CN115594603A - Method for preparing N-tert-butyl-4-aminobenzamide by using microchannel reactor - Google Patents
Method for preparing N-tert-butyl-4-aminobenzamide by using microchannel reactor Download PDFInfo
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- IBSCJDKXUQIEPQ-UHFFFAOYSA-N 4-amino-n-(tert-butyl)benzamide Chemical compound CC(C)(C)NC(=O)C1=CC=C(N)C=C1 IBSCJDKXUQIEPQ-UHFFFAOYSA-N 0.000 title claims abstract description 52
- 238000000034 method Methods 0.000 title claims abstract description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 48
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 48
- FHLKNAGHERYTJV-UHFFFAOYSA-N n-tert-butyl-4-nitrobenzamide Chemical compound CC(C)(C)NC(=O)C1=CC=C([N+]([O-])=O)C=C1 FHLKNAGHERYTJV-UHFFFAOYSA-N 0.000 claims abstract description 47
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 28
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 claims abstract description 25
- SKDHHIUENRGTHK-UHFFFAOYSA-N 4-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C=C1 SKDHHIUENRGTHK-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 20
- 239000002904 solvent Substances 0.000 claims abstract description 20
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000005086 pumping Methods 0.000 claims abstract description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
- 238000002156 mixing Methods 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims description 28
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 27
- 238000005984 hydrogenation reaction Methods 0.000 claims description 16
- 239000007788 liquid Substances 0.000 claims description 14
- 238000006722 reduction reaction Methods 0.000 claims description 14
- 239000012530 fluid Substances 0.000 claims description 13
- 238000001816 cooling Methods 0.000 claims description 12
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 11
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 10
- 230000014759 maintenance of location Effects 0.000 claims description 8
- 239000008096 xylene Substances 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- 150000007529 inorganic bases Chemical class 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 238000004821 distillation Methods 0.000 claims description 6
- 239000012452 mother liquor Substances 0.000 claims description 6
- 238000004064 recycling Methods 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 229910052759 nickel Inorganic materials 0.000 claims description 5
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 4
- 125000003944 tolyl group Chemical group 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000002699 waste material Substances 0.000 abstract description 4
- 239000000047 product Substances 0.000 description 20
- 238000005917 acylation reaction Methods 0.000 description 10
- 239000012295 chemical reaction liquid Substances 0.000 description 8
- 230000008569 process Effects 0.000 description 7
- 150000001263 acyl chlorides Chemical class 0.000 description 6
- 238000005660 chlorination reaction Methods 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 230000006181 N-acylation Effects 0.000 description 4
- 238000005580 one pot reaction Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012847 fine chemical Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- GTZJIQDLDUWGMH-UHFFFAOYSA-N 4-aminobenzamide Chemical compound NC(=O)C1=CC=C(N)C=C1.NC(=O)C1=CC=C(N)C=C1 GTZJIQDLDUWGMH-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- HBMJWWWQQXIZIP-UHFFFAOYSA-N silicon carbide Chemical compound [Si+]#[C-] HBMJWWWQQXIZIP-UHFFFAOYSA-N 0.000 description 1
- 229910010271 silicon carbide Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000002912 waste gas Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- 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
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
-
- 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
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- 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 method for preparing N-tert-butyl-4-aminobenzamide by a microchannel reactor, which comprises the following steps: respectively preparing a p-nitrobenzoic acid solution and a thionyl chloride solution by taking toluene as a solvent; pumping the paranitrobenzoic acid solution and the thionyl chloride solution into a first microchannel reactor respectively to prepare paranitrobenzoyl chloride solution; pumping the paranitrobenzoyl chloride solution, tert-butylamine and an inorganic alkali solution into a second microchannel reactor respectively to prepare N-tert-butyl-4-nitrobenzamide; dissolving the N-tertiary butyl-4-nitrobenzamide in a methanol or ethanol solvent, and carrying out catalytic hydrogenation reaction in a microchannel mixer to prepare the N-tertiary butyl-4-aminobenzamide. The method for preparing the N-tert-butyl-4-aminobenzamide by the microchannel reactor provided by the invention reduces the three-waste pollution, is green and environment-friendly, has high synthesis yield, and is safe, reliable and high in efficiency by strongly mixing the N-tert-butyl-4-nitrobenzamide solution and hydrogen in the microchannel reactor.
