CN116854608A - Preparation process of high-purity 2, 6-difluorobenzamide - Google Patents
Preparation process of high-purity 2, 6-difluorobenzamide Download PDFInfo
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- CN116854608A CN116854608A CN202310843841.8A CN202310843841A CN116854608A CN 116854608 A CN116854608 A CN 116854608A CN 202310843841 A CN202310843841 A CN 202310843841A CN 116854608 A CN116854608 A CN 116854608A
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- difluorobenzamide
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- difluorobenzonitrile
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- AVRQBXVUUXHRMY-UHFFFAOYSA-N 2,6-difluorobenzamide Chemical compound NC(=O)C1=C(F)C=CC=C1F AVRQBXVUUXHRMY-UHFFFAOYSA-N 0.000 title claims abstract description 103
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 238000006243 chemical reaction Methods 0.000 claims abstract description 96
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 82
- BNBRIFIJRKJGEI-UHFFFAOYSA-N 2,6-difluorobenzonitrile Chemical compound FC1=CC=CC(F)=C1C#N BNBRIFIJRKJGEI-UHFFFAOYSA-N 0.000 claims abstract description 71
- 239000000243 solution Substances 0.000 claims abstract description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 45
- 229910001868 water Inorganic materials 0.000 claims abstract description 44
- 238000000034 method Methods 0.000 claims abstract description 42
- 239000000047 product Substances 0.000 claims abstract description 42
- 230000008569 process Effects 0.000 claims abstract description 34
- 239000012043 crude product Substances 0.000 claims abstract description 32
- 238000001914 filtration Methods 0.000 claims abstract description 31
- 239000011259 mixed solution Substances 0.000 claims abstract description 20
- 239000003513 alkali Substances 0.000 claims abstract description 18
- 238000001816 cooling Methods 0.000 claims abstract description 15
- 239000002994 raw material Substances 0.000 claims abstract description 14
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 13
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims abstract description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 57
- 239000012295 chemical reaction liquid Substances 0.000 claims description 35
- 239000007788 liquid Substances 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 15
- 239000000706 filtrate Substances 0.000 claims description 11
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 6
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 238000004064 recycling Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000012670 alkaline solution Substances 0.000 claims 2
- 230000007613 environmental effect Effects 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 2
- ONOTYLMNTZNAQZ-UHFFFAOYSA-N 2,6-difluorobenzoic acid Chemical compound OC(=O)C1=C(F)C=CC=C1F ONOTYLMNTZNAQZ-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 16
- 239000002351 wastewater Substances 0.000 description 16
- 229910017053 inorganic salt Inorganic materials 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 14
- 238000001514 detection method Methods 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 238000005070 sampling Methods 0.000 description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 8
- 239000001301 oxygen Substances 0.000 description 8
- 229910052760 oxygen Inorganic materials 0.000 description 8
- -1 benzoyl urea compound Chemical class 0.000 description 7
- 238000002386 leaching Methods 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 238000004537 pulping Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 238000006386 neutralization reaction Methods 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 238000007792 addition Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 238000004065 wastewater treatment Methods 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- HRYILSDLIGTCOP-UHFFFAOYSA-N N-benzoylurea Chemical class NC(=O)NC(=O)C1=CC=CC=C1 HRYILSDLIGTCOP-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000004811 liquid chromatography Methods 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 229920002101 Chitin Polymers 0.000 description 2
- 239000005893 Diflubenzuron Substances 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- 229920002582 Polyethylene Glycol 600 Polymers 0.000 description 2
- 241000607479 Yersinia pestis Species 0.000 description 2
- 238000005815 base catalysis Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- QQQYTWIFVNKMRW-UHFFFAOYSA-N diflubenzuron Chemical compound FC1=CC=CC(F)=C1C(=O)NC(=O)NC1=CC=C(Cl)C=C1 QQQYTWIFVNKMRW-UHFFFAOYSA-N 0.000 description 2
- 229940019503 diflubenzuron Drugs 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- KTXFXDMDYZIXSJ-UHFFFAOYSA-N 2,4-difluorobenzamide Chemical compound NC(=O)C1=CC=C(F)C=C1F KTXFXDMDYZIXSJ-UHFFFAOYSA-N 0.000 description 1
- YOYAIZYFCNQIRF-UHFFFAOYSA-N 2,6-dichlorobenzonitrile Chemical compound ClC1=CC=CC(Cl)=C1C#N YOYAIZYFCNQIRF-UHFFFAOYSA-N 0.000 description 1
- YPSCQJTUAKNUNF-UHFFFAOYSA-N 2-chloro-n-[(4-chlorophenyl)carbamoyl]benzamide Chemical compound C1=CC(Cl)=CC=C1NC(=O)NC(=O)C1=CC=CC=C1Cl YPSCQJTUAKNUNF-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000001490 Dengue Diseases 0.000 description 1
- 206010012310 Dengue fever Diseases 0.000 description 1
- 239000005912 Lufenuron Substances 0.000 description 1
- 241000316848 Rhodococcus <scale insect> Species 0.000 description 1
- 241000187563 Rhodococcus ruber Species 0.000 description 1
- 239000005942 Triflumuron Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000010945 base-catalyzed hydrolysis reactiony Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000003936 benzamides Chemical class 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000012824 chemical production Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 208000025729 dengue disease Diseases 0.000 description 1
- WOWBFOBYOAGEEA-UHFFFAOYSA-N diafenthiuron Chemical compound CC(C)C1=C(NC(=S)NC(C)(C)C)C(C(C)C)=CC(OC=2C=CC=CC=2)=C1 WOWBFOBYOAGEEA-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- RYLHNOVXKPXDIP-UHFFFAOYSA-N flufenoxuron Chemical compound C=1C=C(NC(=O)NC(=O)C=2C(=CC=CC=2F)F)C(F)=CC=1OC1=CC=C(C(F)(F)F)C=C1Cl RYLHNOVXKPXDIP-UHFFFAOYSA-N 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 239000003630 growth substance Substances 0.000 description 1
- RGNPBRKPHBKNKX-UHFFFAOYSA-N hexaflumuron Chemical compound C1=C(Cl)C(OC(F)(F)C(F)F)=C(Cl)C=C1NC(=O)NC(=O)C1=C(F)C=CC=C1F RGNPBRKPHBKNKX-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- PWPJGUXAGUPAHP-UHFFFAOYSA-N lufenuron Chemical compound C1=C(Cl)C(OC(F)(F)C(C(F)(F)F)F)=CC(Cl)=C1NC(=O)NC(=O)C1=C(F)C=CC=C1F PWPJGUXAGUPAHP-UHFFFAOYSA-N 0.000 description 1
- 229960000521 lufenuron Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 239000011949 solid catalyst Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- XAIPTRIXGHTTNT-UHFFFAOYSA-N triflumuron Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC(=O)NC(=O)C1=CC=CC=C1Cl XAIPTRIXGHTTNT-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into 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
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0235—Nitrogen containing compounds
- B01J31/0239—Quaternary ammonium compounds
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Abstract
A preparation method of high-purity 2, 6-difluorobenzamide takes 2, 6-difluorobenzonitrile as a raw material, water and a quaternary ammonium salt phase transfer catalyst are added to form a mixed solution, hydrogen peroxide and an inorganic alkali solution are simultaneously added into the solution in a dropwise manner, the simultaneous dropwise addition is controlled to be finished, and the temperature is kept until the reaction is finished; cooling, crystallizing and filtering to obtain a crude product of the 2, 6-difluorobenzamide; the crude product is pulped by water, filtered and dried to obtain the 2, 6-difluorobenzamide product. The process has the advantages of high content, high yield, less three wastes, strong safety and the like, is a green process with high selectivity, strong economy and environmental friendliness, and has great guiding significance on industrial production.
