CN115141097A - Intermediate 4-bromine of Freund Lei Lana-2-methylbenzoic acid's production line system - Google Patents
Intermediate 4-bromine of Freund Lei Lana-2-methylbenzoic acid's production line system Download PDFInfo
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- CN115141097A CN115141097A CN202210742159.5A CN202210742159A CN115141097A CN 115141097 A CN115141097 A CN 115141097A CN 202210742159 A CN202210742159 A CN 202210742159A CN 115141097 A CN115141097 A CN 115141097A
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 22
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 title 1
- 229910052794 bromium Inorganic materials 0.000 title 1
- 238000006170 formylation reaction Methods 0.000 claims abstract description 69
- 150000002923 oximes Chemical class 0.000 claims abstract description 69
- 238000003860 storage Methods 0.000 claims abstract description 59
- 239000007788 liquid Substances 0.000 claims abstract description 55
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 54
- JJYPMNFTHPTTDI-UHFFFAOYSA-N 3-methylaniline Chemical compound CC1=CC=CC(N)=C1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 claims abstract description 52
- 238000002425 crystallisation Methods 0.000 claims abstract description 50
- 230000008025 crystallization Effects 0.000 claims abstract description 50
- 230000022244 formylation Effects 0.000 claims abstract description 39
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 39
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 36
- 238000005893 bromination reaction Methods 0.000 claims abstract description 32
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 24
- 239000003513 alkali Substances 0.000 claims abstract description 21
- RVCJOGNLYVNRDN-UHFFFAOYSA-N 4-bromo-2-methylbenzoic acid Chemical compound CC1=CC(Br)=CC=C1C(O)=O RVCJOGNLYVNRDN-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000005457 ice water Substances 0.000 claims abstract description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 13
- 238000005755 formation reaction Methods 0.000 claims abstract description 11
- 239000002699 waste material Substances 0.000 claims abstract description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 106
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 83
- 238000006243 chemical reaction Methods 0.000 claims description 55
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 53
- 235000019253 formic acid Nutrition 0.000 claims description 53
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 49
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 48
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 46
- 238000001035 drying Methods 0.000 claims description 45
- 239000000243 solution Substances 0.000 claims description 45
- 239000011343 solid material Substances 0.000 claims description 39
- 239000002904 solvent Substances 0.000 claims description 28
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 24
- 235000010288 sodium nitrite Nutrition 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 24
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 23
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- 239000000463 material Substances 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- 239000000047 product Substances 0.000 claims description 18
- RGHJWZADAWEIFE-UHFFFAOYSA-N 4-amino-2-methylbenzonitrile Chemical compound CC1=CC(N)=CC=C1C#N RGHJWZADAWEIFE-UHFFFAOYSA-N 0.000 claims description 17
- 238000001914 filtration Methods 0.000 claims description 16
- 238000010438 heat treatment Methods 0.000 claims description 16
- 238000001816 cooling Methods 0.000 claims description 15
- 239000012065 filter cake Substances 0.000 claims description 15
- 239000000543 intermediate Substances 0.000 claims description 15
- 238000005406 washing Methods 0.000 claims description 15
- 230000018044 dehydration Effects 0.000 claims description 14
- 239000002994 raw material Substances 0.000 claims description 14
- XRSQZFJLEPBPOZ-UHFFFAOYSA-N 4-amino-2-methylbenzoic acid Chemical compound CC1=CC(N)=CC=C1C(O)=O XRSQZFJLEPBPOZ-UHFFFAOYSA-N 0.000 claims description 13
- ZBHHWKBPSJWDBX-UHFFFAOYSA-N 4-amino-2-methylbenzaldehyde Chemical compound CC1=CC(N)=CC=C1C=O ZBHHWKBPSJWDBX-UHFFFAOYSA-N 0.000 claims description 12
- 230000007062 hydrolysis Effects 0.000 claims description 12
- 230000031709 bromination Effects 0.000 claims description 11
- 238000007599 discharging Methods 0.000 claims description 10
- 239000011229 interlayer Substances 0.000 claims description 10
- 239000012295 chemical reaction liquid Substances 0.000 claims description 9
- 239000002351 wastewater Substances 0.000 claims description 9
- 239000004280 Sodium formate Substances 0.000 claims description 8
- 230000006837 decompression Effects 0.000 claims description 8
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 8
- 235000019254 sodium formate Nutrition 0.000 claims description 8
- 238000007605 air drying Methods 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 239000000498 cooling water Substances 0.000 claims description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- 238000010494 dissociation reaction Methods 0.000 claims description 3
- 230000005593 dissociations Effects 0.000 claims description 3
- 238000011084 recovery Methods 0.000 claims description 3
- 238000004064 recycling Methods 0.000 claims description 3
- 239000010887 waste solvent Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 description 22
- 231100000331 toxic Toxicity 0.000 description 5
- 230000002588 toxic effect Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- FXWFZIRWWNPPOV-UHFFFAOYSA-N 2-aminobenzaldehyde Chemical compound NC1=CC=CC=C1C=O FXWFZIRWWNPPOV-UHFFFAOYSA-N 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 241000880922 Freyana Species 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 210000000653 nervous system Anatomy 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- IFKWLKCPUIQXPU-UHFFFAOYSA-N (4-bromo-2-methylphenyl)methanol Chemical compound CC1=CC(Br)=CC=C1CO IFKWLKCPUIQXPU-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QOGHRLGTXVMRLM-UHFFFAOYSA-N 4-bromo-1,2-dimethylbenzene Chemical group CC1=CC=C(Br)C=C1C QOGHRLGTXVMRLM-UHFFFAOYSA-N 0.000 description 1
