CN111675624B - Preparation method of o-aminoacetophenone - Google Patents
Preparation method of o-aminoacetophenone Download PDFInfo
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- CN111675624B CN111675624B CN202010531803.5A CN202010531803A CN111675624B CN 111675624 B CN111675624 B CN 111675624B CN 202010531803 A CN202010531803 A CN 202010531803A CN 111675624 B CN111675624 B CN 111675624B
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- GTDQGKWDWVUKTI-UHFFFAOYSA-N o-aminoacetophenone Chemical compound CC(=O)C1=CC=CC=C1N GTDQGKWDWVUKTI-UHFFFAOYSA-N 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 75
- SUGXZLKUDLDTKX-UHFFFAOYSA-N 1-(2-nitrophenyl)ethanone Chemical compound CC(=O)C1=CC=CC=C1[N+]([O-])=O SUGXZLKUDLDTKX-UHFFFAOYSA-N 0.000 claims abstract description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 42
- 239000012286 potassium permanganate Substances 0.000 claims abstract description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 26
- PXWYZLWEKCMTEZ-UHFFFAOYSA-N 1-ethyl-2-nitrobenzene Chemical compound CCC1=CC=CC=C1[N+]([O-])=O PXWYZLWEKCMTEZ-UHFFFAOYSA-N 0.000 claims abstract description 25
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 17
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229960000583 acetic acid Drugs 0.000 claims abstract description 13
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 72
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 42
- 238000010992 reflux Methods 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 25
- 239000000243 solution Substances 0.000 claims description 23
- 235000019270 ammonium chloride Nutrition 0.000 claims description 21
- 238000005406 washing Methods 0.000 claims description 17
- 238000000605 extraction Methods 0.000 claims description 14
- 239000003377 acid catalyst Substances 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- 229910052751 metal Inorganic materials 0.000 claims description 7
- 239000002184 metal Substances 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- 238000000658 coextraction Methods 0.000 claims description 3
- 239000002253 acid Substances 0.000 abstract description 9
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 230000002378 acidificating effect Effects 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 abstract description 3
- 238000007254 oxidation reaction Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 60
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 26
- 229910052748 manganese Inorganic materials 0.000 description 26
- 239000011572 manganese Substances 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 11
- 238000001816 cooling Methods 0.000 description 10
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 9
- 239000000498 cooling water Substances 0.000 description 8
- 210000003298 dental enamel Anatomy 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- -1 boric acid are used Chemical class 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 4
- 229910052804 chromium Inorganic materials 0.000 description 4
- 239000011651 chromium Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 3
- 239000004327 boric acid Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- JHWIEAWILPSRMU-UHFFFAOYSA-N 2-methyl-3-pyrimidin-4-ylpropanoic acid Chemical compound OC(=O)C(C)CC1=CC=NC=N1 JHWIEAWILPSRMU-UHFFFAOYSA-N 0.000 description 2
- SLAMLWHELXOEJZ-UHFFFAOYSA-N 2-nitrobenzoic acid Chemical group OC(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 238000005260 corrosion Methods 0.000 description 2
- 230000007797 corrosion Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 description 2
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 238000001256 steam distillation Methods 0.000 description 2
- LTXREWYXXSTFRX-QGZVFWFLSA-N Linagliptin Chemical compound N=1C=2N(C)C(=O)N(CC=3N=C4C=CC=CC4=C(C)N=3)C(=O)C=2N(CC#CC)C=1N1CCC[C@@H](N)C1 LTXREWYXXSTFRX-QGZVFWFLSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- SOCTUWSJJQCPFX-UHFFFAOYSA-N dichromate(2-) Chemical compound [O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O SOCTUWSJJQCPFX-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229960002397 linagliptin Drugs 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 239000010802 sludge Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- 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
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 the technical field of synthesis of organic intermediates, and particularly relates to a preparation method of o-aminoacetophenone. The preparation method of o-nitroacetophenone provided by the invention comprises the steps of adding o-nitroethylbenzene into potassium permanganate in batches in an acidic environment of dilute sulfuric acid to carry out oxidation reaction to generate o-nitroacetophenone; the method has the advantages that the o-nitroacetophenone is reduced into the o-aminoacetophenone by using the iron powder, then the o-aminoacetophenone is distilled by using water vapor, the reaction condition is mild, the production cost is low, the industrial large-scale production is suitable, the yield of the o-nitroacetophenone can reach more than 70%, the yield of the o-aminoacetophenone can reach more than 90%, when weak acid glacial acetic acid is used as a catalyst, the optimal proportion of the raw materials is kept, and the reaction is carried out under the optimal reaction condition, the yield of the o-nitroacetophenone and the yield of the o-aminoacetophenone can both reach more than 95%.