Description
Technical Field
The invention belongs to the field of fine chemical production, and particularly relates to a preparation process of a benzoyl urea compound intermediate 2, 6-difluorobenzamide.
Background
The benzoyl urea compound is an insect chitin synthesis inhibitor, can inhibit chitin synthesis of target pests to cause death or sterility of the target pests, has a special insecticidal mechanism, and has the characteristics of broad spectrum, high efficiency, low residual quantity, strong selectivity and the like. Thousands of such compounds are reported at present, more than twenty commercial benzoyl urea compounds are also available, and the main components are: diflubenzuron, chlorbenzuron, triflumuron, hexaflumuron, flufenoxuron, diafenthiuron, lufenuron and the like.
2, 6-difluorobenzamide is a key intermediate for synthesizing benzoyl urea compounds, and is also used for medicines, liquid crystal materials and the like, so that the demand of high-quality 2, 6-difluorobenzamide in domestic and foreign markets is increased rapidly.
At present, the synthesis methods reported in the literature mainly comprise the following steps:
patent CN1024023C discloses a "method for producing difluorobenzamide", which uses 2, 6-difluorobenzonitrile as a raw material, and prepares 2, 6-difluorobenzamide by hydrolysis with bacteria of rhodococcus. Patent CN103509833B discloses "a method for preparing 2, 6-difluorobenzamide using rhodococcus ruber", which hydrolyzes 2, 6-difluorobenzonitrile to 2, 6-difluorobenzamide. Patent CN1277637a discloses a "preparation method of substituted benzamide", 2, 6-difluorobenzamide is prepared by biohydrolysis; the methods disclosed in the above patents all adopt biological methods to separate and obtain the 2, 6-difluorobenzamide.
In the synthesis of diflubenzuron as described in pesticide vol.39No. 3.2000, such as dengue, 2, 6-difluorobenzonitrile is used as a raw material, and 90% concentrated sulfuric acid is added for hydrolysis reaction to obtain 2, 6-difluorobenzamide.
Patent CN115677523A discloses a preparation method of 2, 6-difluorobenzamide, which is based on sulfuric acid catalytic hydrolysis, and adopts sulfuric acid and hydrochloric acid mixed catalysis to carry out nucleophilic addition reaction of 2, 6-difluorobenzonitrile to prepare the 2, 6-difluorobenzamide. Disadvantages of acid catalyzed processes: 1. the acidic medium corrodes equipment, and the reaction equipment has strict requirements; 2. a large amount of impurity 2, 6-difluorobenzoic acid is generated in the reaction process; 3. the post-treatment requires neutralization with sodium hydroxide, and finally generates a large amount of high-salt and high-COD wastewater.
Patent CN1218935C discloses a synthesis method of substituted benzoyl urea insect growth regulator, which uses 2, 6-dichlorobenzonitrile as a starting material and obtains the substituted benzoyl urea compound through fluorination, hydrolysis, esterification and addition. The method uses a base-catalyzed hydrolysis reaction in the hydrolysis step to obtain a 2, 6-difluorobenzamide filter cake with a yield of about 92% and a purity of about 98.7%. In the method, a solid catalyst needs to be put into the method, and the operation is complex.
Patent CN112851539B discloses a preparation method of 2, 6-difluorobenzamide, which takes 2, 6-difluorobenzonitrile as a raw material, 10-30% sodium hydroxide solution as a catalyst (the dosage is 0.6-2.0 eq), 20-35% hydrogen peroxide (the dosage is 2.0-4.0 eq) is dropwise added at 45-55 ℃, and after the reaction is finished, the temperature is reduced, the pH is regulated and solid-liquid separation is sequentially carried out to obtain the 2, 6-difluorobenzamide, the purity is 95-99%, the yield is 74-90%, and the yield of most embodiments is about 85-86%. However, this method has the following problems: 1. the consumption of hydrogen peroxide is large, a large amount of oxygen is generated, and the safety risk is high; 2. the consumption of sodium hydroxide is large, the alkalinity of the system is strong, a large amount of 2, 6-difluorobenzoic acid is generated in the reaction process, and the yield of 2, 6-difluorobenzamide is low; 3. after the reaction is finished, a hydrochloric acid neutralization system is needed to generate a large amount of sodium chloride, only water is used for leaching during solid-liquid separation, part of sodium chloride remains in a filter cake, and the purity of the 2, 6-difluorobenzamide product is low; 4. a large amount of sodium chloride and 2, 6-difluorobenzoic acid are dissolved in the filtrate, the COD and inorganic salt content (13%) in the wastewater are high, and the three-waste treatment cost is high.