Description
Technical Field
The invention relates to the field of chemical product synthesis methods, in particular to a method for preparing N-tert-butyl-4-aminobenzamide by using a microchannel reactor.
Background
N-tert-butyl-4-aminobenzamide (molecular formula: C11H16N2O, CAS number: 93483-71-7) is an important intermediate for fine chemical engineering and medicines, and the preparation method comprises the steps of carrying out N-acylation reaction on p-nitrobenzoyl chloride and tert-butylamine to obtain N-tert-butyl-4-nitrobenzamide, and then carrying out hydrogenation reduction to obtain the N-tert-butyl-4-aminobenzamide, wherein the difference of the methods is mainly the difference of hydrogenation reduction processes.
The method (I): journal of Agricultural and Food Chemistry (2013, 61, 517-522) in 2013 and U.S. Pat. No. 6,84033B 1 in 2002 report that p-nitrobenzoic acid is used as a starting material, p-nitrobenzoyl chloride is obtained through thionyl chloride chlorination, N-acylation reaction is carried out on the p-nitrobenzoyl chloride and tert-butylamine to prepare N-tert-butyl-4-nitrobenzamide, and finally, the N-tert-butyl-4-aminobenzamide is obtained through hydrogenation reduction by 10% Pd/C catalyst. The synthetic route is as follows:
the method (II): the Chinese patent CN110305032A in 2019 also reports a preparation method of N-tert-butyl-4-aminobenzamide, which takes p-nitrobenzoyl chloride as a starting material, adopts toluene and water as a mixed solvent to carry out condensation reaction with tert-butylamine to prepare the N-tert-butyl-4-nitrobenzamide, and then the N-tert-butyl-4-aminobenzamide is prepared by catalytic hydrogenation of 5 percent Pd/C. The synthetic route is as follows:
in the method (I), when the p-nitrobenzoic acid is subjected to acyl chlorination, large excess thionyl chloride is adopted, and the pollution of waste gas and waste water in the preparation process is serious; when amide is prepared by N-acylation reaction, organic base triethylamine is used as an acid-binding agent, so that the reaction yield is low, and the raw material cost is high; in the catalytic hydrogenation reaction, an expensive Pd/C catalyst is adopted, although the reaction yield is high, the raw material cost is high, and the batch process has great potential safety hazard. In the method (II), p-nitrobenzoyl chloride with higher price is directly used as a raw material, and in the processes of preparing amide by N-acylation reaction and catalytic hydrogenation reaction, similar to the process method in the method (I), the method also has the defects of high raw material cost, large potential safety hazard of catalytic hydrogenation, long reaction time, serious environmental pollution and the like, and is not suitable for industrial production.
Disclosure of Invention
In view of the above, there is a need for a microchannel reactor for producing N-tert-butyl-4-aminobenzamide that addresses at least one of the problems mentioned above.
The invention provides a method for preparing N-tert-butyl-4-aminobenzamide by a microchannel reactor, which comprises the following steps:
toluene, xylene or benzene are taken as solvents to respectively prepare a p-nitrobenzoic acid solution and a thionyl chloride solution; respectively pumping the p-nitrobenzoic acid solution and the thionyl chloride solution into a first microchannel reactor to prepare a p-nitrobenzoyl chloride solution;
pumping the paranitrobenzoyl chloride solution, tert-butylamine and an inorganic alkali solution into a second microchannel reactor respectively to prepare N-tert-butyl-4-nitrobenzamide;
dissolving the N-tert-butyl-4-nitrobenzamide in a methanol or ethanol solvent, and carrying out catalytic hydrogenation reaction in a microchannel mixer to prepare the N-tert-butyl-4-aminobenzamide.
In one embodiment, the concentration of the p-nitrobenzoic acid solution is 0.5mol/L, and the concentration of the thionyl chloride solution is 1.0mol/L.
In one embodiment, the step of pumping the paranitrobenzoyl chloride solution, the tert-butylamine, and the inorganic base solution into a second microchannel reactor separately comprises: feeding a paranitrobenzoic acid solution and a thionyl chloride solution into the first microchannel reactor in parallel flow at the speed of 20.0-30.0 ml/min and 10.0-15.0 ml/min respectively, wherein the reaction temperature in the first microchannel reactor is 100-150 ℃, the pressure is 0.5-2.0 MPa, and the retention time is 1.1-1.7 min.