Description
Technical Field
The invention relates to the technical field of synthesis of organic intermediates, and particularly relates to a preparation method of o-aminoacetophenone.
Background
O-aminoacetophenone is an important intermediate of the hypoglycemic drug linagliptin, and is one of important hot fields of the current drug research.
Patent CN107162923B discloses a method for preparing o-aminoacetophenone, comprising: in an anhydrous or nearly anhydrous solvent, reacting methyllithium with isatoic anhydride at a reaction temperature below-50 ℃, and performing post-treatment to obtain the target product o-amino acetophenone. In the preparation method, two related main raw materials, namely methyl lithium and isatoic anhydride, are high in price, and in addition, the reaction is carried out at the temperature of minus 50 ℃, the reaction conditions are harsh, and the production cost is high;
the invention patent with application number 201911252092.1 discloses a preparation method of o-aminoacetophenone, which comprises the following steps: (1) Mixing o-nitroethylbenzene, an oxidant, a cocatalyst and an organic solvent, heating the mixed solution to a certain temperature for reaction, and cooling, quenching and extracting the reacted solution to obtain o-nitroacetophenone; (2) Adding a polar solvent and a metal catalyst into the obtained o-nitroacetophenone, carrying out hydrogenation reduction reaction to obtain an o-aminoacetophenone crude product, and filtering and rectifying the o-aminoacetophenone crude product to obtain an o-aminoacetophenone refined product. In the preparation method, the yield of the o-nitroacetophenone in the step (1) is only 40-70%, so that the yield of the final product is low.
Therefore, the development of a preparation method of o-aminoacetophenone with low production cost, mild reaction condition and high yield is of great significance.
Disclosure of Invention
Therefore, the development of the preparation method of the o-aminoacetophenone with low production cost, mild reaction condition and high yield is of great significance.
The technical scheme for solving the technical problems is as follows:
the invention provides a preparation method of o-aminoacetophenone, which comprises the following steps:
(1) Reacting an oxidant potassium permanganate, an acid catalyst and o-nitroethylbenzene in a dilute sulfuric acid environment, and after the reaction is finished, extracting, washing and drying to obtain o-nitroacetophenone;
(2) And (2) adding the o-nitroacetophenone obtained in the step (1) and a reducing metal into an ammonium chloride aqueous solution for continuous reflux reaction, introducing steam into the reaction kettle for distillation after the reaction is finished, and separating the distilled solution to obtain the o-aminoacetophenone.
Wherein the acid catalyst used in the step (1) is weak acid glacial acetic acid.
Wherein the molar ratio of the o-nitroethylbenzene to the potassium permanganate in the step (1) is 1 (1.3-1.8).
Wherein, the dosage of the weak acid catalyst in the step (1) is 2-4% of the weight of the o-nitroethylbenzene.
Wherein the reaction temperature in the step (1) is 30-40 ℃.
Wherein, the extraction in the step (1) comprises two steps: the first step is industrial salt extraction; the second step is the co-extraction of industrial salt and benzene.
Wherein the washing in step (1) comprises two steps: the first step is washing with alkali liquor and the second step is washing with water.
Wherein the mol ratio of the o-nitroacetophenone to the reducing metal in the step (2) is 1: (2-6).
Wherein, the ammonium chloride solution in the step (2) is added in batches according to the reaction process, and the molar ratio of the ammonium chloride to the iron powder is 1: (10-12).
Wherein the temperature of the reflux reaction in the step (2) is 75-90 ℃.