Patent CN113651711A discloses a preparation method of 2, 6-difluorobenzamide, which adopts a microchannel continuous process, 2, 6-difluorobenzamide and deionized water are reacted in the microchannel at 240-260 ℃ under 4-5 MPa to obtain 2, 6-difluorobenzamide, then sodium chloride solution is added for salting out, and then the 2, 6-difluorobenzamide is obtained through filtration, water washing and drying. However, the method has high energy consumption, and the yield of the 2, 6-difluorobenzamide is low, which is only 85-86%.
At present, the main industrial process for producing 2, 6-difluorobenzamide is a base catalysis process similar to that of patent CN112851539B, but the inorganic base and hydrogen peroxide are used in large amounts, and a large amount of 2, 6-difluorobenzoic acid is produced in the reaction process; the reaction system is oil-water two-phase, the 2, 6-difluorobenzonitrile reacts slowly and is not thorough, and the reaction system is separated out and coated in the 2, 6-difluorobenzonitrile product after being cooled, so that the product purity is reduced; after the reaction is finished, hydrochloric acid is used for neutralization to be neutral, a large amount of inorganic salt is generated, the purity of the 2, 6-difluorobenzamide in the filter cake after solid-liquid separation is low, the yield is low, the filtrate is high-salt and high-COD wastewater, and the treatment cost is high. Therefore, the development of a preparation process of 2, 6-difluorobenzamide with high selectivity, high economy and environmental friendliness is needed.
Disclosure of Invention
The invention aims to provide a preparation process of high-purity 2, 6-difluorobenzamide, which has the advantages of high hydrolysis reaction speed, less residual amount of raw material 2, 6-difluorobenzonitrile, less production amount of impurity 2, 6-difluorobenzoic acid, high atom utilization rate, high purity of 2, 6-difluorobenzamide products, low inorganic salt and COD content in wastewater, high overall process selectivity, high economy, environmental friendliness, contribution to industrial production and improvement of market competitiveness of 2, 6-difluorobenzamide products.
In order to achieve the above purpose, the present invention provides the following technical solutions:
a preparation process of high-purity 2, 6-difluorobenzamide comprises the following steps:
1) 2, 6-difluorobenzonitrile is taken as a raw material, water and a quaternary ammonium salt phase transfer catalyst are added into the raw material, a mixed solution is obtained after uniform mixing, and then the mixed solution is heated to a reaction temperature which is 35-45 ℃;
2) Simultaneously dripping hydrogen peroxide and inorganic alkali solution into the mixed solution at a constant speed, controlling the beginning time and the ending time of the dripping of the hydrogen peroxide and the inorganic alkali to be the same, keeping the temperature between 35 and 45 ℃ for reaction after the dripping is ended, detecting the content of 2, 6-difluorobenzonitrile in the reaction solution in the reaction process, and ending the reaction when the qualitative content of the 2, 6-difluorobenzonitrile in the liquid chromatograph is less than 0.05 percent;
the mol ratio of the inorganic base to the 2, 6-difluorobenzonitrile is 0.05-0.15,
the molar ratio of the hydrogen peroxide to the 2, 6-difluorobenzonitrile is 2.0-3.0;
3) After the reaction is finished, cooling, crystallizing and filtering the reaction liquid to obtain a crude product of the 2, 6-difluorobenzamide;
4) And adding water into the obtained crude 2, 6-difluorobenzamide to pulp, and then filtering and drying to obtain a 2, 6-difluorobenzamide product.
Preferably, in the step 1), the weight ratio of the water to the 2, 6-difluorobenzonitrile is 0.5-1.5:1.
Preferably, the quaternary ammonium salt phase transfer catalyst is one or more of tetrabutylammonium chloride, tetrabutylammonium bromide or benzyl triethylammonium chloride.
Preferably, the addition amount of the phase transfer catalyst is 0.5 to 1.5% by weight of the 2, 6-difluorobenzonitrile.
Preferably, the inorganic alkali solution is one of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, and the concentration of the inorganic alkali solution is 2-32 wt%.
Preferably, the concentration of the hydrogen peroxide is 25-50 wt%.
Preferably, in the step 2), the dropping time is 3.0 to 5.0 hours.
Preferably, in the step 4), the filtered filtrate is added into the raw material as water in the step 1) for recycling.
The quaternary ammonium salt phase transfer catalyst is added into the reaction system, so that the reaction materials can be fully contacted, the reaction liquid is ensured to be in a liquid state in the reaction process, no solid is separated out in the reaction process, the 2, 6-difluorobenzonitrile is reacted thoroughly, the central control measurement is carried out in the reaction process, the liquid chromatography qualitative content of the 2, 6-difluorobenzonitrile is less than 0.05%, the conversion rate is improved, and the yield of the 2, 6-difluorobenzonitrile product is improved. When the temperature is reduced to 5 ℃ after the reaction is finished, the 2, 6-difluorobenzamide product is separated out, and the quantitative content of the 2, 6-difluorobenzonitrile in the 2, 6-difluorobenzamide crude product after filtration is less than 0.05 percent, so that the purity of the 2, 6-difluorobenzamide product is improved.
According to the invention, the inorganic alkali solution and the hydrogen peroxide are added into the obtained mixed solution at the same time, the pH value of the system gradually increases from 9 to 12 in the dropping process, the alkalinity of the reaction system is relatively weak, the consumption of the inorganic alkali is catalytic amount, and the consumption is reduced by more than 75%. If the same amount of inorganic alkali is adopted, the inorganic alkali is added at one time when the raw materials are fed, only hydrogen peroxide is added dropwise, the pH of the reaction solution gradually decreases from 13 to 9 in the dropping process, and the alkaline environments of the reaction systems are different. In the traditional base catalysis process, the pH value of the solution is more than 13, and the solution belongs to a strong alkaline environment.