In one embodiment, the thionyl chloride solution can be replaced by a phosphorus trichloride solution or a phosphorus oxychloride solution, and the solvent is toluene, xylene or benzene.
In one embodiment, the step of pumping the solution of paranitrobenzoyl chloride, tert-butylamine, and inorganic base into a second microchannel reactor separately comprises:
at the inlet of the second micro-channel reactor, adding tert-butylamine and 20% of inorganic alkali solution at the speed of 2.0-3.0 ml/min and 4.0-6.0 ml/min in parallel flow respectively; the reaction temperature in the second microchannel reactor is 100-150 ℃, the reaction pressure is 0.5-2.0 MPa, and the reaction residence time is 1.0-1.5 min.
In one embodiment, the step of preparing the N-tert-butyl-4-nitrobenzamide comprises:
and (3) cooling, crystallizing and filtering the N-tert-butyl-4-nitrobenzamide solution output by the second microchannel reactor, recycling mother liquor, and drying a solid to obtain a white intermediate N-tert-butyl-4-nitrobenzamide.
In one embodiment, the step of dissolving the N-tert-butyl-4-nitrobenzamide in a methanol or ethanol solvent comprises: dissolving the N-tert-butyl-4-nitrobenzamide in methanol or ethanol to prepare a solution with the concentration of 0.5 mol/L.
In one embodiment, the step of catalytically hydrogenating the reaction by performing the reaction in a microchannel mixer comprises:
the N-tertiary butyl-4-nitrobenzamide solution and the hydrogen are pumped into the micro-channel mixer in parallel flow at the speed of 20.0 to 30.0ml/min and 1.0 to 2.0L/min respectively;
strongly mixing to form mixed fluid containing micro bubbles, heating to 80-120 ℃, introducing the mixed fluid into a catalytic hydrogenation reaction column for hydrogenation reduction reaction, wherein the reaction pressure is 0.5-1.0 MPa, and the retention time is 1-2 min, so as to obtain solution containing the N-tert-butyl-4-aminobenzamide product.
In one embodiment, the catalyst used in the hydrogenation reduction reaction is skeletal nickel.
In one embodiment, the step of preparing the N-tert-butyl-4-aminobenzamide comprises:
and separating the solution obtained after the catalytic hydrogenation reaction by a gas-liquid separation tank, recovering the alcohol solvent by normal pressure distillation, and cooling, crystallizing and drying the remainder to obtain the N-tert-butyl-4-aminobenzamide.
The technical scheme provided by the embodiment of the invention has the following beneficial technical effects:
the method for preparing the N-tert-butyl-4-aminobenzamide by the microchannel reactor provided by the invention takes the p-nitrobenzoic acid as the starting material, and performs chlorination and acylation reactions in the microchannel reactor in a one-pot manner to obtain the intermediate N-tert-butyl-4-nitrobenzamide, thereby reducing the pollution of three wastes, being green and environment-friendly, having high synthesis yield, strongly mixing the N-tert-butyl-4-nitrobenzamide solution and hydrogen in the microchannel reactor, and obtaining the N-tert-butyl-4-aminobenzamide product safely, reliably and efficiently.
Additional aspects and advantages of the present invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Drawings
FIG. 1 is a schematic flow chart of a process for preparing N-tert-butyl-4-aminobenzamide by using a microchannel reactor according to an embodiment of the present invention;
FIG. 2 is a schematic flow diagram of an intermediate preparation process according to an embodiment of the present invention (where microchannel reactor A is a first microchannel reactor and microchannel reactor B is a second microchannel reactor);
FIG. 3 is a schematic diagram of a process flow of catalytic hydrogenation of a target product according to an embodiment of the present invention (the microchannel C is a microchannel mixer);
FIG. 4 is a liquid chromatogram of the intermediate N-tert-butyl-4-nitrobenzamide prepared in an example of the present invention;
FIG. 5 is a liquid chromatogram of the target product N-tert-butyl-4-aminobenzamide prepared in one example of the present invention.
