CN117510360B - Continuous preparation method, device and product of 2-amino-5-chloro- (N, 3) -dimethylbenzamide - Google Patents
Continuous preparation method, device and product of 2-amino-5-chloro- (N, 3) -dimethylbenzamide Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 82
- 239000002994 raw material Substances 0.000 claims abstract description 62
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 53
- DGDAVTPQCQXLGU-UHFFFAOYSA-N 5437-38-7 Chemical compound CC1=CC=CC(C(O)=O)=C1[N+]([O-])=O DGDAVTPQCQXLGU-UHFFFAOYSA-N 0.000 claims abstract description 52
- 239000012320 chlorinating reagent Substances 0.000 claims abstract description 33
- 238000005576 amination reaction Methods 0.000 claims abstract description 29
- 238000006722 reduction reaction Methods 0.000 claims abstract description 28
- 125000002252 acyl group Chemical group 0.000 claims abstract description 27
- 238000007112 amidation reaction Methods 0.000 claims abstract description 25
- 239000002904 solvent Substances 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 22
- 239000003054 catalyst Substances 0.000 claims abstract description 19
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 16
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims description 86
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 56
- 239000000243 solution Substances 0.000 claims description 42
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 238000000746 purification Methods 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 239000007789 gas Substances 0.000 claims description 19
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 16
- 239000000460 chlorine Substances 0.000 claims description 15
- 229910052801 chlorine Inorganic materials 0.000 claims description 15
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 14
- 230000014759 maintenance of location Effects 0.000 claims description 14
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 12
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 12
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 238000010924 continuous production Methods 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 7
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- JHHMSRLTZAUMOJ-UHFFFAOYSA-N methanamine;oxolane Chemical compound NC.C1CCOC1 JHHMSRLTZAUMOJ-UHFFFAOYSA-N 0.000 claims description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 239000007868 Raney catalyst Substances 0.000 claims description 3
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- 229910052742 iron Inorganic materials 0.000 claims description 3
- CEAJFNBWKBTRQE-UHFFFAOYSA-N methanamine;methanol Chemical compound NC.OC CEAJFNBWKBTRQE-UHFFFAOYSA-N 0.000 claims description 3
- 229910052759 nickel Inorganic materials 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000000047 product Substances 0.000 description 59
- 238000004519 manufacturing process Methods 0.000 description 12
- 238000000926 separation method Methods 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 230000008901 benefit Effects 0.000 description 9
- 230000008569 process Effects 0.000 description 8
- 238000005915 ammonolysis reaction Methods 0.000 description 6
- 238000004891 communication Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- WNAJXPYVTFYEST-UHFFFAOYSA-N 2-Amino-3-methylbenzoate Chemical compound CC1=CC=CC(C(O)=O)=C1N WNAJXPYVTFYEST-UHFFFAOYSA-N 0.000 description 4
- 230000003321 amplification Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 238000011031 large-scale manufacturing process Methods 0.000 description 4
- 238000003199 nucleic acid amplification method Methods 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 239000002699 waste material Substances 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- YVHZCFAUJFDIJY-UHFFFAOYSA-N 3-methyl-2-nitrobenzoyl chloride Chemical compound CC1=CC=CC(C(Cl)=O)=C1[N+]([O-])=O YVHZCFAUJFDIJY-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 150000001263 acyl chlorides Chemical class 0.000 description 3
- 238000010923 batch production Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000005587 bubbling Effects 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 230000009435 amidation Effects 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- NJHDBIXFFZVJGZ-UHFFFAOYSA-N methyl 3-methyl-2-nitrobenzoate Chemical compound COC(=O)C1=CC=CC(C)=C1[N+]([O-])=O NJHDBIXFFZVJGZ-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- PLGLAPAIOBPKMR-UHFFFAOYSA-N 2-bromo-4-chloro-6-methylaniline Chemical compound CC1=CC(Cl)=CC(Br)=C1N PLGLAPAIOBPKMR-UHFFFAOYSA-N 0.000 description 1
- LFXSHFHOJMKZDE-UHFFFAOYSA-N 2-formamidobenzamide Chemical compound NC(=O)C1=CC=CC=C1NC=O LFXSHFHOJMKZDE-UHFFFAOYSA-N 0.000 description 1
- 238000006220 Baeyer-Villiger oxidation reaction Methods 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- LFETXMWECUPHJA-UHFFFAOYSA-N methanamine;hydrate Chemical compound O.NC LFETXMWECUPHJA-UHFFFAOYSA-N 0.000 description 1
- VSFYTPXXMLJNAU-UHFFFAOYSA-N methyl 2-amino-3-methylbenzoate Chemical compound COC(=O)C1=CC=CC(C)=C1N VSFYTPXXMLJNAU-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 231100000989 no adverse effect Toxicity 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 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
- 238000011084 recovery Methods 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
-
- 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
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a continuous preparation method, a device and a product of 2-amino-5-chloro- (N, 3) -dimethylbenzamide. The continuous preparation method comprises the following steps: continuously introducing raw material 2-nitro-3-methylbenzoic acid, a first chlorinating agent and a solvent into a continuous acyl chlorination reactor for continuous acyl chlorination reaction to obtain a first intermediate solution system; continuously introducing the first intermediate solution system and an amination agent into a continuous amination reactor to perform continuous amidation reaction to obtain a second intermediate solution system; continuously introducing the second intermediate solution system, a reducing agent and a hydrogenation catalyst into a continuous hydrogenation reactor to carry out continuous hydrogenation reduction reaction to obtain a third intermediate solution system; and introducing the third intermediate solution system and the second chlorinating agent into a continuous chlorination reactor for continuous chlorination reaction, and purifying the obtained product system to obtain the 2-amino-5-chloro- (N, 3) -dimethylbenzamide product. The method has high yield.
Description
Technical Field
The invention relates to the technical field of organic intermediate synthesis, in particular to a continuous preparation method, a device and a product of 2-amino-5-chloro- (N, 3) -dimethylbenzamide.
Background
The 2-amino-5-chloro- (N, 3) -dimethylbenzamide has important application in the pesticide synthesis field and is an important intermediate for preparing o-formamidobenzamide pesticides.