The preparation method of o-aminoacetophenone provided by the invention comprises the steps of adding o-nitroethylbenzene into potassium permanganate in batches in an acidic environment of dilute sulfuric acid to carry out oxidation reaction to generate o-nitroacetophenone; the o-nitroacetophenone is reduced into o-aminoacetophenone by using iron powder, and then the o-aminoacetophenone is distilled by water vapor, so that the reaction condition is mild, the production cost is low, and the method is suitable for industrial large-scale production, the yield of the o-nitroacetophenone can reach more than 70%, and the yield of the o-aminoacetophenone can reach more than 90%; wherein, when weak acid glacial acetic acid is used as a catalyst, the optimal mixture ratio of the raw materials is kept, and the reaction is carried out under the optimal reaction condition, the yield of the o-nitroacetophenone and the o-aminoacetophenone can reach more than 95 percent.
Detailed Description
The principles and features of this invention are described below in conjunction with specific embodiments, the examples given are intended to illustrate the invention and are not intended to limit the scope of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
A preparation method of o-aminoacetophenone comprises the following steps:
(1) Reacting an oxidant potassium permanganate, an acid catalyst and o-nitroethylbenzene in a dilute sulfuric acid environment, and after the reaction is finished, extracting, washing and drying to obtain o-nitroacetophenone;
(2) And (2) adding the o-nitroacetophenone obtained in the step (1) and a reducing metal into an ammonium chloride aqueous solution for continuous reflux reaction, introducing steam into the reaction kettle for distillation after the reaction is finished, and separating the distilled solution to obtain the o-aminoacetophenone.
It should be noted that: the reaction in step (1) can only be carried out under acidic conditions, and when the reaction is carried out under alkaline conditions, the obtained product can be affected, for example, when the reaction is carried out under alkaline conditions of sodium hydroxide, the obtained product is o-nitrobenzoic acid. The oxidant in the step (1) can only use potassium permanganate, and the applicant adopts dichromate, perchloric acid and other oxidants to carry out experiments, so that the yield of the obtained o-nitroacetophenone is below 55%.
Wherein, the acid catalyst used in step (1) is preferably weak acid glacial acetic acid, and it should be noted that, when other strong acids such as hydrochloric acid and other weak acids such as boric acid are used, the yield of the obtained product o-nitroacetophenone is reduced, for example, when boric acid is used, the yield of the obtained product o-nitroacetophenone is only 40%, when hydrochloric acid is used, the yield of the product o-nitroacetophenone is reduced compared with the yield when glacial acetic acid is used, and hydrochloric acid is not generally used because hydrochloric acid has high corrosivity to equipment.
Wherein the molar ratio of o-nitroethylbenzene to potassium permanganate in the step (1) is 1: (1.3-1.8), among them, 1: (1.4-1.6), most preferably 1:1.5. when the mol ratio of the o-nitroethylbenzene to the potassium permanganate is 1: (1.3-1.8), the yield of the o-nitroacetophenone can reach more than 72%, and when the molar ratio of the o-nitroethylbenzene to the potassium permanganate is 1: (1.4-1.6), the yield of the o-nitroacetophenone can reach more than 81%, and when the molar ratio of the o-nitroethylbenzene to the potassium permanganate is 1:1.5, the yield of the o-nitroacetophenone can reach more than 90%, wherein when the raw materials, the reaction conditions and the like adopt the optimized optimal scheme, the yield of the o-nitroacetophenone can reach more than 95%.
Wherein, the weak acid catalyst is used in the step (1) in an amount of 2-4% by weight, preferably 2.5-3.5% by weight, and more preferably 3% by weight, based on the o-nitroethylbenzene.
Wherein, the reaction temperature in the step (1) is 30-40 ℃, when the temperature is too low, the reaction time is longer, when the temperature is too high, and when the temperature exceeds 50 ℃, the decarboxylation and ring opening of the o-nitroethylbenzene are carried out, the yield of the obtained product o-nitroacetophenone can be obviously reduced, for example, when the reaction is carried out at 55-65 ℃, the yield of the o-nitroacetophenone is only 80%.
Wherein, the extraction in the step (1) comprises two steps: the first step is extracting by using industrial salt; in the second step, industrial salt and benzene are used for co-extraction. The specific operation steps are as follows: after the reaction is finished, adding industrial salt, stirring, cooling, standing, and sucking out the oil layer under negative pressure after the manganese dioxide mud is obviously separated from the oil layer; adding industrial benzene and industrial salt into the oily manganese mud left in the kettle, stirring, after the manganese mud is obviously separated from an oil layer containing the benzene, sucking out the oil layer under negative pressure, discarding the manganese mud, combining the oil layers obtained twice, washing, drying and evaporating the benzene to obtain the manganese-containing manganese oil. The industrial salt used in the step can be sodium chloride or ammonium chloride, and the purpose is to increase the specific gravity of water and facilitate layering.