Detailed Description
To facilitate an understanding of the invention, the invention will now be described more fully with reference to the accompanying drawings. Possible embodiments of the invention are given in the figures. The invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. The embodiments described by way of example with reference to the figures are intended to provide a more complete understanding of the disclosure of the present invention and are not to be construed as limiting the invention. In addition, if a detailed description of known technologies is not necessary for the features of the present invention shown, such technical details may be omitted.
It will be understood by those skilled in the relevant art that, unless otherwise defined, all terms (including 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. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.
As used herein, the singular forms "a", "an", "the" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" and/or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. It is to be understood that the term "and/or" as used herein is intended to include all or any and all combinations of one or more of the associated listed items.
The technical solution of the present invention and how to solve the above technical problems will be described in detail with specific examples.
The method for preparing N-tert-butyl-4-aminobenzamide by using the microchannel reactor, which is disclosed by the invention, is shown as a figure 1 and comprises the following steps:
s100: toluene, xylene or benzene are taken as solvents to respectively prepare a p-nitrobenzoic acid solution and a thionyl chloride solution; and respectively pumping the p-nitrobenzoic acid solution and the thionyl chloride solution into a first microchannel reactor to prepare a p-nitrobenzoyl chloride solution.
S200: and pumping the paranitrobenzoyl chloride solution, the tert-butylamine and the inorganic base solution into a second microchannel reactor respectively to prepare the N-tert-butyl-4-nitrobenzamide. Wherein the paranitrobenzoyl chloride solution directly flows into the second microchannel reactor from the first microchannel reactor, and the tert-butylamine and the inorganic alkali solution are respectively pumped into the second microchannel reactor.
S300: dissolving N-tert-butyl-4-nitrobenzamide in a methanol or ethanol solvent, and carrying out catalytic hydrogenation reaction in a microchannel mixer to prepare the N-tert-butyl-4-aminobenzamide.
The method for preparing N-tert-butyl-4-aminobenzamide by using the microchannel reactor provided by the invention takes p-nitrobenzoic acid as a starting material, and performs chlorination and acylation reactions continuously in one pot in the microchannel reactor to obtain the intermediate N-tert-butyl-4-nitrobenzamide, thereby reducing the pollution of three wastes, being green and environment-friendly, having high synthesis yield, strongly mixing the N-tert-butyl-4-nitrobenzamide solution and hydrogen in the microchannel reactor, and obtaining the N-tert-butyl-4-aminobenzamide product safely, reliably and efficiently.
In one embodiment, the concentration of the p-nitrobenzoic acid solution in S100 is 0.5mol/L, and the concentration of the thionyl chloride solution is 1.0mol/L.
In one embodiment, the step of pumping the p-nitrobenzoyl chloride solution, the tert-butylamine and the inorganic base solution into the second microchannel reactor in S200 comprises: the paranitrobenzoic acid solution and the thionyl chloride solution are respectively fed into a first microchannel reactor in parallel flow at the speed of 20.0-30.0 ml/min and 10.0-15.0 ml/min, the reaction temperature in the first microchannel reactor is 100-150 ℃, the pressure is 0.5-2.0 MPa, and the retention time is 1.1-1.7 min.
In one embodiment, the thionyl chloride solution can be replaced by a phosphorus trichloride solution or a phosphorus oxychloride solution, and the solvent is toluene, xylene or benzene.
In one embodiment, the step of pumping the p-nitrobenzoyl chloride solution, the tert-butylamine and the inorganic base solution into the second microchannel reactor in S200 comprises:
at the inlet of the second micro-channel reactor, tert-butylamine and 20% of inorganic alkali solution are respectively added in parallel flow at the speed of 2.0-3.0 ml/min and 4.0-6.0 ml/min; the reaction temperature in the second microchannel reactor is 100-150 ℃, the reaction pressure is 0.5-2.0 MPa, and the reaction residence time is 1.0-1.5 min.
In one embodiment, the step of preparing N-tert-butyl-4-nitrobenzamide in S200 comprises:
and (3) cooling, crystallizing and filtering the N-tert-butyl-4-nitrobenzamide solution output by the second microchannel reactor, recycling mother liquor, and drying a solid to obtain a white intermediate N-tert-butyl-4-nitrobenzamide. The p-nitrobenzoic acid is used as an initial raw material, chlorination and acylation reactions are continuously carried out in a microchannel reactor in a one-pot mode to obtain an intermediate N-tert-butyl-4-nitrobenzamide, mother liquor can be recycled, three-waste pollution is reduced, the method is green and environment-friendly, and the synthesis yield is high.