The method is carried out in an environment system with relatively weak alkalinity, 2, 6-difluorobenzamide can be prevented from being hydrolyzed to generate 2, 6-difluorobenzoic acid impurity in a large amount in the reaction process, the liquid chromatography qualitative content of the 2, 6-difluorobenzoic acid after the reaction is finished is below 1%, and the generation amount of the 2, 6-difluorobenzoic acid is reduced by more than 70%. On the one hand, the yield of the 2, 6-difluorobenzamide product is improved; on the other hand, the amount of 2, 6-difluorobenzoic acid generated in the reaction process is small, the quantitative content of 2, 6-difluorobenzoic acid in the filtrate can be reduced, and the COD concentration in the wastewater is finally reduced.
Meanwhile, hydrogen peroxide is decomposed into oxygen to participate in the reaction under the alkaline condition, and under the condition that the alkalinity of a reaction system is weak, the speed of generating oxygen by decomposing hydrogen peroxide is smaller than the speed of participating in the reaction, and the oxygen generated by decomposing hydrogen peroxide can be fully utilized in the reaction process, so that the safety risk in the production process is reduced; the oxygen is fully utilized, so that the utilization rate of the hydrogen peroxide is improved, and the feeding amount of the hydrogen peroxide is reduced by more than 35%. When the pH value of the reaction solution is more than 13, the hydrogen peroxide is decomposed to generate oxygen at a higher speed, so that a large amount of oxygen overflows the reaction system and enters the tail gas system to be mixed with other organic tail gases, and safety accidents are easily caused.
In the invention, a catalytic amount of inorganic base is used, and a crude product pulping scheme is added later, after the reaction is finished, the temperature is directly reduced to separate out solid, and the white 2, 6-difluorobenzamide product is obtained after filtration. The using amount of inorganic alkali sodium hydroxide in the main industrial process is large, the inorganic alkali sodium hydroxide is directly filtered and leached after the reaction is finished, the residual amount of sodium hydroxide in the wet 2, 6-difluorobenzamide is large, and the 2, 6-difluorobenzamide is hydrolyzed into 2, 6-difluorobenzamide due to moisture absorption in the drying and storage processes, so that the reaction solution is firstly neutralized to be neutral after the main industrial process is finished, then cooled and filtered, but the reaction solution gradually changes from white to yellow in the neutralization process, and the filtered 2, 6-difluorobenzamide product is light yellow or even light yellow.
The filtrate obtained after the reaction solution is filtered after the reaction is finished is neutralized and discharged as waste water, wherein the inorganic salt content is less than 0.5%, and the inorganic salt content in the waste water is reduced by more than 95% compared with the industrialized main stream process; the inorganic salt content and COD in the wastewater are reduced, the wastewater treatment difficulty is reduced, and the wastewater treatment cost is reduced.
In the invention, the crude product of the 2, 6-difluorobenzamide is pulped by water, and inorganic salt and hydrogen peroxide in the crude product are removed, so that the purity of the 2, 6-difluorobenzamide product is improved. The quantitative content of the 2, 6-difluorobenzamide in the pulping filtrate is about 1%, the pulping filtrate is applied to the reaction to be used as water, the loss of the 2, 6-difluorobenzamide product is reduced, and the discharge of wastewater is avoided.
In the invention, the quantitative content of 2, 6-difluorobenzonitrile in the crude product of 2, 6-difluorobenzonitrile is less than 0.05%, and inorganic salt and hydrogen peroxide in the crude product are removed by pulping with water, so that the purity of the 2, 6-difluorobenzonitrile product is improved to more than 99%.
In the invention, a quaternary ammonium salt phase transfer catalyst is added, and the qualitative content of the 2, 6-difluorobenzonitrile is controlled to be less than 0.05% in liquid chromatography; the catalytic amount of inorganic alkali solution and hydrogen peroxide are simultaneously added in a double-drop way, the alkalinity of the system is relatively weak, and the qualitative content of impurity 2, 6-difluorobenzoic acid is less than 1%; the pulping filtrate is applied to the reaction as water, the yield of the 2, 6-difluorobenzamide product reaches over 96 percent, and is improved by about 10 percent compared with the industrialized main flow process, and the production cost is reduced.
Compared with the prior art, the invention has the following beneficial effects:
according to the invention, the quaternary ammonium salt phase transfer catalyst is added into the reaction system, and inorganic alkali and hydrogen peroxide are added in a double-dropwise manner at the same time, wherein the pH of the system gradually increases from 9 to 12 in the dropwise addition process, compared with the pH of a solution in the conventional reaction process which is more than 13, the pH in the reaction process is reduced, the consumption of the inorganic alkali and the hydrogen peroxide is reduced, the generation of impurity 2, 6-difluorobenzoic acid is reduced, the reaction yield and the product purity of the 2, 6-difluorobenzamide are improved, the yield is more than 96%, the purity of the product is improved to more than 99%, the yield is improved by about 10% compared with the industrialized main flow process, the generation of a large amount of oxygen can be avoided, and the reaction safety risk is reduced to a certain extent.
In the invention, hydrochloric acid is not used for neutralization after the reaction is finished, so that a large amount of sodium chloride generated by neutralization is prevented from being wrapped in the product, and the purity of the 2, 6-difluorobenzamide product is reduced. The increase of inorganic salt in the wastewater can be avoided, the filtrate obtained after the reaction solution is filtered after the reaction is finished is neutralized and discharged as wastewater, wherein the inorganic salt content is less than 0.5%, and the inorganic salt content in the wastewater is reduced by more than 95% compared with the industrial main stream process; the inorganic salt content and COD in the wastewater are reduced, the wastewater treatment difficulty is reduced, and the wastewater treatment cost is reduced.