At present, the synthesis of 2-amino-5-chloro- (N, 3) -dimethylbenzamide has the following processes:
according to the technical scheme I, palladium acetate is used as a catalyst, 2-bromo-4-chloro-6-methylaniline is used as a raw material, ethylene glycol is used as a raw material, and carbon monoxide and methylamine gas are also required to be introduced to prepare 2-amino-5-chloro- (N, 3) -dimethylbenzamide, wherein the yield is 70%;
according to the second technical scheme, o-toluidine is used as a raw material, and amidation reaction, dehydration cyclization reaction, baeyer-Villiger rearrangement reaction, ammonolysis reaction and chlorination reaction are respectively carried out, wherein the total reaction yield is 29.4%;
according to the technical scheme III, 2-nitro-3-methylbenzoic acid is used as a raw material, and 4 steps of reaction are carried out through methyl esterification, iron powder reduction, thionyl chloride chlorination and methylamine ammonolysis, wherein the total reaction yield is 59.0%;
according to the technical scheme IV, 2-nitro-3-methyl benzoate is used as a raw material, and the total reaction yield is 84.0% through methylamine ammonolysis, iron powder reduction and thionyl chloride chlorination reaction;
the fifth technical proposal is that 2-nitro-3-methyl benzoate is taken as raw material, and the total reaction yield is 93.1% through two steps of chlorination with sodium hypochlorite and ammonolysis with methylamine;
the method adopts the technical proposal six that 2-amino-3-methylbenzoic acid is used as a raw material, and the target product is prepared through three steps of chlorination, triphosgene cyclization and ammonolysis of a hydrochloric acid and hydrogen peroxide system, and the reaction yield is 55.1 percent;
according to the technical scheme seven, 2-amino-3-methylbenzoic acid is still used as a raw material, THF is used as a solvent, solid phosgene, methylamine water solution and NCS are used as reaction reagents, so that three reactions of cyclization, ammonolysis and halogenation are realized to prepare a target product by a one-pot reaction, and the reaction yield can reach 87% -90%.
In the process, the technical scheme has the defects of high raw material price, need of using a pressure kettle, involving toxic gas, high catalyst price, difficult catalyst recovery and the like, and has poor economic benefit; in the second technical scheme and the third technical scheme, the reaction route is long, the total yield is low, and the reaction is gradually eliminated; in the technical schemes IV, five, six and seven, the price of the initial raw materials is relatively high, and the yield of the scheme VI is low; in addition, the technical proposal seven has low overall economic benefit due to the high price of the chlorinating agent NCS.
Disclosure of Invention
The invention mainly aims to provide a continuous preparation method, device and product of 2-amino-5-chloro- (N, 3) -dimethylbenzamide, which solve the problems of high production difficulty and poor economic benefit of the 2-amino-5-chloro- (N, 3) -dimethylbenzamide in the prior art.
In order to achieve the above object, according to one aspect of the present invention, there is provided a continuous production method of 2-amino-5-chloro- (N, 3) -dimethylbenzamide, comprising: continuously introducing raw material 2-nitro-3-methylbenzoic acid, a first chlorinating agent and a solvent into a continuous acyl chlorination reactor for continuous acyl chlorination reaction to obtain a first intermediate solution system; continuously introducing the first intermediate solution system and an amination agent into a continuous amination reactor to perform continuous amidation reaction to obtain a second intermediate solution system; continuously introducing the second intermediate solution system, a reducing agent and a hydrogenation catalyst into a continuous hydrogenation reactor to carry out continuous hydrogenation reduction reaction to obtain a third intermediate solution system; and introducing the third intermediate solution system and the second chlorinating agent into a continuous chlorination reactor for continuous chlorination reaction, and purifying the obtained product system to obtain the 2-amino-5-chloro- (N, 3) -dimethylbenzamide product.
Further, the first chlorinating agent comprises any one or more of thionyl chloride, chlorine gas, N-chlorosuccinimide and sulfonyl chloride, and preferably, the first chlorinating agent is thionyl chloride;
and/or the solvent comprises any one or more of tetrahydrofuran, xylene, 2-methyltetrahydrofuran, ethylene glycol, toluene, methylene chloride, 1, 4-dioxane, chloroform and N, N-dimethylformamide;
and/or the amination agent comprises any one or more of monomethylamine aqueous solution, monomethylamine methanol solution, monomethylamine gas and monomethylamine tetrahydrofuran solution, and preferably, the amination agent is monomethylamine gas;
and/or the reducing agent comprises any one or more of a composition of iron powder and hydrochloric acid, hydrogen and hydrazine hydrate, and preferably, the reducing agent is hydrogen;
and/or the hydrogenation catalyst comprises any one or more of palladium carbon, raney nickel, nickel-based catalyst and iron-based catalyst;
and/or the second chlorinating agent comprises any one or more of hydrogen peroxide and hydrochloric acid, chlorine and sulfonyl chloride, and preferably, the second chlorinating agent is chlorine.
Further, the mole ratio of the first chlorinating agent to the raw material 2-nitro-3-methylbenzoic acid is 2.0-10.0:1;
and/or the mol ratio of the amination agent to the raw material 2-nitro-3-methylbenzoic acid is 1.0-5.0:1;
and/or the mol ratio of the second chlorinating agent to the raw material 2-nitro-3-methylbenzoic acid is 2-4:1;
further, the reaction temperature of the continuous acyl chlorination reaction is 40-90 ℃;
and/or, the reaction temperature of the continuous amidation reaction is 40-60 ℃;
and/or the reaction temperature of the continuous hydrogenation reduction reaction is 80-90 ℃;
and/or the reaction temperature of the continuous chlorination reaction is 40-70 ℃.
Further, the retention time of the continuous acyl chlorination reaction is 10-120 min;
and/or the retention time of the continuous amidation reaction is 30-60 min;
and/or the retention time of the continuous hydrogenation reduction reaction is 50-90 min;
and/or the retention time of the continuous chlorination reaction is 1.0 h-10.0 h.