In one embodiment, the step of dissolving N-tert-butyl-4-nitrobenzamide in a methanol or ethanol solvent in S300 comprises: dissolving N-tert-butyl-4-nitrobenzamide in methanol or ethanol to prepare a solution with the concentration of 0.5 mol/L.
In one embodiment, the step of S300 by performing a catalytic hydrogenation reaction in a microchannel mixer comprises:
the N-tertiary butyl-4-nitrobenzamide solution and the hydrogen are pumped into the micro-channel mixer in parallel flow at the speed of 20.0 to 30.0ml/min and 1.0 to 2.0L/min respectively;
strongly mixing to form mixed fluid containing micro bubbles, heating to 80-120 ℃, introducing the mixed fluid into a catalytic hydrogenation reaction column for hydrogenation reduction reaction, wherein the reaction pressure is 0.5-1.0 MPa, and the retention time is 1-2 min, so as to obtain solution containing the N-tert-butyl-4-aminobenzamide product.
In one embodiment, the catalyst used in the S300 hydrogenation reduction reaction is skeletal nickel. The N-tert-butyl-4-nitrobenzamide solution and hydrogen are strongly mixed in a microchannel reactor to form a mixed fluid containing micro bubbles, the mixed fluid enters a catalytic hydrogenation reaction column for rapid reduction, and an N-tert-butyl-4-aminobenzamide product is obtained, the hydrogenation reduction is safe and reliable, and the efficiency is high; the hydrogenation reaction column is filled with a low-price framework nickel catalyst, and the repeated use period is long.
In one embodiment, the step of preparing N-tert-butyl-4-aminobenzamide of S300 comprises:
and (3) separating the solution obtained after the catalytic hydrogenation reaction by a gas-liquid separation tank, recovering the alcohol solvent by normal pressure distillation, and cooling, crystallizing and drying the remainder to obtain the N-tert-butyl-4-aminobenzamide.
Specifically, the preparation method of the fine chemical intermediate N-tert-butyl-4-aminobenzamide is improved, a safe and effective microchannel continuous flow reaction technical method is adopted, the technical defects of the existing preparation at home and abroad are overcome, and the N-tert-butyl-4-aminobenzamide is prepared by a two-step process.
The method comprises the following steps of firstly, taking p-nitrobenzoic acid as a starting material, simultaneously pumping a toluene solution of the p-nitrobenzoic acid and a toluene solution of thionyl chloride into a first microchannel reactor through two flow meters according to a certain proportion, and chlorinating to obtain a p-nitrobenzoyl chloride solution, wherein a toluene solvent can be replaced by dimethylbenzene or benzene. And then directly pumping tert-butylamine into a second microchannel reactor to perform acylation reaction with an inorganic alkali solution to prepare an N-tert-butyl-4-nitrobenzamide solution, cooling, crystallizing and filtering, wherein the obtained mother liquor can be recycled and reused, and the intermediate N-tert-butyl-4-nitrobenzamide is obtained through one-pot continuous reaction, wherein the yield can be more than 90%. The process route of this step can refer to fig. 2.
And secondly, dissolving the N-tert-butyl-4-nitrobenzamide obtained in the first step in a methanol (or ethanol) solvent, enabling the solution and hydrogen to flow into a microchannel mixer in a concurrent mode for strong mixing, finally enabling the mixture to enter a catalytic hydrogenation reaction column for reduction to obtain an N-tert-butyl-4-aminobenzamide solution, recovering the solvent through distillation, cooling, crystallizing and drying to obtain an N-tert-butyl-4-aminobenzamide product, wherein the yield can reach over 95%. The process flow is shown in figure 3.