In the invention, the crude 2, 6-difluorobenzamide is pulped by water, and the pulping mother liquor is applied to the reaction to be used as water, so that the wastewater discharge is reduced; secondly, inorganic salt and hydrogen peroxide in the crude product are removed, so that the purity of the 2, 6-difluorobenzamide product is improved; thirdly, the loss of the 2, 6-difluorobenzamide product is reduced, and the reaction yield of the 2, 6-difluorobenzamide is improved. In the traditional process, water is not added as a reaction solvent, after the reaction is finished, filtering is carried out, water is added for leaching, part of 2, 6-difluorobenzamide products are contained in the leaching solution, the leaching solution cannot be used mechanically because of containing a large amount of inorganic alkali, and the leaching solution can only be combined with filtrate to be used as waste water, so that the waste water treatment capacity is increased, and part of 2, 6-difluorobenzamide products are lost.
The 2, 6-difluorobenzamide product prepared by the process has the purity of more than 99 percent, the yield of more than 96 percent, the yield of about 10 percent higher than that of an industrialized main stream process, less waste water, low inorganic salt content and COD, low comprehensive cost and strong reaction safety, is a green process with high selectivity, strong economy and environmental friendliness, and has great guiding significance on industrial production.
Drawings
FIG. 1 is a liquid chromatograph for the pilot detection of the reaction solution in example 1 of the present invention.
FIG. 2 is a liquid chromatograph for detecting the reaction liquid in the control mode according to comparative example 1 of the present invention
FIG. 3 is a liquid chromatograph for detecting the reaction liquid in the control mode according to comparative example 2 of the present invention
FIG. 4 is a liquid chromatograph for detecting the reaction liquid in the control mode according to comparative example 3 of the present invention
Detailed Description
To facilitate understanding of the present invention, examples are set forth below. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
Example 1
The preparation process of the high-purity 2, 6-difluorobenzamide comprises the following specific steps:
1) 100.00g of 2, 6-difluorobenzonitrile (0.705 mol), 1.00g of tetrabutylammonium bromide and 100.00g of water are added into a reaction bottle, the mixture is stirred uniformly to obtain a mixed solution, and then the solution is heated to 43 ℃;
2) 200.40g of 27.5% hydrogen peroxide (1.620 mol) and 56.36g of 5% sodium hydroxide solution (0.070 mol) are simultaneously added into the mixed solution for 5.0h, the pH value of the reaction solution is 10-12 in the dripping process, and after the dripping is finished, the reaction solution is subjected to sampling, central control and detection after heat preservation at 43 ℃ for 1.0 h;
3) The qualitative content of 2, 6-difluorobenzonitrile in the reaction liquid is 0.01 percent, and the qualitative content of 2, 6-difluorobenzoic acid in the reaction liquid is 0.37 percent; cooling to 5 ℃, preserving heat for 1.0h, and filtering to obtain a crude product of the 2, 6-difluorobenzamide;
4) 150.00g of water is added into the crude product, the mixture is pulped for 1.0h at the temperature of 5 ℃, 108.25g of white 2, 6-difluorobenzamide product is obtained after filtration and drying, the purity is 99.23%, the quantitative content of 2, 6-difluorobenzonitrile is 0.02%, and the yield is 97.04%.
FIG. 1 is a liquid chromatograph of the reaction liquid of the embodiment 1 of the present invention, wherein the qualitative content of each substance in the reaction liquid of the present invention can be obtained from FIG. 1, and the specific results are shown in Table 1.
TABLE 1
| Material name | 2, 6-difluorobenzamide | 2, 6-Difluorobenzoic acid | 2, 6-difluorobenzonitrile |
| Retention time | 4.742min | 9.857min | 19.633min |
| Qualitative content of liquid chromatograph | 99.63％ | 0.37％ | 0.01％ |
Example 2
The preparation process of the high-purity 2, 6-difluorobenzamide comprises the following specific steps:
1) 100.00g of 2, 6-difluorobenzonitrile (0.705 mol), 0.75g of tetrabutylammonium bromide and 180.00g of water are added into a reaction bottle, uniformly stirred to obtain a mixed solution, and then the solution is heated to 43 ℃;
2) 226.54g of 27.5% hydrogen peroxide (1.832 mol) and 53.07g of 3% sodium hydroxide solution (0.070 mol) are simultaneously added into the mixed solution for 4.5h, the pH value of the reaction solution is 10-12 in the dripping process, and after the dripping is finished, the reaction solution is kept at 43 ℃ for 1.5h, sampled, centrally controlled and detected;
3) The qualitative content of 2, 6-difluorobenzonitrile in the reaction liquid is 0.04 percent, and the qualitative content of 2, 6-difluorobenzoic acid in the reaction liquid is 0.25 percent; cooling to 5 ℃, preserving heat for 1.0h, and filtering to obtain a crude product of the 2, 6-difluorobenzamide;
4) 150.00g of water is added into the crude product, the mixture is pulped for 1.0h at the temperature of 5 ℃, 107.75g of white 2, 6-difluorobenzamide product is obtained after filtration and drying, the purity is 99.15%, the quantitative content of 2, 6-difluorobenzonitrile is 0.03%, and the yield is 96.51%.
Example 3
The preparation process of the high-purity 2, 6-difluorobenzamide comprises the following specific steps:
1) 100.00g of 2, 6-difluorobenzonitrile (0.705 mol), 1.25g of tetrabutylammonium chloride and 150.00g of water are added into a reaction bottle, uniformly stirred to obtain a mixed solution, and then the solution is heated to 40 ℃;
2) 199.68g of 30.0% hydrogen peroxide (1.761 mol) and 37.55g of 4% sodium hydroxide solution (0.038 mol) are simultaneously added into the mixed solution in a dropwise manner for 3.0h, the pH value of the reaction solution is 10-12 in the dropwise manner, and after the dropwise addition, the reaction solution is subjected to sampling, central control and detection at 40 ℃ for 2.0 h;
3) The qualitative content of 2, 6-difluorobenzonitrile in the reaction liquid is 0.03 percent, and the qualitative content of 2, 6-difluorobenzoic acid in the reaction liquid is 0.45 percent; cooling to 5 ℃, preserving heat for 1.0h, and filtering to obtain a crude product of the 2, 6-difluorobenzamide;
4) 180.00g of water is added into the crude product, the mixture is subjected to heat preservation and pulping for 1.0h at the temperature of 5 ℃, 107.35g of white 2, 6-difluorobenzamide product is obtained after filtration and drying, the purity is 99.08%, the quantitative content of 2, 6-difluorobenzonitrile is 0.03%, and the yield is 96.09%.