Further, carrying out water removal treatment on the solution system obtained after the continuous hydrogenation reduction reaction to obtain a third intermediate solution system;
and/or purifying treatment comprises continuously separating solid and solvent in the product system, and drying to obtain 2-amino-5-chloro- (N, 3) -dimethylbenzamide product.
According to another aspect of the present application, there is provided a continuous production apparatus of 2-amino-5-chloro- (N, 3) -dimethylbenzamide, comprising: a continuous acid chlorination unit having a feedstock inlet, a continuous acid chlorination reactor, and a first intermediate outlet; a continuous amination unit having a first intermediate inlet, a continuous amination reactor and a second intermediate outlet, the first intermediate inlet being in communication with the first intermediate outlet; a continuous hydrogenation unit having a second intermediate inlet, a continuous hydrogenation reactor, and a third intermediate outlet, the second intermediate inlet being in communication with the second intermediate outlet; and the continuous chlorination unit is provided with a third intermediate inlet, a continuous chlorination reactor and a product outlet, and the third intermediate inlet is communicated with the third intermediate outlet.
Further, the continuous acyl chlorination reactor comprises any one of a continuous plug flow reactor, a continuous kettle reactor and a continuous column reactor;
and/or, the continuous amination reactor comprises any one of a continuous plug flow reactor, a continuous kettle reactor and a continuous column reactor;
and/or, the continuous hydrogenation reactor comprises a fixed bed reactor, a continuous fluidized bed reactor, a slurry bed reactor, a column reactor, a continuous overflow kettle reactor and a plug flow reactor;
and/or, the continuous chlorination reactor comprises a continuous bubble column reactor, a continuous overflow reactor, a continuous column reactor, a fixed bed reactor, a fluidized bed reactor, a slurry bed reactor and a continuous solid-liquid reactor.
Further, the continuous preparation device further comprises a raw material supply unit, wherein the continuous raw material supply unit is provided with a raw material outlet, and the raw material outlet is connected with the raw material inlet;
and/or the continuous preparation device further comprises a continuous water removal unit, wherein the continuous water removal unit is communicated with the continuous hydrogenation reactor;
and/or the continuous preparation device further comprises a continuous purification unit, wherein the continuous purification unit is provided with a product inlet, a purification device and a product outlet, and the product inlet is communicated with the product outlet.
According to still another aspect of the present application, there is provided a 2-amino-5-chloro- (N, 3) -dimethylbenzamide product prepared by the continuous preparation method of any one of the above or the continuous preparation apparatus of any one of the above.
By applying the technical scheme of the invention, in the continuous preparation method of the 2-amino-5-chloro- (N, 3) -dimethylbenzamide, the 2-nitro-3-methylbenzoic acid which is relatively cheap and easy to obtain is used as a starting material, and the 2-amino-5-chloro- (N, 3) -dimethylbenzamide is prepared by continuous acyl chlorination reaction, continuous amidation reaction, continuous hydrogenation reduction reaction and continuous chlorination reaction in sequence, so that the 2-amino-5-chloro- (N, 3) -dimethylbenzamide product system has fewer impurities, separation and purification are convenient, and the intermediate solution system obtained by each step of reaction can enter a reactor for the next reaction without separation and purification, so that the preparation process of the 2-amino-5-chloro- (N, 3) -dimethylbenzamide is greatly simplified, the three wastes generated in batch production are greatly reduced, and the conversion rate is relatively high, thereby greatly reducing the production cost of the 2-amino-5-chloro- (N, 3) -dimethylbenzamide; on the other hand, the continuous preparation method of the 2-amino-5-chloro- (N, 3) -dimethylbenzamide has the advantages that in process safety evaluation, the involved reaction risk level is less than or equal to 3 levels, the production process is environment-friendly, efficient and safe, the large-scale production is easy to realize, and the problems of difficult amplification of batch reaction and high risk coefficient are fundamentally solved.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention. In the drawings:
FIG. 1 is a schematic structural view showing a continuous production apparatus of 2-amino-5-chloro- (N, 3) -dimethylbenzamide according to an embodiment of the invention
Detailed Description
It should be noted that, in the case of no conflict, the embodiments and features in the embodiments may be combined with each other. The invention will be described in detail below with reference to the drawings in connection with embodiments.
As analyzed by the background technology of the application, the problems of high production difficulty and poor economic benefit of the 2-amino-5-chloro- (N, 3) -dimethylbenzamide exist in the prior art, and batch reaction is mostly adopted in the production of the 2-amino-5-chloro- (N, 3) -dimethylbenzamide in the prior art, so that the reaction pressure of partial working procedures is high, the hazard degree is high, and the implementation is difficult. In order to solve the problems, the application provides a continuous preparation method, a device and a product of 2-amino-5-chloro- (N, 3) -dimethylbenzamide.
According to an exemplary embodiment of the present application, there is provided a continuous production method of 2-amino-5-chloro- (N, 3) -dimethylbenzamide, comprising: continuously introducing raw material 2-nitro-3-methylbenzoic acid, a first chlorinating agent and a solvent into a continuous acyl chlorination reactor for continuous acyl chlorination reaction to obtain a first intermediate solution system; continuously introducing the first intermediate solution system and an amination agent into a continuous amination reactor to perform continuous amidation reaction to obtain a second intermediate solution system; continuously introducing the second intermediate solution system, a reducing agent and a hydrogenation catalyst into a continuous hydrogenation reactor to carry out continuous hydrogenation reduction reaction to obtain a third intermediate solution system; and introducing the third intermediate solution system and the second chlorinating agent into a continuous chlorination reactor for continuous chlorination reaction, and purifying the obtained product system to obtain the 2-amino-5-chloro- (N, 3) -dimethylbenzamide product.