The specific details of the two steps include:
the first microchannel reactor, the second microchannel reactor and the microchannel mixer can all adopt equipment existing in the industry, wherein the core reaction vessel part is formed by connecting 5 microchannel plates in series, the total volume of each of the microchannel reactors or the microchannel mixers is 50ml, the microchannel plates are made of silicon carbide, and the microchannel plates are internally provided with abundant curved channels with the inner diameter of 0.5-1.0 mm. The reaction temperature in the reactor is regulated by a temperature controller, the pressure is regulated by a backpressure valve, the gas-liquid flow is regulated by a metering pump, and a reaction product enters a liquid storage tank through the backpressure valve. The microchannel reactor has good mass transfer and heat transfer effects, can diffuse a large amount of heat generated by chlorination and hydrogenation reduction reaction in time, ensures that the process is safe and controllable, and meets the safety control requirements of dangerous chemical processes issued by the national safety supervision bureau. And the microchannel reactor realizes amplification production by parallel connection, adopts a continuous process, has simple and convenient operation and low industrial cost, and is more suitable for industrial automatic control.
In the first step, p-nitrobenzoic acid is dissolved in an organic solvent (toluene, xylene, benzene, etc.) to prepare a solution with the concentration of 0.5mol/L, and thionyl chloride (phosphorus trichloride or phosphorus oxychloride) is dissolved in the organic solvent (toluene, xylene, benzene, etc.) to prepare a solution with the concentration of 1.0mol/L. Feeding a p-nitrobenzoic acid solution and a thionyl chloride (phosphorus trichloride or phosphorus oxychloride) solution into a first microchannel reactor respectively at the speed of 20.0-30.0 ml/min and 10.0-15.0 ml/min in a cocurrent manner, wherein the reaction temperature is 100-150 ℃, the pressure is 0.5-2.0 MPa, the residence time is 1.1-1.7 min, discharging the generated acyl chloride reaction liquid, then feeding the acyl chloride reaction liquid into a second microchannel reactor, simultaneously feeding the generated acyl chloride reaction liquid into the second microchannel reactor in a cocurrent manner at the speed of 2.0-3.0 ml/min and 4.0-6.0 ml/min respectively at the inlet of the second microchannel reactor, carrying out acylation reaction at the temperature of 100-150 ℃, the reaction pressure is 0.5-2.0 MPa, the reaction residence time is 1.0-1.5 min, finally feeding the solution of the reaction product into a liquid storage tank through a back pressure valve, obtaining N-tert-butyl-4-methyl formamide, cooling, recovering the crystallization pressure, recycling the intermediate solution, and obtaining the product with purity of more than 0.90 percent, and recycling the product of the product.
In the second step, dissolving the intermediate N-tert-butyl-4-nitrobenzamide in methanol (or ethanol) to prepare a solution with the concentration of 0.5mol/L, pumping the N-tert-butyl-4-nitrobenzamide solution and hydrogen into a micro-channel mixer C in parallel flow of 20.0-30.0 ml/min and 1.0-2.0L/min respectively for strong mixing to form a mixed fluid containing micro bubbles, heating to 80-120 ℃, feeding the mixed fluid into a catalytic hydrogenation reaction column, carrying out hydrogenation reduction reaction under the action of catalyst framework nickel, keeping the mixed fluid at the pressure of 0.5-1.0 MPa for 1-2 min to obtain a solution containing an N-tert-butyl-4-aminobenzamide product, feeding the solution into a gas-liquid separation tank for separation, then carrying out atmospheric distillation and recovery, cooling and crystallizing the alcohol solvent residue, and drying to obtain white N-tert-butyl-4-aminobenzamide powder, wherein the yield is more than 95%, and the liquid phase chromatography purity is more than 99.0%.
The following are specific examples:
example 1:
16.7g of p-nitrobenzoic acid was weighed out and dissolved in 192ml of toluene to prepare a 0.5mol/L solution, and 7.3ml (11.9 g) of thionyl chloride was weighed out and dissolved in 93ml of toluene to prepare a 1.0mol/L solution. Feeding a p-nitrobenzoic acid solution and a thionyl chloride solution into a first microchannel reactor respectively at the speed of 20.0mL/min and 10.0mL/min in a cocurrent manner, enabling the reaction temperature to be 120 ℃, the pressure to be 1.0MPa and the retention time to be 1.7min, enabling the generated acyl chloride reaction liquid to flow out of the microchannel reactor A and enter a second microchannel reactor, respectively adding tert-butylamine and a 20% sodium hydroxide solution into an inlet of the second microchannel reactor at the speed of 2.0mL/min and 4.0mL/min in a cocurrent manner at the same time, enabling the acyl chloride reaction liquid and the acyl chloride reaction liquid to simultaneously enter the second microchannel reactor for acylation reaction at the temperature of 120 ℃, the pressure to be 1.0MPa and the reaction retention time to be 1.5min, enabling the reaction liquid to enter a liquid storage tank through a back pressure valve to obtain an N-tert-butyl-4-nitrobenzamide solution, cooling, crystallizing, filtering, recycling mother liquor, drying the solid to obtain 20.1g of a white N-tert-butyl-4-nitrobenzamide powder product, enabling the synthetic yield to be 90.5%, and detecting the product through a liquid chromatography (AgLC); the detector is DAD, the chromatographic column is Kromasil-C18,5 mu m, 4.6X 150mm, the mobile phase is methanol, water (60.