- LPEBMDFRIKYFCF-UHFFFAOYSA-N 4-bromo-2-methylbenzonitrile Chemical compound CC1=CC(Br)=CC=C1C#N LPEBMDFRIKYFCF-UHFFFAOYSA-N 0.000 description 1
- 108010062745 Chloride Channels Proteins 0.000 description 1
- 102000011045 Chloride Channels Human genes 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 102000005915 GABA Receptors Human genes 0.000 description 1
- 108010005551 GABA Receptors Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 241001674048 Phthiraptera Species 0.000 description 1
- 230000000895 acaricidal effect Effects 0.000 description 1
- 239000000642 acaricide Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- -1 chlorine ions Chemical class 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000002826 coolant Substances 0.000 description 1
- DFBKLUNHFCTMDC-PICURKEMSA-N dieldrin Chemical compound C([C@H]1[C@H]2[C@@]3(Cl)C(Cl)=C([C@]([C@H]22)(Cl)C3(Cl)Cl)Cl)[C@H]2[C@@H]2[C@H]1O2 DFBKLUNHFCTMDC-PICURKEMSA-N 0.000 description 1
- 229950006824 dieldrin Drugs 0.000 description 1
- NGPMUTDCEIKKFM-UHFFFAOYSA-N dieldrin Natural products CC1=C(Cl)C2(Cl)C3C4CC(C5OC45)C3C1(Cl)C2(Cl)Cl NGPMUTDCEIKKFM-UHFFFAOYSA-N 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 235000019233 fast yellow AB Nutrition 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- MLBZKOGAMRTSKP-UHFFFAOYSA-N fluralaner Chemical compound C1=C(C(=O)NCC(=O)NCC(F)(F)F)C(C)=CC(C=2CC(ON=2)(C=2C=C(Cl)C=C(Cl)C=2)C(F)(F)F)=C1 MLBZKOGAMRTSKP-UHFFFAOYSA-N 0.000 description 1
- 229960004498 fluralaner Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 125000003971 isoxazolinyl group Chemical group 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229940127554 medical product Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 238000005648 named reaction Methods 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/02—Formation of carboxyl groups in compounds containing amino groups, e.g. by oxidation of amino alcohols
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/08—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reaction of hydroxylamines with carbonyl compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
Abstract
The invention provides a production system of a Fr Lei Lana intermediate 4-bromo-2-methylbenzoic acid, which comprises a formylation reaction kettle, an oxime formation reaction kettle, a dehydration reaction kettle, a hydrolysis reaction kettle and a bromination reaction kettle, wherein a nitrogen pipeline, a reaction solvent adding pipeline, a phosphorus oxychloride adding pipeline and a 3-methylaniline adding pipeline are arranged on the formylation reaction kettle, the reaction solvent adding pipeline, the phosphorus oxychloride adding pipeline and the 3-methylaniline adding pipeline are respectively connected with a reaction solvent metering tank, a phosphorus oxychloride metering tank and a 3-methylaniline metering tank, a liquid discharge pipe is arranged at the bottom of the formylation reaction kettle and connected with the formylation crystallization kettle, a pH meter is arranged in the formylation crystallization kettle, an alkali liquid adding pipeline and an ice water centrifuge adding pipeline are arranged at the top of the formylation crystallization kettle, the alkali liquid adding pipeline and the ice water adding pipeline are respectively connected with the alkali liquid metering tank and the ice water metering tank, a liquid discharge pipe is arranged at the bottom of the formylation kettle and connected with a waste liquid storage tank.
Description
Technical Field
The invention belongs to the field of medicine production, and particularly relates to a production system of a Freund Lei Lana intermediate 4-bromo-2-methylbenzoic acid.
Background
Freyn Lei Lana Fluralaner is an isoxazoline insecticide and acaricide, and chlorine ions cannot penetrate into a postsynaptic membrane by antagonizing a gamma-aminobutyric acid receptor and a glutamic acid receptor gated chloride ion channel, so that transmembrane signal transmission of a nervous system is interfered, and the insect nervous system is disturbed and then dies. The fluorine Lei Lana has no cross-resistance with dieldrin, and is the earliest and only one veterinary medical product capable of quickly and effectively killing lice and fleas.
4-bromo-2-methylbenzoic acid is used as an important intermediate of Freyana Lei Lana, and plays an important role in cost and quality control in the production process of Freyana medicaments. The synthesis methods of 4-bromo-2-methylbenzoic acid reported in the literature at present mainly comprise the following methods.
Patent WO2017034994 reports synthesis using (4-bromo-2-methylphenyl) methanol as a raw material, and the method is not easy to obtain the raw material, expensive and not beneficial to industrialization.
Patent CN112441907 reports that 4-bromo-1,2-xylene is used as a raw material, and a target product is synthesized by oxidation under the catalysis of noble metal. The process has the advantages of easily obtained raw materials, poor selectivity, low yield, main product yield of only 43 percent, generation of various byproducts in the oxidation process, difficult separation, difficult industrialization and high cost.
The preparation of the target product from 4-bromo-2-methylbenzonitrile was reported by Chiarelli et al in 2018. This protocol is simple to operate, however the cyanide used is toxic, expensive and not readily available.
Therefore, a new synthetic route is designed, raw materials are cheap and easy to obtain, a noble metal catalyst is not used, the use of highly toxic cyanide is avoided, the whole production process is simple and convenient to operate, and industrialization is facilitated. We have therefore also devised a new production system.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a production system of a Freund Lei Lana intermediate 4-bromo-2-methylbenzoic acid, which is simple and convenient to operate and beneficial to industrialization.