In the continuous preparation method of the 2-amino-5-chloro- (N, 3) -dimethylbenzamide, the 2-nitro-3-methylbenzoic acid which is cheap and easy to obtain is used as a starting material, and the 2-amino-5-chloro- (N, 3) -dimethylbenzamide is prepared by continuous acyl chlorination reaction, continuous amidation reaction, continuous hydrogenation reduction reaction and continuous chlorination reaction in sequence, so that the 2-amino-5-chloro- (N, 3) -dimethylbenzamide product system has fewer impurities, is convenient for separation and purification, and the intermediate solution system obtained in each step of reaction can enter a reactor for the next step of reaction without separation and purification, thereby greatly simplifying the preparation process of the 2-amino-5-chloro- (N, 3) -dimethylbenzamide, greatly reducing the three wastes generated in the production batch, having higher conversion rate and greatly reducing the production cost of the 2-amino-5-chloro- (N, 3) -dimethylbenzamide; on the other hand, the continuous preparation method of the 2-amino-5-chloro- (N, 3) -dimethylbenzamide has the advantages that in process safety evaluation, the involved reaction risk level is less than or equal to 3 levels, the production process is environment-friendly, efficient and safe, the large-scale production is easy to realize, and the problems of difficult amplification of batch reaction and high risk coefficient are fundamentally solved.
The reaction equation of the continuous preparation method of the 2-amino-5-chloro- (N, 3) -dimethylbenzamide is as follows:
in the continuous chlorination reaction, the raw material 2-nitro-3-methylbenzoic acid and a first chlorinating agent are subjected to continuous acyl chlorination reaction in the presence of a solvent, so that the 2-nitro-3-methylbenzoic acid is converted into a first intermediate 2-nitro-3-methylbenzoyl chloride.
The first chlorinating agent may be selected in the prior art, and in some embodiments of the present application, the first chlorinating agent includes any one or more of thionyl chloride, chlorine, N-chlorosuccinimide (NCS) and sulfonyl chloride, which is beneficial to further increase the yield of the first intermediate, preferably thionyl chloride, and the yield increase of the first intermediate is more significant. In order to further improve the yield and economy of the acid chlorination reaction, the molar ratio of the first chlorinating agent to the raw material 2-nitro-3-methylbenzoic acid is preferably 2.0 to 10.0:1, more preferably 2.5 to 6.5:1.
In some embodiments of the present application, the reaction temperature of the continuous acyl chlorination reaction is 40-90 ℃, preferably 55-65 ℃, and the conditions are mild, and the method is easy to implement in the continuous acyl chlorination reactor. Preferably, the retention time of the continuous acyl chlorination reaction is 10 min-120 min, preferably 10 min-40 min.
The solvent may also be selected in the prior art, in some embodiments of the present application, in order to avoid a decrease or a slow down of the reaction yield caused by the solvent in the subsequent step, or poor solubility of the product generated in the subsequent step, the solvent includes any one or more of tetrahydrofuran, xylene, 2-methyltetrahydrofuran, ethylene glycol, toluene, methylene dichloride, 1, 4-dioxane, chloroform and N, N-dimethylformamide, which has no adverse effect on the reactions in each step in the continuous preparation method of the present application, has better solubility on the raw materials and products of each reaction, and is convenient for separation and purification of the final product. Preferably, the solvent is tetrahydrofuran, and when the tetrahydrofuran is used as the solvent, the fluidity of the system is improved, and the yield of the 2-amino-5-chloro- (N, 3) -dimethylbenzamide is further improved.
In some embodiments of the present application, the mass ratio of solvent to starting 2-nitro-3-methylbenzoic acid is 12: 1-25: 1, the fluidity and the economy of the system can be better considered. The solvent can be independently introduced into the continuous acyl chloride reactor, or can be mixed with one or more of the raw materials of 2-nitro-3-methylbenzoic acid and the amination agent and then introduced into the continuous acyl chloride reactor, and the solvent can be continuously added into the reaction vessel in the subsequent reaction process.
In a continuous amidation reaction, the first intermediate 2-nitro-3-methylbenzoyl chloride is converted to the second intermediate 2-nitro- (N, 3) -dimethylbenzamide.
In some embodiments of the present application, the amination agent comprises any one or more of an aqueous monomethylamine solution, an aqueous monomethylamine methanol solution, monomethylamine gas, and an aqueous monomethylamine tetrahydrofuran solution. Preferably, the amination agent is monomethylamine gas, the mass transfer effect in the reaction process is good, and the conversion rate of the product is improved.
In some embodiments of the present application, in order to further improve the conversion efficiency of the first intermediate 2-nitro-3-methylbenzoyl chloride into the second intermediate 2-nitro- (N, 3) -dimethylbenzamide, under the premise of fully considering the saving of raw materials, the molar ratio of the amination agent to the raw material 2-nitro-3-methylbenzoic acid is 1.0-5.0:1, and the preferable ratio is 2.5-5:1.
In some embodiments of the present application, the reaction temperature of the continuous amidation reaction is 40-60 ℃. Preferably, the retention time of the continuous amidation reaction is 30-60 min.
The second intermediate 2-nitro- (N, 3) -dimethylbenzamide prepared by the continuous amidation reaction converts the nitro group into amino group by hydrogenation reduction in the continuous hydrogenation reduction reaction to generate a third intermediate 2-amino- (N, 3) -dimethylbenzamide.
In this reaction, a reducing agent and a hydrogenation catalyst are required to be added, and specific types of the reducing agent and the hydrogenation catalyst can refer to the prior art, and in some embodiments of the present application, the reducing agent comprises any one or more of a composition of iron powder and hydrochloric acid, hydrogen and hydrazine hydrate, preferably hydrogen, so as to facilitate separation and purification. In some embodiments of the present application, the hydrogenation catalyst includes any one or more of palladium carbon, raney nickel, nickel-based catalyst and iron-based catalyst, preferably palladium carbon, and has good catalytic effect, low cost and easy availability. In some preferred embodiments of the present application, in the continuous hydrogenation reduction reaction, the reducing agent is hydrogen, and in order to further increase the reaction rate and the yield of the third intermediate, the pressure of the hydrogen is controlled to be 1-2 mpa during the reaction.