Example 4
The preparation process of the high-purity 2, 6-difluorobenzamide comprises the following specific steps:
1) 100.00g of 2, 6-difluorobenzonitrile (0.705 mol), 0.50g of benzyltriethylammonium chloride and 75.00g of water were added to a reaction flask and stirred uniformly to obtain a mixed solution, and then the solution was heated to 38 ℃;
2) Simultaneously dropwise adding 191.69g of 30.0% hydrogen peroxide (1.691 mol) and 30.96g of 7% sodium hydroxide solution (0.054 mol) into the mixed solution for 4.0h, wherein the pH value of the reaction solution is 10-12 in the dropwise adding process, and after the dropwise adding is finished, preserving the temperature of the reaction solution at 40 ℃ for 2.0h, sampling, and centrally detecting;
3) The qualitative content of 2, 6-difluorobenzonitrile in the reaction liquid is 0.02 percent, and the qualitative content of 2, 6-difluorobenzoic acid in the reaction liquid is 0.38 percent; cooling to 5 ℃, preserving heat for 1.0h, and filtering to obtain a crude product of the 2, 6-difluorobenzamide;
4) 100.00g of water is added into the crude product, the mixture is pulped for 1.0h at the temperature of 5 ℃, 108.05g of white 2, 6-difluorobenzamide product is obtained after filtration and drying, the purity is 99.20%, the quantitative content of 2, 6-difluorobenzonitrile is 0.01%, and the yield is 96.83%.
Example 5
The preparation process of the high-purity 2, 6-difluorobenzamide comprises the following specific steps:
1) 100.00g of 2, 6-difluorobenzonitrile (0.705 mol), 1.50g of tetrabutylammonium bromide and 50.00g of water are added into a reaction bottle, uniformly stirred to obtain a mixed solution, and then the solution is heated to 40 ℃;
2) 216.08g of 27.5% hydrogen peroxide (1.747 mol) and 65.76g of 6% sodium hydroxide solution (0.099 mol) are simultaneously added into the mixed solution in a dropwise manner for 4.5h, the pH value of the system is controlled to be 11-12 in the dropwise manner, and after the dropwise addition, the reaction solution is subjected to sampling, central control and detection at 40 ℃ for 2.0 h;
3) The qualitative content of 2, 6-difluorobenzonitrile in the reaction liquid is 0.02 percent, and the qualitative content of 2, 6-difluorobenzoic acid in the reaction liquid is 0.38 percent; cooling to 5 ℃, preserving heat for 1.5 hours, and filtering to obtain a crude product of the 2, 6-difluorobenzamide;
4) 100.00g of water is added into the crude product, the mixture is pulped for 1.0h at the temperature of 5 ℃, 107.57g of white 2, 6-difluorobenzamide product is obtained after filtration and drying, the purity is 99.10%, the quantitative content of 2, 6-difluorobenzonitrile is 0.02%, and the yield is 96.30%.
Example 6
The preparation process of the high-purity 2, 6-difluorobenzamide comprises the following specific steps:
1) 100.00g of 2, 6-difluorobenzonitrile (0.705 mol), 1.00g of tetrabutylammonium bromide and 100.00g of water are added into a reaction bottle, the mixture is stirred uniformly to obtain a mixed solution, and then the solution is heated to 43 ℃;
2) 200.40g of 27.5% hydrogen peroxide (1.620 mol) and 63.25g of 5% potassium hydroxide solution (0.056 mol) are simultaneously added into the mixed solution for 5.0h, the pH value of the reaction solution is 11-12 in the dripping process, and after the dripping is finished, the reaction solution is subjected to sampling, central control and detection after heat preservation at 43 ℃ for 1.0 h;
3) The qualitative content of 2, 6-difluorobenzonitrile in the reaction liquid is 0.02 percent, and the qualitative content of 2, 6-difluorobenzoic acid in the reaction liquid is 0.38 percent; cooling to 5 ℃, preserving heat for 1.0h, and filtering to obtain a crude product of the 2, 6-difluorobenzamide;
4) 150.00g of water is added into the crude product, the mixture is pulped for 1.0h at the temperature of 5 ℃, 108.20g of white 2, 6-difluorobenzamide product is obtained after filtration and drying, the purity is 99.15%, the quantitative content of 2, 6-difluorobenzonitrile is 0.02%, and the yield is 96.91%.
Comparative example 1
Referring to patent CN112851539B, a preparation process of 2, 6-difluorobenzamide comprises the following specific steps:
into the reaction flask, 100.00g of 2, 6-difluorobenzonitrile (0.705 mol) and 375.75g of 10% sodium hydroxide solution (1.409 mol) were successively introduced, and the temperature was raised to 48 ℃; 348.52g of 27.5% hydrogen peroxide (2.818 mol) is added dropwise for 6.0h; after the dripping is finished, continuing to keep the temperature for 2.0 hours, sampling and detecting the mixture in a central control way, wherein the qualitative content of the 2, 6-difluorobenzonitrile in the reaction liquid is 3.32 percent, and the qualitative content of the 2, 6-difluorobenzoic acid is about 26.70 percent; cooling to 25 ℃, adding 31% hydrochloric acid dropwise to adjust the pH of the system to 6-8, filtering, leaching with 50.00g of water, and drying a filter cake to obtain about 88.00g of pale yellow 2, 6-difluorobenzamide product, wherein the purity is about 97%, the quantitative content of 2, 6-difluorobenzonitrile is about 1%, and the yield is about 77.11%.
FIG. 2 is a liquid chromatograph of the reaction liquid of comparative example 1 for the control detection, and the qualitative content of each substance in the reaction liquid of the present invention can be obtained from FIG. 2, and the specific results are shown in Table 2.