In order to realize the purpose, the invention is realized by the following technical scheme: a production system of a Fr Lei Lana intermediate 4-bromo-2-methylbenzoic acid is characterized in that:
the device comprises a formylation reaction kettle, an oxime formation reaction kettle, a dehydration reaction kettle, a hydrolysis reaction kettle and a bromination reaction kettle, wherein a nitrogen pipeline, a reaction solvent adding pipeline, a phosphorus oxychloride adding pipeline and a 3-methylaniline adding pipeline are arranged on the formylation reaction kettle, the reaction solvent adding pipeline, the phosphorus oxychloride adding pipeline and the 3-methylaniline adding pipeline are respectively connected with a reaction solvent metering tank, a phosphorus oxychloride metering tank and a 3-methylaniline metering tank, a liquid discharge pipe is arranged at the bottom of the formylation reaction kettle and connected with the formylation crystallization kettle, a pH meter is arranged in the formylation crystallization kettle, an alkali liquid adding pipeline and an ice water adding pipeline are arranged at the top of the formylation crystallization kettle, the alkali liquid adding pipeline and the ice water adding pipeline are respectively connected with the alkali liquid metering tank and the ice water metering tank, a liquid discharge pipe is arranged at the bottom of the formylation kettle and connected with a centrifuge, and a liquid outlet pipe of the centrifuge is connected with a waste liquid storage tank;
the top of the oxime forming reaction kettle is provided with a solid material feeding port and a solvent feeding pipeline, the solid material feeding port is used for adding hydroxylamine hydrochloride and 2-methyl-4-aminobenzaldehyde, the solvent feeding pipeline is connected with a solvent metering tank, the oxime forming reaction kettle is also provided with a return pipe communicated with the oxime forming reaction kettle, the bottom of the oxime forming reaction kettle is provided with a liquid discharge pipe connected with an oxime forming crystallization kettle, the bottom of the oxime forming crystallization kettle is provided with a liquid discharge pipe connected with an oxime forming centrifugal machine, the liquid discharge pipe of the oxime forming centrifugal machine is connected with a waste solvent storage tank, and the material of the oxime forming centrifugal machine is sent to a blast drying box for drying;
the top of the dehydration reaction kettle is provided with a solid material feeding port and a formic acid feeding pipeline, the solid material feeding port is used for feeding a product obtained by forming oxime and sodium formate, the formic acid feeding pipeline is connected with a formic acid metering tank, the bottom of the dehydration reaction kettle is provided with a liquid discharge pipe connected with a reduced pressure concentration kettle, a steam outlet pipeline of the reduced pressure concentration kettle is connected with a formic acid condenser, the formic acid condenser is connected with a formic acid recovery storage tank, the formic acid concentration kettle is also provided with a water feeding pipeline connected with a first water metering tank, the kettle bottom of the formic acid concentration kettle is provided with a liquid discharge pipe connected with a dehydration centrifuge, a liquid outlet pipe of the dehydration centrifuge is connected with a wastewater storage tank, and the material of the dehydration centrifuge is sent to a blast drying box for drying;
the top of the hydrolysis reaction kettle is provided with a solid material feeding port and a water feeding pipeline, the solid material feeding port is used for adding 2-methyl-4-aminobenzonitrile and sodium hydroxide, the water feeding pipeline is connected with a second water metering tank, the hydrolysis reaction kettle is also provided with a hydrochloric acid feeding pipeline connected with a hydrochloric acid metering tank, the hydrolysis reaction kettle is also provided with a return pipe communicated with the hydrolysis reaction kettle, the bottom of the hydrolysis reaction kettle is provided with a liquid discharge pipe connected with a hydrolysis reactor, the liquid discharge pipe of the hydrolysis centrifuge is connected with a wastewater storage tank, and the material of the hydrolysis centrifuge is sent to a blast drying box for drying;
the top of the bromination reaction kettle is provided with a solid material adding port, a hydrobromic acid adding pipeline, a water adding pipeline, a sodium nitrite solution adding pipeline and a copper bromide solution adding pipeline, the solid material adding pipeline is used for adding 2-methyl-4-aminobenzoic acid, the hydrobromic acid adding pipeline, the water adding pipeline, the sodium nitrite solution adding pipeline and the copper bromide solution adding pipeline are respectively connected with a hydrobromic acid metering tank, a third water metering tank, a sodium nitrite solution metering tank and a copper bromide solution metering tank, the kettle bottom of the bromination reaction kettle is provided with a liquid discharge pipe connected with a bromination centrifuge, a liquid discharge pipe of the bromination centrifuge is connected with a wastewater storage tank, and the solid material is sent to a blast drying box for drying;
interlayers are arranged outside the formylation reaction kettle, the formylation crystallization kettle, the oxime-forming reaction kettle, the oxime-forming crystallization kettle, the dehydration reaction kettle, the hydrolysis reaction kettle, the bromination reaction kettle and the decompression concentration kettle, a medium adding pipeline is arranged at the bottom of each interlayer, and a medium discharging pipeline is arranged at the top of each interlayer; the formylation reaction kettle, the formylation crystallization kettle, the oxime formation reaction kettle, the oxime formation crystallization kettle, the dehydration reaction kettle, the hydrolysis reaction kettle, the bromination reaction kettle and the decompression concentration kettle are all internally provided with stirring.
In the scheme, the method comprises the following steps: reaction solvent metering tank, phosphorus oxychloride metering tank, 3-methylaniline metering tank, alkali lye metering tank, solvent metering tank, formic acid metering tank, hydrochloric acid metering tank, hydrobromic acid metering tank, sodium nitrite solution metering tank, frozen water metering tank and copper bromide solution metering tank link to each other with reaction solvent storage tank, phosphorus oxychloride storage tank, 3-methylaniline storage tank, alkali lye storage tank, solvent storage tank, formic acid storage tank, hydrochloric acid storage tank, hydrobromic acid storage tank, sodium nitrite solution storage tank, frozen water storage tank and copper bromide solution storage tank respectively, first water metering tank, second water metering tank, third water metering tank link to each other with the feed pipe respectively.