Weighing 22.2g of N-tert-butyl-4-nitrobenzamide, dissolving the N-tert-butyl-4-nitrobenzamide in 193mL of methanol to prepare a solution with the concentration of 0.5mol/L, pumping the N-tert-butyl-4-nitrobenzamide solution and hydrogen into a microchannel mixer C in parallel at 20.0mL/min and 1.0L/min respectively to perform intensive mixing to form a mixed fluid containing micro bubbles, heating to 90 ℃, enabling the mixed fluid to enter a catalytic hydrogenation reaction column, performing hydrogenation reduction reaction under the action of catalyst skeleton nickel under the pressure of 0.8MPa for 1.0min to obtain a methanol solution of the N-tert-butyl-4-aminobenzamide, separating the reaction liquid in a gas-liquid separation tank, recovering the methanol through atmospheric distillation, cooling and crystallizing the remainder, drying to obtain a white N-tert-butyl-4-aminobenzamide powder product with the yield of 18.3g and the hydrogenation yield of 95.3%, detecting the product by a liquid chromatograph (AgilLC; DAD; a chromatographic column: kromasil-C, a chromatographic column with the purity of 18. Mu.5 x.4-aminobenzamide powder product, the product of 18.3g, the product is detected by a high performance liquid chromatograph: agilLC; the flow rate of 20.40. Mu. 20: 60 mm; the flow rate of the sample water is 20.40: 40: 60: 40.40: 60: 10 min), and the flow rate of the sample is detected by a high performance liquid chromatograph.
Those of skill in the art will understand that various operations, methods, steps in the flow, measures, schemes discussed in this application can be alternated, modified, combined, or deleted. Further, other steps, measures, or schemes in various operations, methods, or flows that have been discussed in this application can be alternated, altered, rearranged, broken down, combined, or deleted. Further, steps, measures, schemes in the prior art having various operations, methods, procedures disclosed in the present application may also be alternated, modified, rearranged, decomposed, combined, or deleted.
The terms "first", "second" and "first" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present application, the meaning of "a plurality" is two or more unless otherwise specified.
In the description herein, particular features, structures, materials, or characteristics may be combined in any suitable manner in any one or more embodiments or examples.
It should be understood that, although the steps in the flowcharts of the figures are shown in order as indicated by the arrows, the steps are not necessarily performed in order as indicated by the arrows. The steps are not performed in the exact order shown and may be performed in other orders unless otherwise indicated herein. Moreover, at least a portion of the steps in the flow chart of the figure may include multiple sub-steps or multiple stages, which are not necessarily performed at the same time, but may be performed at different times, which are not necessarily performed in sequence, but may be performed alternately or alternately with other steps or at least a portion of the sub-steps or stages of other steps.
The foregoing is only a few embodiments of the present application and it should be noted that those skilled in the art can make various improvements and modifications without departing from the principle of the present application, and that these improvements and modifications should also be considered as the protection scope of the present application.
Claims (10)
1. A method for preparing N-tertiary butyl-4-aminobenzamide by a microchannel reactor is characterized by comprising the following steps:
toluene, xylene or benzene are used as solvents to respectively prepare a p-nitrobenzoic acid solution and a thionyl chloride solution; pumping the paranitrobenzoic acid solution and the thionyl chloride solution into a first microchannel reactor respectively to prepare paranitrobenzoyl chloride solution;
pumping the paranitrobenzoyl chloride solution, tert-butylamine and an inorganic alkali solution into a second microchannel reactor respectively to prepare N-tert-butyl-4-nitrobenzamide;
dissolving the N-tertiary butyl-4-nitrobenzamide in a methanol or ethanol solvent, and then carrying out catalytic hydrogenation reaction in a microchannel mixer to prepare the N-tertiary butyl-4-aminobenzamide.