Wherein, the washing in the step (1) also comprises two steps: the first step is washing with an alkaline solution capable of neutralizing the acid, and the second step is washing with water. The specific operation steps are as follows: and (3) combining the obtained oil layers after extraction, washing twice with alkaline liquor, then washing twice with water, drying the oil layers, and evaporating benzene to obtain the o-nitroacetophenone. The alkali liquor used in the step can be sodium hydroxide alkali liquor or other alkali liquor capable of neutralizing acid, such as potassium hydroxide alkali liquor; the oil layer may be dried with anhydrous calcium chloride or dried with other means such as molecular sieves.
Wherein the mol ratio of the o-nitroacetophenone to the iron powder in the step (2) is 1: (2-6), preferably 1: (3-5), more preferably 1:4.
wherein, the ammonium chloride solution in the step (2) is added in batches according to the reaction process, and the molar ratio of the ammonium chloride to the iron powder is 1: (10-12). The method comprises the following specific operation steps: ammonium chloride is prepared into a 20% aqueous solution, and then added in batches according to the reaction progress. It should be noted that the ammonium chloride used in this step also has the effect of activating the iron powder, and the use of ammonium chloride has little corrosion to equipment and better activation effect to iron powder, and when other chlorides, such as hydrochloric acid, are used, the product yield is low and the corrosion to equipment is severe.
Wherein, the temperature of the reflux reaction in the step (2) is 75-90 ℃, wherein the effect is best when the temperature is 84-84 ℃, when the temperature is higher than 90 ℃, a large amount of water vapor can be generated in the reaction process, the product yield is low, and when the temperature is too low, the reaction is slow.
The reaction process of the reaction is as follows: adding o-nitroethylbenzene into potassium permanganate in batches in an acidic environment of dilute sulfuric acid to perform oxidation reaction to generate o-nitroacetophenone; the o-nitroacetophenone is reduced into o-aminoacetophenone by iron powder, and then the o-aminoacetophenone is distilled by water vapor, so that the content of the obtained product can reach more than 99.5 percent, the yield of the o-nitroacetophenone can reach 70 percent, and the yield of the o-aminoacetophenone can reach 90 percent. Wherein, when weak acid glacial acetic acid is used as a catalyst, the optimal mixture ratio of the raw materials is kept, and the reaction is carried out under the optimal reaction condition, the yield of o-nitroacetophenone and o-aminoacetophenone can reach more than 95%. The reaction principle of the above reaction is as follows:
example 1
Preparing o-nitroacetophenone: adding 210L of water into a 1000L enamel reaction kettle, starting stirring, introducing cooling water into a kettle jacket, slowly dropwise adding 94kg of concentrated sulfuric acid, adding 3kg of glacial acetic acid, controlling the temperature to be 30-40 ℃, then adding 100kg of o-nitroethylbenzene (662 mol), adding 162kg of potassium permanganate (1025 mol) in small batches within 6 hours under rapid stirring, keeping the temperature in the kettle not more than 50 ℃, keeping the temperature and stirring for 2 hours after the potassium permanganate is added, then adding 10kg of industrial salt, stirring and cooling to 30 ℃, standing for half an hour, and sucking out an oil layer under negative pressure after manganese dioxide mud is obviously separated from the oil layer; adding 110kg of industrial benzene and 10kg of industrial salt into the oil-containing manganese mud left in the kettle, quickly stirring for 20 minutes, then slowly stirring for 10 minutes, after the manganese mud is obviously separated from the oil-containing layer, sucking out the oil layer under negative pressure, and discarding the manganese mud. The oil layers of the above two times are combined, washed twice by 5 percent sodium hydroxide solution 60L and twice by water 60L, the oil layer is dried by 4kg of anhydrous calcium chloride, filtered, benzene is distilled out under normal pressure for the next extraction, and the rest is o-nitroacetophenone, 105kg is obtained, and the yield is 96 percent.