The reaction process of the invention is as follows: the method comprises the following steps of taking 3-methylaniline as a raw material, firstly formylating the 3-methylaniline with phosphorus oxychloride to generate 2-methyl-4-aminobenzaldehyde, then reacting with hydroxylamine hydrochloride to generate oxime, dehydrating the oxime to obtain 2-methyl-4-aminobenzonitrile, then hydrolyzing the 2-methyl-4-aminobenzonitrile with sodium hydroxide to obtain 2-methyl-4-aminobenzoic acid, and finally carrying out Sandmeyer bromination reaction to obtain 4-bromo-2-methylbenzoic acid, wherein the reaction formula is as follows:
in the scheme, the method comprises the following steps: the operation of formylation production is:
opening a nitrogen pipeline of a formylation reaction kettle, adding nitrogen to replace air in the kettle, introducing nitrogen for protection all the time, adding a reaction solvent DMF (dimethyl formamide) into the formylation reaction kettle through a reaction solvent metering tank, introducing cooling water into an interlayer, controlling the temperature to be 0-5 ℃, adding phosphorus oxychloride into the system in batches through a phosphorus oxychloride metering tank, continuously stirring and reacting at the temperature of 0-5 ℃ for 1h, adding 3-methylaniline into the formylation reaction kettle in batches at the temperature of 0-5 ℃, heating to 60-65 ℃ after the addition, reacting for 5-6h, detecting until raw materials disappear, cooling to room temperature, discharging a reaction liquid into the formylation crystallization kettle for crystallization, continuously using the formylation reaction kettle for formylation reaction, adding ice water into the formylation crystallization kettle through an ice water metering tank, controlling the temperature to be 0-5 ℃ when the reaction liquid is discharged into the formylation crystallization kettle, adding a sodium hydroxide solution into the alkali liquor metering tank to adjust the pH to be 8-9, then filtering a filter cake, washing with water, and drying to obtain yellow solid 2-methyl-4-aminobenzaldehyde.
The temperature is controlled to be 0-5 ℃ for reaction, phosphorus oxychloride is selectively added into the system in batches, the generation of side reactions is reduced, the selective reaction is carried out at the para position of amino, DMF is selected as a solvent, on one hand, the temperature requirement of the reaction can be met, on the other hand, DMF can be mutually soluble with water, the product is insoluble in water and soluble in DMF, the product can be washed out by directly adding water into DMF during subsequent treatment, the crystallization and filtration of the product can be realized, the operation is simple, and the method is suitable for industrial production. The yield of the step can reach more than 87 percent, and the purity of the product is 99.5 percent. The method does not need complex special equipment, and has low production cost.
In the scheme, the method comprises the following steps: the reaction steps of the 2-methyl-4-aminobenzaldehyde and the hydroxylamine hydrochloride are as follows:
adding 2-methyl-4-aminobenzaldehyde and hydroxylamine hydrochloride through a solid material adding port of an oxime forming reaction kettle, then adding solvent ethanol through a solvent metering tank, heating and refluxing for 3-4h after the material addition is finished, completely reacting, opening a liquid discharge pipe to discharge reaction liquid into an oxime forming crystallization kettle, continuously reacting the next batch of materials in the oxime forming reaction kettle, cooling the materials in the oxime forming crystallization kettle to 0-5 ℃, continuously stirring until the crystallization is complete, filtering by an oxime forming centrifugal machine, washing a filter cake by ethanol, and drying by an air drying box to obtain oxime. The reaction is carried out at 0-5 ℃ to reduce side reactions, and similarly, ethanol is selected as a solvent, the ethanol is mutually soluble with water, and the product and the raw material are dissolved in the ethanol but are insoluble in the water, so that the crystallization of the product can be realized by directly adding water into the reaction solution in the following process, the operation is simpler, the product is crystallized without distilling to remove the solvent, the yield is high and can reach more than 95%, and the purity is 99.8%.
In the scheme, the method comprises the following steps: the steps for obtaining the 2-methyl-4-aminobenzonitrile by oxime dehydration are as follows:
adding the obtained oxime and sodium formate through a solid material inlet on a dehydration reaction kettle, adding formic acid into the dehydration reaction kettle through a formic acid metering tank, heating to 100 ℃ for reaction for 3-4h, cooling to room temperature after the reaction is finished, discharging into a liquid discharge pipe, carrying out reduced pressure concentration to remove formic acid, collecting the formic acid condensed by a formic acid condenser into a formic acid storage tank for recycling, adding water into the formic acid concentration kettle through a first water metering tank, continuously stirring for crystallization, filtering by a dehydration centrifugal machine, washing a filter cake, and drying by an air-blast drying oven to obtain the 2-methyl-4-aminobenzonitrile. The reaction yield can reach more than 93 percent and the product purity can reach 99.8 percent through the setting of conditions in the step.
In the scheme, the method comprises the following steps: the step of hydrolyzing the 2-methyl-4-aminobenzonitrile to obtain the 2-methyl-4-aminobenzoic acid comprises the following steps:
adding 2-methyl-4-aminobenzonitrile and sodium hydroxide through a solid material adding port of a hydrolysis reaction kettle, adding water through a second water metering tank, heating to reflux reaction for 6-8h, cooling to room temperature after the reaction is finished, adding hydrochloric acid through a hydrochloric acid metering tank to adjust the pH value to 3-4, continuously stirring and crystallizing at 0-5 ℃, filtering through a water dissociation heart machine, washing filter cakes with water, and drying through a forced air drying oven to obtain 2-methyl-4-aminobenzoic acid. By strictly controlling the conditions, the side reaction is less, the yield of the step can reach 96%, and the purity is 99.3%.
In the above scheme, the sandmeyer bromination reaction is:
adding 2-methyl-4-aminobenzoic acid into a bromination reaction kettle through a solid material inlet, adding hydrobromic acid and water through a hydrobromic acid metering tank and a third water metering tank, stirring to dissolve, cooling to 0-5 ℃, controlling the temperature to be 0-5 ℃, adding a sodium nitrite aqueous solution in batches through a sodium nitrite solution metering tank, continuously stirring for about 1h after the addition is finished, controlling the temperature to be 0-5 ℃, adding a copper bromide aqueous solution in batches through a copper bromide solution metering tank, heating to room temperature, stirring until the reaction is complete, filtering by a bromination centrifugal machine, washing a filter cake with water, and drying by a forced air drying oven to obtain a product. The method is a classical name reaction, the yield is up to 88 percent and the purity of the final product is more than 99.5 percent by controlling conditions
Has the advantages that:
1) The raw material used in the invention is 3-methylaniline which is easily available and has the price of about 10 yuan per kilogram, and the cost is low. Phosphorus oxychloride, hydroxylamine hydrochloride, sodium formate, sodium hydroxide, sodium nitrite, copper bromide and the like used in the reaction process are conventional reagents, and have the advantages of low cost, easiness in obtaining and small toxic and side effects.