Since water is generated in the continuous hydrogenation reduction reaction, water in the system can have adverse effect on the subsequent continuous chlorination reaction, and the selectivity of the chlorination reaction is reduced, in some preferred embodiments of the present application, the reaction solution of the continuous hydrogenation reduction reaction system is subjected to water removal treatment to obtain a third intermediate solution system without water, and a specific method of water removal treatment can be selected from the prior art, for example, distillation water removal, rectification water removal, extraction water removal or drying agent water removal.
In some embodiments of the present application, the reaction temperature of the continuous hydrogenation reduction reaction is 80-90 ℃, and the reaction rate and the conversion rate are relatively high; preferably, the retention time of the continuous hydrogenation reduction reaction is 50 to 90min, more preferably 60 to 70min.
And the third intermediate obtained through the continuous hydrogenation reduction reaction is subjected to substitution of hydrogen on a benzene ring in the continuous chlorination reaction process to obtain the final product 2-amino-5-chloro- (N, 3) -dimethylbenzamide.
In some embodiments of the present application, the second chlorinating agent used in the continuous chlorination reaction includes any one or more of a combination of hydrogen peroxide and hydrochloric acid, chlorine and sulfonyl chloride, and the chlorinating agent has better selectivity, high conversion rate of the target product, and fewer byproducts. Preferably, the second chlorinating agent is chlorine, so that the conversion rate of the target product is high, and the subsequent product separation is facilitated.
Further, in order to better consider the yield of the target product, the reaction rate and the consumption of the chlorinating agent, the molar ratio of the second chlorinating agent to the raw material 2-nitro-3-methylbenzoic acid is 2-4:1.
Further, the reaction temperature of the continuous chlorination reaction is 40-70 ℃, preferably 55-60 ℃, which is favorable for further improving the yield of target products and reducing the reaction time. Preferably, and/or, the retention time of the continuous chlorination reaction is 1.0h to 10.0h, more preferably 3.0 to 5.0h.
The product system obtained by the method can be subjected to simple purification treatment to obtain a high-purity 2-amino-5-chloro- (N, 3) -dimethylbenzamide product, and the specific purification treatment method can refer to the prior art. In addition, as will be appreciated by those skilled in the art, since hydrogen chloride is formed in the system in the continuous chlorination reaction, the hydrogen chloride forms a salt with an amino group on a benzene ring, and thus the resulting product is a salt of 2-amino-5-chloro- (N, 3) -dimethylbenzamide, which can be converted into 2-amino-5-chloro- (N, 3) -dimethylbenzamide by a simple process, as will be appreciated by those skilled in the art.
In some embodiments of the present application, the purification treatment comprises continuously separating the solids and solvent in the product system, and oven drying to provide a 2-amino-5-chloro- (N, 3) -dimethylbenzamide product; preferably, the purification treatment comprises the steps of filtering and drying the product system to obtain the 2-amino-5-chloro- (N, 3) -dimethylbenzamide product.
According to another exemplary embodiment of the present application, there is provided a continuous production apparatus of 2-amino-5-chloro- (N, 3) -dimethylbenzamide, including: a continuous acid chlorination unit having a feedstock inlet, a continuous acid chlorination reactor, and a first intermediate outlet; a continuous amination unit having a first intermediate inlet, a continuous amination reactor and a second intermediate outlet, the first intermediate inlet being in communication with the first intermediate outlet; a continuous hydrogenation unit having a second intermediate inlet, a continuous hydrogenation reactor, and a third intermediate outlet, the second intermediate inlet being in communication with the second intermediate outlet; and the continuous chlorination unit is provided with a third intermediate inlet, a continuous chlorination reactor and a product outlet, and the third intermediate inlet is communicated with the third intermediate outlet.
The continuous preparation device of 2-amino-5-chloro- (N, 3) -dimethylbenzamide can take cheap and easily obtained 2-nitro-3-methylbenzoic acid as a starting material, and sequentially carries out continuous acyl chlorination reaction, continuous amidation reaction, continuous hydrogenation reduction reaction and continuous chlorination reaction to prepare the 2-amino-5-chloro- (N, 3) -dimethylbenzamide, the obtained 2-amino-5-chloro- (N, 3) -dimethylbenzamide has fewer impurities in a product system, separation and purification are convenient, and an intermediate solution system obtained in each step of reaction can enter a reactor for the next step of reaction without separation and purification, so that the preparation process of 2-amino-5-chloro- (N, 3) -dimethylbenzamide is greatly simplified, the three wastes generated in batch production are greatly reduced, the conversion rate is higher, and the production cost of 2-amino-5-chloro- (N, 3) -dimethylbenzamide is greatly reduced; on the other hand, the continuous preparation method of the 2-amino-5-chloro- (N, 3) -dimethylbenzamide has the advantages that the related reaction risk level is less than or equal to 3 levels, the production process is environment-friendly, efficient and safe, the large-scale production is easy to realize, and the problems of difficult amplification of batch reaction and high risk coefficient are fundamentally solved.
The specific types of the continuous acyl chloride reactor, continuous amination reactor, continuous hydrogenation reactor and continuous chlorination reactor described above may be selected in the prior art.
Illustratively, the continuous acyl chlorination reactor comprises any one of a continuous plug flow reactor, a continuous kettle reactor and a continuous column reactor, preferably a continuous plug flow reactor, and the continuous acyl chlorination reactor has good heat transfer performance, strong flow stability, relatively good equipment economy and low failure rate.
Illustratively, the continuous amination reactor described above includes, but is not limited to, any one of a continuous plug flow reactor, a continuous tank reactor, and a continuous column reactor, with a continuous plug flow reactor being preferred.
Illustratively, the above-described continuous hydrogenation reactor includes, but is not limited to, a fixed bed reactor, a continuous fluidized bed reactor, a slurry bed reactor, a column reactor, a continuous overflow tank reactor, and a plug flow reactor, and is preferably a fixed bed reactor.
Illustratively, continuous chlorination reactors include, but are not limited to, continuous bubble column reactors, continuous overflow reactors, continuous column reactors, fixed bed reactors, fluidized bed reactors, slurry bed reactors, and continuous solid-liquid reactors, with continuous bubble column reactors being preferred.