Preparation of o-aminoacetophenone: adding 142.5kg (2545 mol) of reduced iron powder and half of solution formed by dissolving 570L and 12kg of ammonium chloride in 60L of water into a 1000L reaction kettle with a reflux condenser while stirring, heating a kettle jacket steam to reflux, stopping heating, keeping the temperature at 80-84 ℃, slowly adding 105kg of o-nitroacetophenone (636 mol) in the previous batch under rapid stirring, obtaining the feeding time for 3 hours, keeping the reflux in the feeding process, adding the rest half of ammonium chloride solution after the feeding is finished, continuously heating and refluxing for 4 hours, sampling and filtering, acidifying to pH3-4 by using 10% hydrochloric acid, reaching the reaction end point if no oil layer exists, continuously stirring and refluxing for reaction to be complete if an oil layer exists, keeping the mild reflux state during the whole reaction period, introducing steam into the kettle after the reaction is finished, distilling the water steam to carry out o-aminoacetophenone and water, and separating the water after the water steam is distilled to be finished until no oil beads basically, wherein the oil layer is the o-aminoacetophenone, the oil layer is 82kg, the HPLC content is 99.5%, and the yield is 95.4%.
Example 2
Preparing o-nitroacetophenone: adding 210L of water into a 1000L enamel reaction kettle, starting stirring, introducing cooling water into a kettle jacket, slowly dropwise adding 94kg of concentrated sulfuric acid, adding 2.5kg of glacial acetic acid, controlling the temperature to be 30-40 ℃, then adding 100kg of o-nitroethylbenzene (662 mol), adding 138kg of potassium permanganate (873 mol) in small batches at 6 hours under rapid stirring, keeping the temperature in the kettle to be not more than 50 ℃, keeping the temperature of the potassium permanganate and stirring for 2 hours after the potassium permanganate is added, then adding 10kg of industrial salt, stirring and cooling to 30 ℃, standing for half an hour, and sucking out an oil layer under negative pressure after manganese dioxide sludge is obviously separated from the oil layer; adding 110kg of industrial benzene and 10kg of industrial salt into the oily manganese mud left in the kettle, stirring quickly for 20 minutes, then stirring slowly for 10 minutes, sucking out the oil layer under negative pressure after the manganese mud and the oil-containing layer are separated obviously, and discarding the manganese mud. The oil layers of the two times are combined, the mixture is washed twice by 5 percent sodium hydroxide solution 60L and twice by water 60L, the oil layer is dried by 4kg of anhydrous calcium chloride, the mixture is filtered, benzene is distilled out under normal pressure and used for next extraction, and the rest is o-nitroacetophenone, 82kg is obtained, and the yield is 75 percent.
Preparation of o-aminoacetophenone: adding 83.4kg (1489.5 mol) of reduced iron powder and half of solution of 570L and 12kg of ammonium chloride dissolved in 60L of water into a 1000L reaction kettle with a reflux condenser while stirring, heating a kettle jacket by steam until the solution flows back, stopping heating, keeping the temperature at 80-84 ℃, slowly adding 82kg of o-nitroacetophenone (496.5 mol) in the previous batch under rapid stirring, obtaining the feeding time for 3 hours, keeping the reflux in the feeding process, adding the rest half of ammonium chloride solution after the feeding is finished, continuously heating and refluxing for 4 hours, sampling and filtering, acidifying to pH3-4 by 10% hydrochloric acid, obtaining the reaction end point if no oil layer exists, continuing stirring and refluxing the reaction to be complete if an oil layer exists, keeping the mild reflux state during the whole reaction period, introducing steam into the kettle after the reaction is finished, distilling the water by steam to bring out the o-aminoacetophenone and the water by steam distillation until no oil exists basically, and separating the water, obtaining the o-aminoacetophenone oil layer, namely the o-aminoacetophenone content of 62.4kg, the HPLC yield of 99.3%, 93%, and the HPLC yield of 93.3%.