2) In the whole steps of the invention, the used solvents are ethanol, DMF, formic acid and a large amount of water, which are conventional solvents, and the invention has the advantages of low cost, small toxic and side effects and convenient treatment.
3) The invention has the advantages that through the elaborate design of the process route, the selected raw materials are cheap and easy to obtain, the toxic and side effects are small, the whole reaction operation is easy, the used equipment only needs a conventional reaction kettle, special equipment and special reagents are not needed, and the industrial production is easy to realize.
4) The method has the advantages of high yield, high purity, high total yield, good product quality and low cost through the careful design of conditions of each step of the reaction route.
Drawings
FIG. 1 is a flow diagram of the formylation process of the present invention.
FIG. 2 is a flow chart of the oxime formation process of the present invention.
FIG. 3 is a flow chart of the dehydration process.
FIG. 4 is a flow diagram of a hydrolysis process.
Fig. 5 is a flow chart of the bromination process.
Detailed Description
The present invention will be further described with reference to the following examples.
The reaction formula of the whole process is as follows:
as shown in fig. 1-5, a production system of a intermediates 4-bromo-2-methylbenzoic acid of furcellaran Lei Lana comprises a formylation reaction kettle 1, an oxime formation reaction kettle 2, a dehydration reaction kettle 3, a hydrolysis reaction kettle 4 and a bromination reaction kettle 5.
The formylation reaction kettle 1 is provided with a nitrogen pipeline 101, a reaction solvent adding pipeline, a phosphorus oxychloride adding pipeline and a 3-methylaniline adding pipeline, the reaction solvent adding pipeline, the phosphorus oxychloride adding pipeline and the 3-methylaniline adding pipeline are respectively connected with a reaction solvent metering tank 102, a phosphorus oxychloride metering tank 103 and a 3-methylaniline metering tank 104 through pumps, and the reaction solvent metering tank 102, the phosphorus oxychloride metering tank 103 and the 3-methylaniline metering tank 104 are respectively connected with a reaction solvent storage tank 105, a phosphorus oxychloride storage tank 106 and a 3-methylaniline storage tank 107 through pipelines.
The bottom of formylation reation kettle 1 is provided with the fluid-discharge tube and links to each other with formylation crystallizer 108, be provided with the pH meter in the formylation crystallizer 108, the top of formylation crystallizer 108 is provided with alkali lye and adds the pipeline and the frozen water adds the pipeline, alkali lye adds the pipeline and the frozen water adds the pipeline and links to each other with alkali lye metering tank 109 and frozen water metering tank 110 through the pump respectively, alkali lye metering tank 109 and frozen water metering tank 110 link to each other with alkali water storage tank 111 and frozen water storage tank 112 respectively, the cauldron bottom of formylation crystallizer 108 is provided with the fluid-discharge tube and links to each other with centrifuge 6, centrifuge 6's drain pipe links to each other with waste liquid storage tank 113. The solid centrifuged by the centrifuge 6 is dried by a vacuum drying oven 8.
The top of the oxime forming reaction kettle 2 is provided with a solid material adding port and a solvent adding pipeline, the solid material adding port is used for adding hydroxylamine hydrochloride and 2-methyl-4-aminobenzaldehyde, the solvent adding pipeline is connected with a solvent metering tank 202 through a pump, the solvent metering tank 202 is connected with a solvent storage tank 203, the oxime forming reaction kettle 2 is further provided with a return pipe 205 (a cooling water interlayer is arranged outside the return pipe and is used for introducing cooling water to cool solvent steam, the cooled solvent flows back to the oxime forming reaction kettle 2) and is communicated with the oxime forming reaction kettle 2, the bottom of the oxime forming reaction kettle 2 is provided with a drain pipe which is connected with an oxime forming crystallization kettle 201, the kettle bottom of the oxime forming crystallization kettle 201 is provided with a drain pipe which is connected with an oxime forming centrifugal machine 7, the drain pipe of the oxime forming centrifugal machine 7 is connected with a waste solvent storage tank 204, and the material of the oxime forming centrifugal machine 7 is blown to a drying box 12 for drying.
The top of dehydration reaction kettle 3 is provided with solid material inlet and formic acid and adds the pipeline, solid material inlet is used for adding into the product and the sodium formate that become oxime and obtain, the formic acid adds the pipeline and links to each other with formic acid metering tank 301 through the pump, formic acid metering tank 301 links to each other with formic acid storage tank 302, the bottom of dehydration reaction kettle 3 is provided with the fluid-discharge tube and links to each other with concentrated cauldron 303 of decompression, the steam outlet pipeline of concentrated cauldron 303 of decompression links to each other with formic acid condenser 304, formic acid condenser 304 links to each other with formic acid recovery storage tank 305, still be provided with water on the concentrated cauldron 304 of formic acid and add the pipeline, this water is added the pipeline and is linked to each other with first water metering tank 306, first water metering tank links to each other with the water pipe. The kettle bottom of the formic acid concentration kettle 304 is provided with a liquid discharge pipe connected with a dewatering centrifuge 9, a liquid discharge pipe of the dewatering centrifuge 9 is connected with a waste water storage tank 307, and the materials of the dewatering centrifuge 9 are sent to a blast drying box 12 for drying.
The top of hydrolysis reaction kettle 4 is provided with a solid material inlet and a water inlet pipeline, the solid material inlet is used for adding 2-methyl-4-aminobenzonitrile and sodium hydroxide, the water inlet pipeline is connected with second water metering tank 401 through a pump, and second water metering tank 401 is connected with a tap water pipe. The hydrolysis reaction kettle 4 is further provided with a hydrochloric acid adding pipeline connected with a hydrochloric acid metering tank 402, the hydrochloric acid adding pipeline is connected with the hydrochloric acid metering tank 402 through a pump, the hydrochloric acid metering tank 402 is connected with a hydrochloric acid storage tank 403, the hydrochloric acid storage tank 403 is used for preparing hydrochloric acid solution and storing hydrochloric acid solution, the hydrolysis reaction kettle 4 is further provided with a return pipe communicated with the hydrolysis reaction kettle 4, the bottom of the hydrolysis reaction kettle 4 is provided with a liquid discharge pipe connected with the hydrolysis reactor 10, the liquid discharge pipe of the hydrolysis reactor 10 is connected with a wastewater storage tank 307, and materials of the hydrolysis reactor 10 are conveyed to the blast drying box 12 for drying.