In some embodiments of the present application, the continuous production apparatus further includes a feedstock supply unit having a feedstock outlet connected to the feedstock inlet. In some exemplary embodiments of the present application, the continuous raw material supply unit further includes a continuous feed pump and a continuous metering device, wherein the continuous feed pump includes any one or more of, preferably, a hydraulic diaphragm pump, a pneumatic diaphragm pump, a hydraulic diaphragm pump, a syringe pump, a magnetically driven pump, and a mechanical diaphragm pump; the continuous metering device includes, but is not limited to, any one or more of an electromagnetic flowmeter, a coriolis flowmeter, an electronic scale, and a rotameter, preferably a coriolis flowmeter.
Since reagents are also required to be fed into the reactor in the continuous amination unit, the continuous hydrogenation unit and the continuous chlorination unit, a continuous feed pump and a continuous metering device can be adopted correspondingly.
In some embodiments of the present application, the continuous preparation apparatus further comprises a continuous water removal unit in communication with the continuous hydrogenation reactor, capable of effectively removing water generated in the continuous hydrogenation reactor, and in some embodiments of the present application, the continuous water removal unit comprises a rectifying column, a reflux drum, an overhead condenser, a reboiler, a bottom discharge pump, a reflux pump, and an overhead discharge pump.
In some embodiments of the present application, the continuous production apparatus further comprises a continuous purification unit having a product inlet, a purification apparatus, and a product outlet, the product inlet in communication with the product outlet, wherein the purification apparatus comprises a continuous filtration apparatus.
In some exemplary embodiments of the present application, the continuous preparation apparatus for 2-amino-5-chloro- (N, 3) -dimethylbenzamide, as shown in fig. 1, comprises a raw material supply unit, a continuous acyl chlorination unit, a continuous amination unit, a continuous hydrogenation unit, a continuous chlorination unit and a continuous purification unit, which are sequentially communicated, and a continuous water removal unit communicated with the continuous hydrogenation unit, and a continuous batching unit communicated with the continuous chlorination unit.
According to still another exemplary embodiment of the present application, there is provided a 2-amino-5-chloro- (N, 3) -dimethylbenzamide product prepared by any one of the continuous preparation methods or continuous preparation apparatuses described above.
The 2-amino-5-chloro- (N, 3) -dimethylbenzamide product obtained by the continuous preparation method or the preparation device has high purity, obviously reduced preparation cost and good market prospect.
The advantages that can be achieved by the present application will be further described below with reference to examples and comparative examples.
Example 1
Adopting a continuous device shown in figure 1, conveying raw materials into continuous equipment through a raw material conveying pump, mixing a solvent and raw material 2-nitro-3-methylbenzoic acid, and then pumping into a continuous plug flow reactor, wherein the solvent is tetrahydrofuran, and the weight ratio of the solvent to the raw material 2-nitro-3-methylbenzoic acid is 14:1, feeding speed is 500g/h, a chlorinating agent and the raw material system are pumped into a reactor at the same time, the chlorinating agent is thionyl chloride, and the molar ratio of the thionyl chloride to the raw material 2-nitro-3-methylbenzoic acid is 2.5:1, feed rate 54.7g/h. The reaction temperature was 60℃and the retention time 40min.
The first intermediate system is conveyed into a continuous plug flow reactor to carry out amidation reaction through a conveying pump together with monomethylamine gas, wherein the molar ratio of the monomethylamine gas to the raw material 3-methyl-2-nitrobenzoic acid is 4:1, the temperature of the reaction system is 55 ℃, and a second intermediate system is generated.
And (3) introducing the second intermediate system and hydrogen into a continuous fixed bed reactor filled with palladium-carbon to carry out hydrogenation reaction, wherein the temperature of the reaction system is 85 ℃, the pressure is 1.5MPa, and after the reaction is finished, removing water from the reaction solution through a water removal unit to obtain a third intermediate system.
Pumping the third intermediate into a bubbling tower to carry out chlorination reaction with chlorine, wherein the mol ratio of the chlorine to the raw material 2-nitro-3-methylbenzoic acid is 2.5:1, preserving heat at 60 ℃ to generate a product system, feeding the product system into a continuous purification unit, continuously filtering, and drying a filter cake to obtain a product solid, wherein the purity of the product is 99.3%. The continuous stable operation time of the equipment exceeds 500 hours.
Wherein the incubation times for the acid chlorination reaction, the amidation reaction, the hydrogenation reaction and the chlorination reaction and the yields of the products of each step are shown in Table 1, and the yields are molar yields.
Example 2
The difference from example 1 is that the temperature of the acid chlorination reaction is 40 ℃.
Example 3
The difference from example 1 is that the temperature of the acid chlorination reaction is 75 ℃.
Example 4
The difference from example 1 is that the temperature of the acid chlorination reaction is 90 ℃.
Example 5
The difference from example 1 is that the chlorinating agent in the acyl chlorination reaction is chlorine.
Example 6
The difference from example 1 is that in the amidation reaction, monomethylamine tetrahydrofuran solution having a concentration of 20% by weight was used as an amination agent instead of monomethylamine gas, the molar ratio of monomethylamine to starting material 2-nitro-3-methylbenzoic acid being 4:1.
example 7
The difference from example 1 is that in the amidation reaction, a monomethylamine aqueous solution having a concentration of 40% by weight was used as an amination agent instead of monomethylamine gas, the molar ratio of monomethylamine to starting material 2-nitro-3-methylbenzoic acid being 4:1.
example 8
The difference from example 1 is that in the amidation reaction, the molar ratio of monomethylamine gas to the starting 3-methyl-2-nitrobenzoic acid is 2.5:1.
example 9
The difference from example 1 is that in the amidation reaction, the molar ratio of monomethylamine gas to the starting 3-methyl-2-nitrobenzoic acid is 1.5:1.
example 10
The difference from example 1 is that the solvent added in the first step of the acid chloride reaction is toluene.
Example 11
The difference from example 1 is that the solvent added in the first step of the acid chloride reaction is chloroform.
Example 12
The difference from example 1 is that the solvent added in the first step of the acid chloride reaction is acetonitrile.