Example 3
Preparing o-nitroacetophenone: adding 210L of water into a 1000L enamel reaction kettle, starting stirring, introducing cooling water into a kettle jacket, slowly dropwise adding 94kg of concentrated sulfuric acid, adding 4kg of glacial acetic acid, controlling the temperature to be 30-40 ℃, then adding 100kg of o-nitroethylbenzene (662 mol), adding 180kg of potassium permanganate (1139 mol) in small batches at 6 hours under rapid stirring, keeping the temperature in the kettle not to exceed 50 ℃, keeping the temperature and stirring for 2 hours after the potassium permanganate is added, then adding 10kg of industrial salt, stirring and cooling to 30 ℃, standing for half an hour, and sucking out an oil layer under negative pressure after manganese dioxide mud is obviously separated from the oil layer; adding 110kg of industrial benzene and 10kg of industrial salt into the oil-containing manganese mud left in the kettle, quickly stirring for 20 minutes, then slowly stirring for 10 minutes, after the manganese mud is obviously separated from the oil-containing layer, sucking out the oil layer under negative pressure, and discarding the manganese mud. The oil layers of the above two times are combined, washed twice by 5 percent sodium hydroxide solution 60L and twice by water 60L, the oil layer is dried by 4kg of anhydrous calcium chloride, filtered, benzene is distilled out under normal pressure for the next extraction, and the rest is o-nitroacetophenone, 98.3kg is obtained, and the yield is 90 percent.
Preparation of o-aminoacetophenone: 200kg (3570 mol) of reduced iron powder, 570L of water and 12kg of ammonium chloride are added into a 1000L reaction kettle with a reflux condenser while stirring, the kettle jacket is heated to reflux by steam, heating is stopped, the temperature is kept at 80-84 ℃, the previous batch of 98.3kg of o-nitroacetophenone (595 mol) is slowly added under rapid stirring, the feeding time is 3 hours, reflux is kept in the feeding process, 20 minutes are carried out after the feeding is finished, the rest half of the ammonium chloride solution is added, heating reflux reaction is continuously carried out for 4 hours, then sampling and filtering are carried out, 10% hydrochloric acid is used for acidification to PH3-4, if no oil layer exists, the reaction end point is reached, if an oil layer needs to be continuously stirred and refluxed and reacted completely, the whole reaction period is kept in a mild reflux state, after the reaction is completed, steam is introduced into the kettle, the water vapor distillation is carried out to carry out o-aminoacetophenone and the water out, until no oil beads exist basically, the water is separated, namely the o-aminoacetophenone is obtained, the oil layer is 72.4% HPLC, the yield is 99.4%, the 90% yield of the HPLC method.
Example 4
Preparing o-nitroacetophenone: adding 210L of water into a 1000L enamel reaction kettle, starting stirring, introducing cooling water into a kettle jacket, slowly dropwise adding 94kg of concentrated sulfuric acid, adding 3kg of hydrochloric acid, controlling the temperature to be 30-40 ℃, then adding 100kg of o-nitroethylbenzene (662 mol), adding 162kg of potassium permanganate (1025 mol) in small batches within 6 hours under rapid stirring, keeping the temperature in the kettle not more than 50 ℃, keeping the temperature and stirring for 2 hours after the potassium permanganate is added, then adding 10kg of industrial salt, stirring and cooling to 30 ℃, standing, and sucking out an oil layer under negative pressure after manganese dioxide mud is obviously separated from the oil layer for half an hour; adding 110kg of industrial benzene and 10kg of industrial salt into the oily manganese mud left in the kettle, stirring quickly for 20 minutes, then stirring slowly for 10 minutes, sucking out the oil layer under negative pressure after the manganese mud and the oil-containing layer are separated obviously, and discarding the manganese mud. The oil layers of the above two times are combined, washed twice by 5 percent sodium hydroxide solution 60L and twice by water 60L, the oil layer is dried by 4kg of anhydrous calcium chloride, filtered, benzene is distilled out under normal pressure for the next extraction, and the rest is o-nitroacetophenone, 98.3kg is obtained, and the yield is 90 percent.
Preparation of o-aminoacetophenone: in a 1000L reaction kettle with a reflux condenser, 133.3kg (2380 mol) of reduced iron powder, 570L of water and half of a solution formed by dissolving 10 g of ammonium chloride in 60L of water are added while stirring, the kettle jacket is heated by steam to reflux, the heating is stopped, the temperature is kept between 80 and 84 ℃, the previous batch of 98.3kg of o-nitroacetophenone (595 mol) is slowly added under rapid stirring, the feeding time is 3 hours, the reflux is kept in the feeding process, after 20 minutes after the feeding is finished, the rest half of ammonium chloride solution is added, the heating reflux reaction is continuously carried out for 4 hours, then a sample is sampled and filtered, the mixture is acidified to PH3-4 by 10 percent hydrochloric acid, if an oil-free layer reaches the reaction end point, if an oil layer needs to be continuously stirred and refluxed to be completely reacted, the whole reaction period is kept in a reflux state, after the reaction is completely finished, the steam is fed into the kettle, the water steam distillation is carried out to remove the o-aminoacetophenone and the water until no oil is basically, the oil layer is separated, namely the o-aminoacetophenone, the oil layer is 72.5 kg, the HPLC content is 99.5 percent, and the yield is 90 percent yield.