The top of bromination reation kettle 5 is provided with solid material and adds the mouth, hydrobromic acid adds the pipeline, water adds the pipeline, sodium nitrite solution adds the pipeline, copper bromide solution adds the pipeline, solid material adds the pipeline and is used for adding 2-methyl-4-aminobenzoic acid, hydrobromic acid adds the pipeline, water adds the pipeline, sodium nitrite solution adds the pipeline, copper bromide solution adds the pipeline and is connected hydrobromic acid metering tank 501, third water metering tank 502, sodium nitrite solution metering tank 503 and copper bromide solution metering tank 504 through the pump respectively, third water metering tank 502 links to each other with the water pipe, hydrobromic acid metering tank 501, sodium nitrite solution metering tank 503 and copper bromide metering tank 504 link to each other with hydrobromic acid storage tank 505, sodium nitrite solution storage tank 506 and copper bromide solution storage tank 507 respectively. The hydrobromic acid storage tank 505, the sodium nitrite solution storage tank 506 and the copper bromide solution storage tank 507 are respectively used for preparing and storing hydrobromic acid, a sodium nitrite solution and a copper bromide solution. And a liquid discharge pipe arranged at the bottom of the bromination reaction kettle 5 is connected with the bromination centrifugal machine 11, a liquid outlet pipe of the bromination centrifugal machine 11 is connected with a waste water storage tank, and the solid materials are conveyed to the blast drying box 12 for drying.
Formylation reation kettle, formylation crystallization kettle, become oxime reation kettle, become oxime crystallization kettle, dehydration reation kettle, hydrolysis reation kettle, bromo reation kettle and decompression concentration cauldron all are provided with the intermediate layer outward, and interbedded bottom is provided with the medium and adds the pipeline, and there is medium discharge pipeline at the top for let in the liquid of coolant liquid or heating and control the temperature to in the cauldron. The formylation reaction kettle, the formylation crystallization kettle, the oxime formation reaction kettle, the oxime formation crystallization kettle, the dehydration reaction kettle, the hydrolysis reaction kettle, the bromination reaction kettle and the decompression concentration kettle are all internally provided with stirring. All connecting pipelines are provided with automatic control valves.
1. The operation of formylation production is:
the volume of the formylation reaction kettle is 100L, and the volume of the formylation crystallization kettle is 300L.
Opening a nitrogen pipeline of a formylation reaction kettle, adding nitrogen to replace air in the kettle, introducing nitrogen for protection all the time, adding a reaction solvent DMF (dimethyl formamide) into the formylation reaction kettle through a reaction solvent metering tank, introducing cooling water into an interlayer to control the temperature to be 0-5 ℃, adding phosphorus oxychloride into the system in batches through a phosphorus oxychloride metering tank, after the addition is finished, continuously stirring for reaction for 1h at the temperature of 0-5 ℃, adding 3-methylaniline in batches through a 3-methylaniline metering tank at the temperature of 0-5 ℃, heating to 60-65 ℃, reacting for 5-6h, detecting by TLC (PE: EA = 3:1) until the raw materials disappear, cooling to room temperature, discharging the reaction liquid into a formylation crystallization kettle for crystallization, continuously using the formylation reaction kettle for the formylation reaction, adding 100L of ice water into the formylation crystallization kettle through an ice water metering tank, controlling the temperature to be 0-5 ℃ when the reaction liquid is discharged into the formylation kettle, adding 10% sodium hydroxide solution (mass concentration) into an alkali liquor to adjust the pH to be 8-9, then filtering, washing filter cake with water, drying, obtaining yellow solid aminobenzaldehyde with the purity of 2-11.5-11.87% and the aminobenzaldehyde purity of 99 kg.
2. The reaction of 2-methyl-4-aminobenzaldehyde and hydroxylamine hydrochloride comprises the following steps:
the volume of the oxime-forming reaction kettle is 100L, and the volume of the oxime-forming crystallization kettle is 100L.
Adding 2-methyl-4-aminobenzaldehyde and hydroxylamine hydrochloride through a solid material inlet of an oxime forming reaction kettle, adding solvent ethanol through a solvent metering tank, heating and refluxing for 3-4h after the addition is finished, detecting complete reaction by TLC (PE: EA = 2:1), opening a liquid discharge pipe, discharging reaction liquid into an oxime forming crystallization kettle, continuing to perform reaction on the next batch of materials in the oxime forming reaction kettle, cooling the materials in the oxime forming crystallization kettle to 0-5 ℃, continuously stirring until complete crystallization, filtering by an oxime forming centrifugal machine, washing a filter cake by ethanol, and drying by an air blast drying box to obtain 10.65kg of yellow solid with the yield of 95.9% and the purity of 99.8%.
3. The steps for obtaining the 2-methyl-4-aminobenzonitrile by oxime dehydration are as follows:
material proportioning
| Name of material | Molecular weight | Molecular ratio | Feed amount | Univalent (kilogram) |
| |
150.08 | 1 | 10kg | |
| Sodium formate | 68.01 | 1.5 | 6.8kg | |
| Formic acid | 40L |
The volume of the dehydration reaction kettle is 300L.
Adding the obtained oxime and sodium formate through a solid material inlet on a dehydration reaction kettle, adding formic acid into the dehydration reaction kettle through a formic acid metering tank, heating to 100 ℃, reacting for 3-4H, detecting disappearance of raw materials by TLC (PE: EA = 3:1), cooling to room temperature, discharging into a liquid discharge pipe, concentrating under reduced pressure to remove formic acid, collecting the formic acid condensed by a formic acid condenser into a formic acid storage tank for recycling, adding 100L of water into the formic acid concentration kettle through a first water metering tank, continuously stirring and crystallizing, filtering by a dehydration centrifuge, washing filter cakes by water, and drying by an air blast drying box to obtain 8.2kg of 2-methyl-4-aminobenzonitrile, the yield of 93.5%, the purity of 99.8%, H NMR (300MHz, DMSO-d 6): 2.28 (3H, s), 6.04 (2H, bs), 6.44 (1H, m), 6.48 (1H, m), 7.31 (1H, m).