TABLE 2
| Material name | 2, 6-difluorobenzamide | 2, 6-Difluorobenzoic acid | 2, 6-difluorobenzonitrile |
| Retention time | 4.112min | 9.317min | 18.608min |
| Qualitative content of liquid chromatograph | 69.98％ | 26.70％ | 3.32％ |
Comparative example 2
In comparison with example 1, the preparation process of 2, 6-difluorobenzamide, which is prepared without adding a phase transfer catalyst, comprises the following specific steps:
into a reaction flask, 100.00g of 2, 6-difluorobenzonitrile (0.705 mol), 100.00g of water were successively introduced, and the temperature was raised to 43 ℃;
200.40g of 27.5% hydrogen peroxide (1.620 mol) and 56.36g of 5% sodium hydroxide solution (0.070 mol) are added dropwise for about 5.0h, and the pH value of the reaction solution is 10-12 in the dropping process; after the dripping is finished, continuing to keep the temperature for 4.0 hours, sampling and detecting in a central control manner, wherein the qualitative content of the 2, 6-difluorobenzonitrile in the reaction liquid is 0.73% and the qualitative content of the 2, 6-difluorobenzoic acid in the reaction liquid is 0.44%;
cooling to 5 ℃, preserving heat for 1.0h, and filtering to obtain a crude product of the 2, 6-difluorobenzamide; 150.00g of water is added into the crude product, the mixture is pulped for 1.0h at the temperature of 5 ℃, 107.20g of white 2, 6-difluorobenzamide product is obtained after filtration and drying, the purity is 98.50%, the quantitative content of 2, 6-difluorobenzonitrile is 0.35%, and the yield is 95.39%.
FIG. 3 is a liquid chromatograph of the control detection in the reaction liquid of comparative example 2, and the qualitative content of each substance in the reaction liquid of the present invention can be obtained from FIG. 3, and the specific results are shown in Table 3.
When no phase transfer catalyst is added, inorganic alkali solution and hydrogen peroxide are added dropwise to half, the system gradually separates out 2, 6-difluorobenzamide solid, part of 2, 6-difluorobenzonitrile is wrapped in the solid separation process, the part of 2, 6-difluorobenzonitrile cannot continuously participate in the reaction in the subsequent process, the qualitative content of 2, 6-difluorobenzonitrile is 0.5-1.0% in the process of reaction central control detection, the quantitative content of 2, 6-difluorobenzonitrile in the 2, 6-difluorobenzobenzamide crude product is 0.3-0.5% after filtration, the purity of the 2, 6-difluorobenzobenzamide product is low, and the raw material conversion rate is low.
TABLE 3 Table 3
| Material name | 2, 6-difluorobenzamide | 2, 6-Difluorobenzoic acid | 2, 6-difluorobenzonitrile |
| Retention time | 4.736min | 9.832min | 19.659min |
| Qualitative content of liquid chromatograph | 98.83％ | 0.44％ | 0.73％ |
Comparative example 3
Compared with the embodiment 1, only hydrogen peroxide is added dropwise, and the preparation process of the 2, 6-difluorobenzamide comprises the following specific steps:
into a reaction flask, 100.00g of 2, 6-difluorobenzonitrile (0.705 mol), 1.00g of tetrabutylammonium bromide, 100.00g of water, 56.36g of 5% sodium hydroxide solution (0.070 mol) were successively introduced, and the temperature was raised to 44 ℃;
200.40g of 27.5% hydrogen peroxide (1.620 mol) is added dropwise for about 5.0h, and the pH value of the reaction solution is 10-12 in the dropping process; after the dripping is finished, continuing to keep the temperature for 1.0h, sampling and detecting the mixture in a central control way, wherein the qualitative content of the 2, 6-difluorobenzonitrile in the reaction liquid is 0.14% and the qualitative content of the 2, 6-difluorobenzoic acid is 3.54%;
cooling to 5 ℃, preserving heat for 1.0h, and filtering to obtain a crude product of the 2, 6-difluorobenzamide; 150.00g of water is added into the crude product, the mixture is pulped for 1.0h at the temperature of 5 ℃, 102.70g of white 2, 6-difluorobenzamide product is obtained after filtration and drying, the purity is 99.05%, the quantitative content of 2, 6-difluorobenzonitrile is 0.05%, and the yield is 91.90%.
FIG. 4 is a liquid chromatograph of the control detection in the reaction liquid of comparative example 3, and the qualitative content of each substance in the reaction liquid of the present invention can be obtained from FIG. 4, and the specific results are shown in Table 4.
TABLE 4 Table 4
| Material name | 2, 6-difluorobenzamide | 2, 6-difluorobenzeneFormic acid | 2, 6-difluorobenzonitrile |
| Retention time | 4.127min | 8.394min | 18.618min |
| Qualitative content of liquid chromatograph | 96.32％ | 3.54％ | 0.14％ |
In the comparative example 3, inorganic base is firstly added into the raw materials, then hydrogen peroxide is added dropwise, the pH of the reaction solution gradually decreases from 13 to 9 in the dropwise adding process, the alkaline environment of the reaction system is different, and the final yield is lower.
Comparative example 4
Compared with the example 1, the preparation process of the 2, 6-difluorobenzamide comprises the following specific steps of:
into a reaction flask, 100.00g of 2, 6-difluorobenzonitrile (0.705 mol), 1.00g of tetrabutylammonium bromide, 100.00g of water were successively introduced, and the temperature was raised to 44 ℃;
simultaneously, 200.40g of 27.5% hydrogen peroxide (1.620 mol) and 56.36g of 5% sodium hydroxide solution (0.070 mol) are added dropwise for about 5.0h, and the pH value of the reaction solution is 10-12 in the dropping process; after the dripping is finished, continuing to keep the temperature for 1.0h, sampling and performing central control detection, wherein the qualitative content of the 2, 6-difluorobenzonitrile in the reaction liquid is 0.04% and the qualitative content of the 2, 6-difluorobenzoic acid in the central control detection reaction liquid is 0.34%;
cooling to 5 ℃, neutralizing with hydrochloric acid until the pH is 6-8, preserving heat for 1.0h, and filtering to obtain a 2, 6-difluorobenzamide crude product; 150.00g of water is added into the crude product, the mixture is pulped for 1.0h at the temperature of 5 ℃, the mixture is filtered and dried to obtain 108.15g of pale yellow 2, 6-difluorobenzamide product, the purity is 98.50%, the quantitative content of 2, 6-difluorobenzonitrile is 0.02%, and the yield is 96.23%.