Example 13
The difference from example 1 is that in the hydrogenation reaction, the reducing agent is a composition of iron powder and hydrochloric acid, wherein the molar ratio of iron powder to hydrochloric acid is 1.5:1, the mol ratio of hydrochloric acid to raw material 2-nitro-3-methylbenzoic acid is 4:1.
example 14
The difference from example 1 is that hydrogen peroxide and hydrogen chloride are used instead of chlorine in the chlorination reaction, wherein the molar ratio of hydrogen peroxide to hydrogen chloride is 1: the mole ratio of the hydrogen peroxide to the raw material 2-nitro-3-methylbenzoic acid is 2.5:1.
example 15
The difference from example 1 is that in the chlorination reaction, the bubble column soak temperature is 40 ℃.
Example 16
The difference from example 1 is that in the chlorination reaction, the bubble column soak temperature is 70 ℃.
Example 17
The difference from example 1 is that the same molar amount of sulfonyl chloride is used instead of chlorine in the chlorination reaction.
Comparative example 1
Accurately weighing 500g of 3-methyl-2-nitrobenzoic acid, adding into a batch reactor, adding tetrahydrofuran, stirring for dissolution, and heating to 60 ℃.
The temperature was controlled at 60℃and 1950g of thionyl chloride was initially added. The reaction is kept for 40min, sampling and tracking are carried out, and the content of 3-methyl-2-nitrobenzoic acid is less than or equal to 0.5 percent.
Introducing monomethylamine gas into the reaction system, wherein the molar ratio of the monomethylamine gas to the raw material 3-methyl-2-nitrobenzoic acid is 4:1, at 55 ℃ to produce an intermediate B system.
Transferring the intermediate B system into a batch hydrogenation reaction kettle filled with palladium-carbon catalyst, introducing hydrogen, preparing a hydrogenation reaction raw material system, producing an intermediate C at the temperature of 90 ℃ and the pressure of 2.0MPa, and transferring the intermediate C into a chlorination batch reaction kettle after water removal.
Gradually heating the system to 60 ℃, controlling the temperature to 60 ℃, and introducing chlorine into the batch reaction kettle, wherein the molar ratio of the chlorine to the raw material 2-nitro-3-methylbenzoic acid is 2.5:1, reacting for 5.0h, and finishing the reaction to obtain the product.
And filtering and drying to obtain a solid product, wherein the sample-feeding detection purity of the product is 93%, and the total yield of the product is 60.6% based on the raw material 3-methyl-2-nitrobenzoic acid.
Comparative example 2
50g of 3-methyl-2-nitrobenzoic acid is accurately weighed and added into a reaction bottle, 500g of methanol is added, stirring and dissolution are started, and the temperature is raised to 50 ℃.
And (3) controlling the temperature to be 50 ℃, beginning to dropwise add concentrated sulfuric acid, and after dropwise adding 150g of concentrated sulfuric acid, carrying out heat preservation reaction for 150min, sampling and tracking, wherein the 3-methyl-2-nitrobenzoic acid is less than or equal to 0.5 percent.
55g of iron powder is slowly added into the reaction system to generate reduction reaction to generate 2-amino-3-methyl benzoate.
After filtration, the reduction system is heated to 55 ℃, thionyl chloride is slowly added dropwise into the reduction system, and the molar ratio of the thionyl chloride to the 3-methyl-2-nitrobenzoic acid is 2.5:1, controlling the temperature to 55 ℃ and reacting for 5 hours to generate 2-amino-5-chloro- (N, 3) -dimethyl benzoic acid methyl ester, quenching thionyl chloride, neutralizing the system, and drying, wherein tetrahydrofuran is used for preparing a solution, and the mass ratio of the tetrahydrofuran to the raw material 3-methyl-2-nitrobenzoic acid is 14:1.
slowly adding 27.6g of 40% sodium hydroxide solution into the system, heating to 75 ℃ after the temperature is stable, and introducing monomethylamine gas into the system, wherein the molar ratio of the monomethylamine gas to the raw material 3-methyl-2-nitrobenzoic acid is 5:1, carrying out heat preservation reaction for 6h to obtain 2-amino-5-chloro- (N, 3) -dimethylbenzamide.
After suction filtration, the filtrate is dried and dried to obtain a solid product, the sample-feeding detection purity of the product is 90%, and the total yield of the product is 59.0% based on the raw material 3-methyl-2-nitrobenzoic acid.
Comparative example 3
The raw materials are dissolved in methanol and are conveyed to a plug flow reaction device through a raw material conveying pump, meanwhile, concentrated sulfuric acid is pumped into the plug flow reaction device, and the molar ratio of the sulfuric acid to the raw material 2-nitro-3-methylbenzoic acid is 5:1, the mass ratio of methanol to raw material 2-nitro-3-methylbenzoic acid is 10:1, the feeding speed of the raw material system is 500g/h, the temperature of the reaction system is 50 ℃, the retention time is 100min, and 3-methyl-2-nitrobenzoic acid methyl ester is produced.
The 3-methyl-2-nitrobenzoic acid methyl ester system is pumped into a continuous overflow reactor through a conveying pump, meanwhile, iron powder is added by using a solid feeding machine, and the mole ratio of the iron powder to the raw material 2-nitro-3-methylbenzoic acid is 3.6:1, carrying out reduction reaction to generate 2-amino-3-methyl benzoate.
The methyl 2-amino-3-methylbenzoate system passes through a bag filter and then enters a buffer tank, the buffer tank is pumped into a plug flow reactor, and simultaneously, the mole ratio of the thionyl chloride to the raw material 3-methyl-2-nitrobenzoic acid is 2.5:1, controlling the temperature to 50 ℃ and keeping the temperature for 3 hours to generate 2-amino-5-chloro- (N, 3) -dimethylbenzoic acid methyl ester, introducing the system into a continuous post-treatment device, adding tetrahydrofuran to prepare a solution, and the mass ratio of the tetrahydrofuran to the raw material 3-methyl-2-nitrobenzoic acid is 14:1.
the methyl 2-amino-5-chloro- (N, 3) -dimethylbenzoate system was pumped into a continuous mixer with 40% sodium hydroxide solution, the molar ratio of sodium hydroxide to starting 3-methyl-2-nitrobenzoic acid being 1:1, flowing the mixed system into a bubbling tower, heating the bubbling tower to 75 ℃, and simultaneously, introducing monomethylamine gas, wherein the molar ratio of the monomethylamine gas to the raw material 2-nitro-3-methylbenzoic acid is 5:1, carrying out heat preservation reaction for 4.5 hours, generating a product system, filtering, drying a filter cake to obtain a product solid, wherein the product purity is 99%, the total product yield is 67.3% based on the raw material 3-methyl-2-nitrobenzoic acid, and the continuous and stable operation time of the equipment exceeds 500 hours.