4. The step of hydrolyzing the 2-methyl-4-aminobenzonitrile to obtain the 2-methyl-4-aminobenzoic acid comprises the following steps:
material proportioning
Hydrolysis reactor 200L.
Adding 2-methyl-4-aminobenzonitrile and sodium hydroxide through a solid material inlet of a hydrolysis reaction kettle, adding water through a second water metering tank, heating to reflux reaction for 6-8h, detecting by TLC (PE: EA = 1:1) until the raw materials disappear, cooling to room temperature, adding hydrochloric acid through a hydrochloric acid metering tank to adjust the pH value to 3-4, continuously stirring and crystallizing at 0-5 ℃, filtering by a water dissociation heart machine, washing filter cakes with water, and drying by an air blast drying oven to obtain 14.7kg of 2-methyl-4-aminobenzoic acid yellow solid, wherein the yield is 97%, and the purity is 99.3%. HNMR (300MHz, CD3OD) 7.80 (d, J =8.4Hz,1H, H6), 7.48 (s, 1H, H3), 7.42 (d, J =8.4Hz,1H, H5), 2.56 (s, 3H, CH3)
5. The sandmeyer bromination reaction is as follows:
material proportioning
Adding 2-methyl-4-aminobenzoic acid into a bromination reaction kettle through a solid material inlet, adding hydrobromic acid and water through a hydrobromic acid metering tank and a third water metering tank, stirring to dissolve, cooling to 0-5 ℃, controlling the temperature to be 0-5 ℃, adding a sodium nitrite aqueous solution in batches through a sodium nitrite solution metering tank, continuously stirring for about 1h after the addition is finished, controlling the temperature to be 0-5 ℃, adding a copper bromide aqueous solution in batches through a copper bromide solution metering tank, heating to room temperature, stirring until the reaction is complete, filtering by a bromination centrifugal machine, washing filter cakes with water, and drying by a blast drying oven to obtain 6.2kg of a product, wherein the yield is 88% and the purity is 99.5%. H-NMR (300MHz, DMSO-d6,) 11.79 (1H, brs, COOH), 7.63 (1H, dd, J =9.2,2.8Hz, C6-H), 6.38 (2H, m, C3, 5-H), 2.41 (3H, s, CH1).
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (7)
1. A production system of a Freund Lei Lana intermediate 4-bromo-2-methylbenzoic acid is characterized in that:
the device comprises a formylation reaction kettle, an oxime formation reaction kettle, a dehydration reaction kettle, a hydrolysis reaction kettle and a bromination reaction kettle, wherein a nitrogen pipeline, a reaction solvent adding pipeline, a phosphorus oxychloride adding pipeline and a 3-methylaniline adding pipeline are arranged on the formylation reaction kettle, the reaction solvent adding pipeline, the phosphorus oxychloride adding pipeline and the 3-methylaniline adding pipeline are respectively connected with a reaction solvent metering tank, a phosphorus oxychloride metering tank and a 3-methylaniline metering tank, a liquid discharge pipe is arranged at the bottom of the formylation reaction kettle and connected with the formylation crystallization kettle, a pH meter is arranged in the formylation crystallization kettle, an alkali liquid adding pipeline and an ice water adding pipeline are arranged at the top of the formylation crystallization kettle, the alkali liquid adding pipeline and the ice water adding pipeline are respectively connected with the alkali liquid metering tank and the ice water metering tank, a liquid discharge pipe is arranged at the bottom of the formylation kettle and connected with a centrifuge, and a liquid outlet pipe of the centrifuge is connected with a waste liquid storage tank;
the top of the oxime forming reaction kettle is provided with a solid material feeding port and a solvent feeding pipeline, the solid material feeding port is used for adding hydroxylamine hydrochloride and 2-methyl-4-aminobenzaldehyde, the solvent feeding pipeline is connected with a solvent metering tank, the oxime forming reaction kettle is also provided with a return pipe which is communicated with the oxime forming reaction kettle, the bottom of the oxime forming reaction kettle is provided with a liquid discharge pipe which is connected with an oxime forming crystallization kettle, the kettle bottom of the oxime forming crystallization kettle is provided with a liquid discharge pipe which is connected with an oxime forming centrifugal machine, the liquid discharge pipe of the oxime forming centrifugal machine is connected with a waste solvent storage tank, and the material of the oxime forming centrifugal machine is sent to a blast drying box for drying;
the top of the dehydration reaction kettle is provided with a solid material feeding port and a formic acid feeding pipeline, the solid material feeding port is used for feeding a product obtained by forming oxime and sodium formate, the formic acid feeding pipeline is connected with a formic acid metering tank, the bottom of the dehydration reaction kettle is provided with a liquid discharge pipe connected with a reduced pressure concentration kettle, a steam outlet pipeline of the reduced pressure concentration kettle is connected with a formic acid condenser, the formic acid condenser is connected with a formic acid recovery storage tank, the formic acid concentration kettle is also provided with a water feeding pipeline connected with a first water metering tank, the kettle bottom of the formic acid concentration kettle is provided with a liquid discharge pipe connected with a dehydration centrifugal machine, a liquid discharge pipe of the dehydration centrifugal machine is connected with a wastewater storage tank, and the material of the dehydration centrifugal machine is sent to a blast drying box for drying;
the top of the hydrolysis reaction kettle is provided with a solid material feeding port and a water feeding pipeline, the solid material feeding port is used for adding 2-methyl-4-aminobenzonitrile and sodium hydroxide, the water feeding pipeline is connected with a second water metering tank, the hydrolysis reaction kettle is also provided with a hydrochloric acid feeding pipeline connected with a hydrochloric acid metering tank, the hydrolysis reaction kettle is also provided with a return pipe communicated with the hydrolysis reaction kettle, the bottom of the hydrolysis reaction kettle is provided with a liquid discharge pipe connected with a hydrolysis reactor, the liquid discharge pipe of the hydrolysis centrifuge is connected with a wastewater storage tank, and the material of the hydrolysis centrifuge is sent to a blast drying box for drying;
the top of the bromination reaction kettle is provided with a solid material adding port, a hydrobromic acid adding pipeline, a water adding pipeline, a sodium nitrite solution adding pipeline and a copper bromide solution adding pipeline, the solid material adding pipeline is used for adding 2-methyl-4-aminobenzoic acid, the hydrobromic acid adding pipeline, the water adding pipeline, the sodium nitrite solution adding pipeline and the copper bromide solution adding pipeline are respectively connected with a hydrobromic acid metering tank, a third water metering tank, a sodium nitrite solution metering tank and a copper bromide solution metering tank, the kettle bottom of the bromination reaction kettle is provided with a liquid discharge pipe connected with a bromination centrifuge, a liquid discharge pipe of the bromination centrifuge is connected with a wastewater storage tank, and the solid material is sent to a blast drying box for drying;
interlayers are arranged outside the formylation reaction kettle, the formylation crystallization kettle, the oxime-forming reaction kettle, the oxime-forming crystallization kettle, the dehydration reaction kettle, the hydrolysis reaction kettle, the bromination reaction kettle and the decompression concentration kettle, a medium adding pipeline is arranged at the bottom of each interlayer, and a medium discharging pipeline is arranged at the top of each interlayer; the formylation reaction kettle, the formylation crystallization kettle, the oxime formation reaction kettle, the oxime formation crystallization kettle, the dehydration reaction kettle, the hydrolysis reaction kettle, the bromination reaction kettle and the decompression concentration kettle are all internally provided with stirring.