Example 5
Preparing o-nitroacetophenone: adding 210L of water into a 1000L enamel reaction kettle, starting stirring, introducing cooling water into a kettle jacket, slowly dropwise adding 94kg of concentrated sulfuric acid, adding 3kg of glacial acetic acid, controlling the temperature to be 55-65 ℃, then adding 100kg of o-nitroethylbenzene (662 mol), adding 162kg of potassium permanganate (1025 mol) in small batches within 6 hours under rapid stirring, keeping the temperature in the kettle to be not lower than 55 ℃, keeping the temperature and stirring for 2 hours after the potassium permanganate is added, then adding 10kg of industrial salt, stirring and cooling to 30 ℃, standing for half an hour, and sucking out an oil layer under negative pressure after manganese dioxide mud is obviously separated from the oil layer; adding 110kg of industrial benzene and 10kg of industrial salt into the oil-containing manganese mud left in the kettle, quickly stirring for 20 minutes, then slowly stirring for 10 minutes, after the manganese mud is obviously separated from the oil-containing layer, sucking out the oil layer under negative pressure, and discarding the manganese mud. The oil layers from the two times were combined, washed twice with 60L of 5% sodium hydroxide solution, twice with 60L of water, dried with 4kg of anhydrous calcium chloride, filtered, and the benzene was distilled off at normal pressure for the next extraction, leaving the o-nitroacetophenone to give 87.4kg with a yield of 80%.
Preparation of o-aminoacetophenone: the method of example 1 is adopted to operate according to the proportion, and the yield and the quality are stable.
Comparative example 1
Preparing o-nitroacetophenone: adding 210L of water into a 1000L enamel reaction kettle, starting stirring, introducing cooling water into a kettle jacket, slowly dropwise adding 210kg of 30% sodium hydroxide alkali liquor, controlling the temperature to be 30-40 ℃, then adding 100kg of o-nitroethylbenzene (662 mol), adding 162kg of potassium permanganate (1025 mol) in small batches in 6 hours under rapid stirring, keeping the temperature in the kettle not more than 50 ℃, keeping the temperature and stirring for 2 hours after the potassium permanganate is added, then adding 10kg of industrial salt, stirring and cooling to 30 ℃, standing for half an hour, and sucking out an oil layer under negative pressure after manganese dioxide mud is obviously separated from the oil layer; adding 110kg of industrial benzene and 10kg of industrial salt into the oily manganese mud left in the kettle, stirring quickly for 20 minutes, then stirring slowly for 10 minutes, sucking out the oil layer under negative pressure after the manganese mud and the oil-containing layer are separated obviously, and discarding the manganese mud. The oil layers from the two previous steps were combined, washed twice with 60L of 5% sodium hydroxide solution, twice with 60L of water, dried with 4kg of anhydrous calcium chloride, filtered, and the benzene was distilled off at atmospheric pressure for the next extraction. The obtained product is detected, and the result is o-nitrobenzoic acid.
Comparative example 2
Preparing o-nitroacetophenone: adding 210L of water into a 1000L enamel reaction kettle, starting stirring, introducing cooling water into a kettle jacket, slowly dropwise adding 94kg of concentrated sulfuric acid, adding 3kg of boric acid, controlling the temperature to be 30-40 ℃, then adding 100kg of o-nitroethylbenzene (662 mol), adding 162kg of potassium permanganate (1025 mol) in small batches at 6 hours under rapid stirring, keeping the temperature in the kettle not more than 50 ℃, keeping the temperature and stirring for 2 hours after the potassium permanganate is added, then adding 10kg of industrial salt, stirring and cooling to 30 ℃, standing, and sucking out an oil layer under negative pressure after manganese dioxide mud is obviously separated from the oil layer for half an hour; adding 110kg of industrial benzene and 10kg of industrial salt into the oily manganese mud left in the kettle, stirring quickly for 20 minutes, then stirring slowly for 10 minutes, sucking out the oil layer under negative pressure after the manganese mud and the oil-containing layer are separated obviously, and discarding the manganese mud. The oil layers from the two times were combined, washed twice with 60L of 5% sodium hydroxide solution, twice with 60L of water, dried with 4kg of anhydrous calcium chloride, filtered, and the benzene was distilled off at normal pressure for the next extraction, leaving the o-nitroacetophenone to obtain 43.7kg with a yield of 40%.