2. The method for preparing N-tert-butyl-4-aminobenzamide by using the microchannel reactor as claimed in claim 1, wherein the concentration of the p-nitrobenzoic acid solution is 0.5mol/L, and the concentration of the thionyl chloride solution is 1.0mol/L.
3. The process for preparing N-tert-butyl-4-aminobenzamide by the microchannel reactor of claim 1, wherein the step of pumping the solution of paranitrobenzoyl chloride, tert-butylamine, and inorganic base solution separately into a second microchannel reactor comprises: feeding a p-nitrobenzoic acid solution and a thionyl chloride solution into the first microchannel reactor respectively at the speed of 20.0-30.0 ml/min and the speed of 10.0-15.0 ml/min in a parallel flow mode, wherein the reaction temperature in the first microchannel reactor is 100-150 ℃, the pressure in the first microchannel reactor is 0.5-2.0 MPa, and the retention time is 1.1-1.7 min.
4. The method for preparing N-tert-butyl-4-aminobenzamide by using the microchannel reactor as claimed in claim 1, wherein the thionyl chloride solution is replaced by a phosphorus trichloride solution or a phosphorus oxychloride solution, and the solvent is toluene, xylene or benzene.
5. The process for preparing N-tert-butyl-4-aminobenzamide by using the microchannel reactor according to claim 1, wherein the step of pumping the solution of paranitrobenzoyl chloride, tert-butylamine, and inorganic base solution separately into a second microchannel reactor comprises:
at the inlet of the second micro-channel reactor, adding tert-butylamine and 20% of inorganic alkali solution at the speed of 2.0-3.0 ml/min and 4.0-6.0 ml/min in parallel flow respectively; the reaction temperature in the second microchannel reactor is 100-150 ℃, the reaction pressure is 0.5-2.0 MPa, and the reaction residence time is 1.0-1.5 min.
6. The process for preparing N-tert-butyl-4-aminobenzamide by using the microchannel reactor according to claim 1, wherein the step of preparing N-tert-butyl-4-nitrobenzamide comprises:
and (3) cooling, crystallizing and filtering the N-tert-butyl-4-nitrobenzamide solution output by the second microchannel reactor, recycling mother liquor, and drying a solid to obtain a white intermediate N-tert-butyl-4-nitrobenzamide.
7. The process for preparing N-tert-butyl-4-aminobenzamide according to claim 1, wherein the step of dissolving the N-tert-butyl-4-nitrobenzamide in a methanol or ethanol solvent comprises: dissolving the N-tert-butyl-4-nitrobenzamide in methanol or ethanol to prepare a solution with the concentration of 0.5 mol/L.
8. The microchannel reactor of claim 7, wherein the step of catalytically hydrogenating the N-tert-butyl-4-aminobenzamide by performing a hydrogenation reaction in the microchannel mixer comprises:
the N-tertiary butyl-4-nitrobenzamide solution and the hydrogen are pumped into the micro-channel mixer in parallel flow at the speed of 20.0 to 30.0ml/min and 1.0 to 2.0L/min respectively;
strongly mixing to form mixed fluid containing micro bubbles, heating to 80-120 ℃, introducing the mixed fluid into a catalytic hydrogenation reaction column to perform hydrogenation reduction reaction, wherein the reaction pressure is 0.5-1.0 MPa, and the retention time is 1-2 min, so as to obtain solution containing the N-tert-butyl-4-aminobenzamide product.
9. The method for preparing N-tert-butyl-4-aminobenzamide by using the microchannel reactor as claimed in claim 8, wherein the catalyst used in the hydrogenation reduction reaction is skeletal nickel.
10. The process for preparing N-tert-butyl-4-aminobenzamide according to claim 1, wherein the step of preparing N-tert-butyl-4-aminobenzamide comprises:
and separating the solution obtained after the catalytic hydrogenation reaction by a gas-liquid separation tank, recovering the alcohol solvent by normal pressure distillation, and cooling, crystallizing and drying the remainder to obtain the N-tert-butyl-4-aminobenzamide.
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