Comparative example 5
Compared with the example 1, PEG-600 is used for replacing quaternary ammonium salt catalyst, the reaction is finished, the temperature reduction 2, 6-difluorobenzamide product is not separated out, and the preparation process of the 2, 6-difluorobenzamide comprises the following specific steps:
into a reaction flask, 100.00g of 2, 6-difluorobenzonitrile (0.705 mol), 1.00g of PEG-600, 100.00g of water were successively introduced, and the temperature was raised to 43 ℃;
simultaneously, 200.40g of 27.5% hydrogen peroxide (1.620 mol) and 56.36g of 5% sodium hydroxide solution (0.070 mol) are added dropwise for about 5.0h, and the pH value of the reaction solution is 10-12 in the dropping process; after the dripping is finished, continuing to keep the temperature for 1.0h, sampling and performing central control detection, wherein the qualitative content of the 2, 6-difluorobenzonitrile in the reaction liquid is 0.05% and the qualitative content of the 2, 6-difluorobenzoic acid in the central control detection reaction liquid is 0.38%;
cooling to 5 ℃, adding sodium chloride, precipitating solid, preserving heat for 1.0h, and filtering to obtain a 2, 6-difluorobenzamide crude product; 150.00g of water is added into the crude product, the mixture is pulped for 1.0h at the temperature of 5 ℃, 109.55g of white 2, 6-difluorobenzamide product is obtained after filtration and drying, the purity is 97.50%, the quantitative content of 2, 6-difluorobenzonitrile is 0.03%, and the yield is 96.49%.
As can be seen from the comparison of comparative example 5 and the inventive examples, when other types of phase transfer catalysts are added and the temperature is reduced to 5 ℃ after the reaction is finished, 2, 6-difluorobenzamide solid is not precipitated, a large amount of inorganic salt is required to be added to precipitate 2, 6-difluorobenzamide solid from water, the purity of the 2, 6-difluorobenzamide product is reduced, and the purity is about 97.5%.
Comparative example 6
Patent CN112851539B, adding a quaternary ammonium salt catalyst, a preparation process of 2, 6-difluorobenzamide, comprises the following specific steps:
into a reaction flask, 100.00g of 2, 6-difluorobenzonitrile (0.705 mol), 1.00g of tetrabutylammonium bromide and 375.75g of 10% sodium hydroxide solution (1.409 mol) were successively introduced, and the temperature was raised to 48 ℃; 348.52g of 27.5% hydrogen peroxide (2.818 mol) is added dropwise for 6.0h; after the dripping is finished, continuing to keep the temperature for 2.0 hours, sampling and detecting the mixture in a central control way, wherein the qualitative content of the 2, 6-difluorobenzonitrile in the reaction liquid is 0.45 percent, and the qualitative content of the 2, 6-difluorobenzoic acid is about 26.70 percent; cooling to 25 ℃, adding 31% hydrochloric acid dropwise to adjust the pH of the system to 6-8, filtering, leaching with 50.00g of water, and drying a filter cake to obtain about 93.20g of pale yellow 2, 6-difluorobenzamide product, wherein the purity is about 98.12%, the quantitative content of 2, 6-difluorobenzonitrile is about 0.25%, and the yield is about 82.51%.
Claims (8)
1. A preparation process of high-purity 2, 6-difluorobenzamide comprises the following steps:
1) 2, 6-difluorobenzonitrile is taken as a raw material, water and a quaternary ammonium salt phase transfer catalyst are added into the raw material, a mixed solution is obtained after uniform mixing, and then the mixed solution is heated to a reaction temperature which is 35-45 ℃;
2) Simultaneously dripping hydrogen peroxide and inorganic alkali solution into the mixed solution at a constant speed, controlling the beginning time and the ending time of the dripping of the hydrogen peroxide and the inorganic alkali to be the same, keeping the temperature between 35 and 45 ℃ for reaction after the dripping is ended, detecting the content of 2, 6-difluorobenzonitrile in the reaction solution in the reaction process, and ending the reaction when the qualitative content of the 2, 6-difluorobenzonitrile in the liquid chromatograph is less than 0.05 percent;
the mol ratio of the inorganic base to the 2, 6-difluorobenzonitrile is 0.05-0.15,
the molar ratio of the hydrogen peroxide to the 2, 6-difluorobenzonitrile is 2.0-3.0;
3) After the reaction is finished, cooling, crystallizing and filtering the reaction liquid to obtain a crude product of the 2, 6-difluorobenzamide;
4) And adding water into the obtained crude 2, 6-difluorobenzamide to pulp, and then filtering and drying to obtain a 2, 6-difluorobenzamide product.
2. The process according to claim 1, wherein in step 1), the weight ratio of water to 2, 6-difluorobenzonitrile is 0.5 to 1.5:1.
3. The process of claim 1, wherein the quaternary ammonium salt phase transfer catalyst is one or more of tetrabutylammonium chloride, tetrabutylammonium bromide, or benzyltriethylammonium chloride.
4. The process according to claim 1 or 3, wherein the quaternary ammonium salt phase transfer catalyst is added in an amount of 0.5 to 1.5% by weight based on the weight of 2, 6-difluorobenzonitrile.
5. The preparation process according to claim 1, wherein the inorganic alkaline solution is one of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, and the concentration of the inorganic alkaline solution is 2-32 wt%.
6. The preparation process according to claim 1, wherein the concentration of hydrogen peroxide is 25-50 wt%.
7. The process according to claim 1, wherein in step 2), the dropping time is 3.0 to 5.0 hours.
8. The preparation process according to claim 1, wherein in step 4), the filtered filtrate is added as water in step 1) to the raw material for recycling.
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