TABLE 1
As can be seen from example 1 and comparative example 1, even under the same reaction conditions, the continuous preparation method adopted by the method for preparing 2-amino-5-chloro- (N, 3) -dimethylbenzamide has obvious improvement on yield compared with batch reaction, especially in the processes of acyl chlorination and amidation, and supposedly has obvious influence on the product yield of acyl chlorination and amidation due to better mass transfer effect in the process of preparing 2-amino-5-chloro- (N, 3) -dimethylbenzamide by adopting the continuous reactor.
From the above description, it can be seen that the above embodiments of the present invention achieve the following technical effects: the method takes 2-nitro-3-methylbenzoic acid which is cheap and easy to obtain as a starting raw material, and sequentially carries out continuous acyl chlorination reaction, continuous amidation reaction, continuous hydrogenation reduction reaction and continuous chlorination reaction to prepare and generate 2-amino-5-chloro- (N, 3) -dimethylbenzamide, the obtained 2-amino-5-chloro- (N, 3) -dimethylbenzamide product system has fewer impurities, separation and purification are convenient, and the intermediate solution system obtained in each step of reaction can enter a reactor for the next step of reaction without separation and purification, so that the preparation process of the 2-amino-5-chloro- (N, 3) -dimethylbenzamide is greatly simplified, the three wastes generated in batch production are greatly reduced, and the conversion rate is higher, thereby greatly reducing the production cost of the 2-amino-5-chloro- (N, 3) -dimethylbenzamide; on the other hand, the continuous preparation method of the 2-amino-5-chloro- (N, 3) -dimethylbenzamide has the advantages that the related reaction risk level is less than or equal to 3 levels, the production process is environment-friendly, efficient and safe, the large-scale production is easy to realize, and the problems of difficult amplification of batch reaction and high risk coefficient are fundamentally solved.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (4)
1. A continuous process for the preparation of 2-amino-5-chloro- (N, 3) -dimethylbenzamide, comprising:
continuously introducing raw material 2-nitro-3-methylbenzoic acid, a first chlorinating agent and a solvent into a continuous acyl chlorination reactor to perform continuous acyl chlorination reaction to obtain a first intermediate solution system, wherein the continuous acyl chlorination reactor is any one of a continuous plug flow reactor, a continuous kettle type reactor and a continuous column type reactor, the first chlorinating agent is any one or more of thionyl chloride, chlorine, N-chlorosuccinimide and sulfonyl chloride, the solvent is any one or more of tetrahydrofuran, xylene, 2-methyltetrahydrofuran, ethylene glycol, toluene, methylene dichloride, 1, 4-dioxane, chloroform and N, N-dimethylformamide, the molar ratio of the first chlorinating agent to the raw material 2-nitro-3-methylbenzoic acid is 2.0-10.0:1, the reaction temperature of the continuous acyl chlorination reaction is 55-65 ℃, and the retention time is 10-40 min;
continuously introducing the first intermediate solution system and an amination agent into a continuous amination reactor to perform continuous amidation reaction to obtain a second intermediate solution system, wherein the amination agent is one or more of monomethylamine aqueous solution, monomethylamine methanol solution, monomethylamine gas and monomethylamine tetrahydrofuran solution, the molar ratio of the amination agent to the raw material 2-nitro-3-methylbenzoic acid is 1.0-5.0:1, and the reaction temperature of the continuous amidation reaction is 40-60 ℃;
continuously introducing the second intermediate solution system, a reducing agent and a hydrogenation catalyst into a continuous hydrogenation reactor to perform continuous hydrogenation reduction reaction to obtain a third intermediate solution system, wherein the reducing agent is any one or more of a composition of iron powder and hydrochloric acid, hydrogen and hydrazine hydrate, the hydrogenation catalyst is any one or more of palladium carbon, raney nickel, a nickel-based catalyst and an iron-based catalyst, and the reaction temperature of the continuous hydrogenation reduction reaction is 80-90 ℃;
introducing the third intermediate solution system and a second chlorinating agent into a continuous chlorination reactor for continuous chlorination reaction, purifying the obtained product system to obtain a 2-amino-5-chloro- (N, 3) -dimethylbenzamide product, wherein the second chlorinating agent is any one or more of a hydrogen peroxide and hydrochloric acid composition, chlorine and sulfonyl chloride, the molar ratio of the second chlorinating agent to the raw material 2-nitro-3-methylbenzoic acid is 2-4:1, and the reaction temperature of the continuous chlorination reaction is 40-70 ℃.
2. The continuous production method according to claim 1, wherein the first chlorinating agent is thionyl chloride;
and/or, the amination agent is monomethylamine gas;
and/or the reducing agent is hydrogen;
and/or the second chlorinating agent is chlorine.
3. The continuous production method according to claim 1, wherein the retention time of the continuous amidation reaction is 30 to 60min;
and/or the retention time of the continuous hydrogenation reduction reaction is 50-90 min;
and/or the retention time of the continuous chlorination reaction is 1.0 h-10.0 h.
4. A continuous production method according to any one of claims 1 to 3, characterized in that the solution system obtained after the continuous hydrogenation reduction reaction is subjected to a water removal treatment to obtain the third intermediate solution system;
and/or, the purification treatment comprises the steps of continuously separating solid and solvent in the product system, and drying to obtain the 2-amino-5-chloro- (N, 3) -dimethylbenzamide product.
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