Preparation of o-aminoacetophenone: the method of example 1 is adopted to operate according to the proportion, and the yield and the quality are stable.
Comparative example 3
Preparing o-nitroacetophenone: adding 210L of water into a 1000L enamel reaction kettle, starting stirring, introducing cooling water into a kettle jacket, slowly dropwise adding 94kg of concentrated sulfuric acid, adding 3kg of glacial acetic acid, controlling the temperature to be 30-40 ℃, then adding 100kg of o-nitroethylbenzene (662 mol), adding 305.5kg of sodium dichromate (1025 mol) in small batches at 6 hours under rapid stirring, keeping the temperature in the kettle not more than 50 ℃, keeping the temperature and stirring for 2 hours after the sodium dichromate is added, then adding 10kg of industrial salt, stirring and cooling to 30 ℃, standing for half an hour, and sucking out an oil layer under negative pressure after chromium mud is obviously separated from the oil layer; adding 110kg of industrial benzene and 10kg of industrial salt into the oily chromium mud left in the kettle, quickly stirring for 20 minutes, slowly stirring for 10 minutes, after the chromium mud is obviously separated from an oil layer containing benzene, sucking out an oil layer under negative pressure, discarding the chromium mud, combining the oil layers of the two times, washing the oil layers twice with 5% sodium hydroxide solution 60L, washing the oil layers twice with water 60L, drying the oil layers with 4kg of anhydrous calcium chloride, filtering, evaporating benzene at normal pressure for next extraction, and obtaining 57.9kg of o-nitroacetophenone with the rest, wherein the yield is 53%.
Preparation of o-aminoacetophenone: the method of example 1 is adopted to operate according to the proportion, and the yield and the quality are stable.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (6)
1. The preparation method of o-aminoacetophenone is characterized by comprising the following steps:
(1) Reacting an oxidant potassium permanganate, an acid catalyst glacial acetic acid and o-nitroethylbenzene at 30 to 40 ℃ in a dilute sulfuric acid environment, and after the reaction is finished, extracting, washing and drying to obtain o-nitroacetophenone;
(2) Adding the o-nitroacetophenone obtained in the step (1) and a reducing metal into an ammonium chloride aqueous solution for continuous reflux reaction, introducing steam into a reaction kettle for distillation after the reaction is finished, and separating the distilled solution to obtain o-aminoacetophenone;
wherein the molar ratio of o-nitroethylbenzene to potassium permanganate in the step (1) is 1 (1.3-1.8);
in the step (1), the dosage of the weak acid catalyst glacial acetic acid is 2-4% of the weight of the o-nitroethylbenzene.
2. The process for producing o-aminoacetophenone according to claim 1, characterized in that the extraction in step (1) comprises two steps: the first step is industrial salt extraction; the second step is the co-extraction of industrial salt and benzene.
3. The process for producing o-aminoacetophenone according to claim 1, characterized in that the washing in the step (1) comprises two steps: the first step is washing with alkali liquor and the second step is washing with water.
4. The method for preparing o-aminoacetophenone according to claim 1, characterized in that the molar ratio of o-nitroacetophenone to the reducing metal in step (2) is 1: (2-6).
5. The method for preparing o-aminoacetophenone according to claim 1, characterized in that the reducing metal is iron powder, the ammonium chloride solution in step (2) is added in portions according to the reaction progress, the molar ratio of ammonium chloride to iron powder is 1: (10-12).
6. The process for producing o-aminoacetophenone according to claim 1, characterized in that the temperature of the reflux reaction in the step (2) is 75 to 90 ℃.
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| CN110938008A (en) * | 2019-12-09 | 2020-03-31 | 南京杰运医药科技有限公司 | Preparation method of o-aminoacetophenone |
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