtering, concentrating the filtrate to dryness, adding 600ml of ethyl acetate and water, stirring, standing for liquid separation, drying the organic phase, adding activated carbon for reflux decoloring, concentrating to obtain a large amount of precipitate, cooling for crystallization, filtering and drying to obtain 2-hydroxy-3-nitroacetophenone, wherein 83.9g of white solid is obtained, and the yield is 87.2%.
Claims (10)
1. A preparation method of 2-hydroxy-3-nitroacetophenone is characterized by comprising the following steps: the method specifically comprises the following steps:
adding a solvent I into a reaction bottle, adding 1.0mol of phenol and 0.5-1.6mol of a catalyst I under stirring, adding 1.1-1.5mol of a methylation reagent under the condition of keeping the temperature at 20-60 ℃, reacting completely after adding, concentrating under reduced pressure to dryness, adding ethyl acetate and water, stirring, standing for liquid separation, drying an organic phase, then refluxing and decoloring by using activated carbon, concentrating a filtrate to dryness, recrystallizing by using toluene, filtering and drying to obtain an intermediate I;
(2) adding a solvent II into a reaction bottle, adding 0.74-0.86mol of an intermediate I under stirring, adding 0.82-1.3mol of a nitrating reagent under the condition of controlling the temperature to be 0-60 ℃, reacting completely after the addition is finished, concentrating under reduced pressure, adding water, extracting with ethyl acetate, drying an organic phase, concentrating and crystallizing, filtering and drying to obtain an intermediate II;
(3) adding a solvent III into a reaction bottle, adding 0.63-0.70mol of an intermediate II and 1.1-1.6mol of anhydrous aluminum trichloride under stirring, dropwise adding 0.7-0.9mol of an acetylation reagent under the condition of controlling the temperature to be 0-40 ℃, stirring for reaction till completion, heating to 60-70 ℃ for reaction, cooling to room temperature, slowly pouring into ice water, stirring, standing for liquid separation, drying an organic phase, concentrating to dryness, recrystallizing with acetone, filtering and drying to obtain an intermediate III;
(4) adding a solvent IV into a reaction bottle, adding 0.53-0.61mol of an intermediate III and 1.6-3.0mol of a catalyst II under stirring, heating to 50-80 ℃ to react completely, cooling and filtering, concentrating the filtrate to dryness, adding ethyl acetate and water, stirring, standing for liquid separation, drying the organic phase, adding activated carbon for reflux and decoloration, concentrating to a large amount of precipitates, cooling and crystallizing, filtering and drying to obtain the 2-hydroxy-3-nitroacetophenone.
2. The process for the preparation of 2-hydroxy-3-nitroacetophenone according to claim 1, wherein: in the step (1), the methyl sulfide reagent is one of chlorothiomethane and dimethyl disulfide.
3. The process for the preparation of 2-hydroxy-3-nitroacetophenone according to claim 1, wherein: in the step (1), the catalyst I is one of N-methylmorpholine, copper diacetate and anhydrous aluminum trichloride.
4. The process for the preparation of 2-hydroxy-3-nitroacetophenone according to claim 1, wherein: in the step (1), the solvent I is one of dichloromethane, tetrahydrofuran and trichloromethane.
5. The process for the preparation of 2-hydroxy-3-nitroacetophenone according to claim 1, wherein: in the step (2), the solvent II is one of ethanol, acetic acid and acetonitrile.
6. The process for the preparation of 2-hydroxy-3-nitroacetophenone according to claim 1, wherein: the nitrating reagent in the step (2) is one of ferric nitrate, nitric acid and tert-butyl nitrite.
7. The process for the preparation of 2-hydroxy-3-nitroacetophenone according to claim 1, wherein: in the step (3), the solvent III is one of dichloroethane, chloroform and o-dichlorobenzene.
8. The process for the preparation of 2-hydroxy-3-nitroacetophenone according to claim 1, wherein: and (3) the acetylation reagent is one of acetyl chloride and acetic anhydride.
9. The process for the preparation of 2-hydroxy-3-nitroacetophenone according to claim 1, wherein: in the step (4), the solvent IV is one of methanol, ethanol and tetrahydrofuran.
10. The process for the preparation of 2-hydroxy-3-nitroacetophenone according to claim 1, wherein: in the step (4), the catalyst II is one of W2 type Raney nickel and molybdenum hexacarbonyl.
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| CN202210148259.5A CN114456074A (en) | 2022-02-18 | 2022-02-18 | Preparation method of 2-hydroxy-3-nitroacetophenone |
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