2. The production system of intermediates 4-bromo-2-methylbenzoic acid of claim 1 from Lei Lana, wherein: reaction solvent metering tank, phosphorus oxychloride metering tank, 3-methylaniline metering tank, alkali lye metering tank, solvent metering tank, formic acid metering tank, hydrochloric acid metering tank, hydrobromic acid metering tank, sodium nitrite solution metering tank, frozen water metering tank and copper bromide solution metering tank link to each other with reaction solvent storage tank, phosphorus oxychloride storage tank, 3-methylaniline storage tank, alkali lye storage tank, solvent storage tank, formic acid storage tank, hydrochloric acid storage tank, hydrobromic acid storage tank, sodium nitrite solution storage tank, frozen water storage tank and copper bromide solution storage tank respectively, first water metering tank, second water metering tank, third water metering tank link to each other with the feed pipe respectively.
3. The production system of intermediates 4-bromo-2-methylbenzoic acid of claim 1 of fr Lei Lana, wherein the formylation production is performed by:
opening a nitrogen pipeline of a formylation reaction kettle, adding nitrogen to replace air in the kettle, introducing nitrogen for protection all the time, adding a reaction solvent DMF (dimethyl formamide) into the formylation reaction kettle through a reaction solvent metering tank, introducing cooling water into an interlayer to control the temperature to be 0-5 ℃, adding phosphorus oxychloride into the system in batches through a phosphorus oxychloride metering tank, after the addition is finished, continuously stirring for reaction at the temperature of 0-5 ℃ for 1 hour, adding 3-methylaniline into the formylation reaction kettle in batches through a 3-methylaniline metering tank at the temperature of 0-5 ℃, heating to 60-65 ℃ for reaction for 5-6 hours, detecting that the raw materials disappear, cooling to room temperature, discharging the reaction liquid into a formylation kettle for crystallization, continuously using the formylation reaction kettle for formylation, adding ice water into the formylation kettle through an ice water metering tank, controlling the temperature to be 0-5 ℃ when the reaction liquid is discharged into the formylation kettle, then adding a sodium hydroxide solution into an alkali liquor metering tank to adjust the pH to be 8-9, then filtering a filter cake, washing, and drying to obtain yellow solid 2-methyl-4-aminobenzaldehyde.
4. The production system of intermediate 4-bromo-2-methylbenzoic acid of claim 3, which is an intermediate of f Lei Lana, wherein the reaction step of 2-methyl-4-aminobenzaldehyde with hydroxylamine hydrochloride is:
adding 2-methyl-4-aminobenzaldehyde and hydroxylamine hydrochloride through a solid material adding port of an oxime forming reaction kettle, then adding solvent ethanol through a solvent metering tank, heating and refluxing for 3-4h after the material addition is finished, completely reacting, opening a liquid discharge pipe, discharging reaction liquid into an oxime forming crystallization kettle, continuously reacting the next batch of materials in the oxime forming reaction kettle, cooling the materials in the oxime forming crystallization kettle to 0-5 ℃, continuously stirring until the crystallization is complete, filtering by an oxime forming centrifugal machine, washing a filter cake by ethanol, and drying by a blast drying box to obtain oxime.
5. The production system of intermediates 4-bromo-2-methylbenzoic acid of claim 4 of fr Lei Lana, which is characterized by: the steps for obtaining the 2-methyl-4-aminobenzonitrile by oxime dehydration are as follows:
adding the obtained oxime and sodium formate through a solid material inlet on a dehydration reaction kettle, adding formic acid into the dehydration reaction kettle through a formic acid metering tank, heating to 100 ℃ for reaction for 3-4h, cooling to room temperature after the reaction is finished, discharging into a liquid discharge pipe, reducing pressure, concentrating and removing the formic acid, collecting the formic acid condensed by a formic acid condenser into a formic acid storage tank for recycling, adding water into the formic acid concentration kettle through a first water metering tank, continuously stirring for crystallization, filtering by a dehydration centrifugal machine, washing filter cakes with water, and drying by a forced air drying oven to obtain the 2-methyl-4-aminobenzonitrile.
6. The production system of 4-bromo-2-methylbenzoic acid as an intermediate in Fr Lei Lana of claim 5, wherein the step of hydrolyzing 2-methyl-4-aminobenzonitrile to obtain 2-methyl-4-aminobenzoic acid comprises:
adding 2-methyl-4-aminobenzonitrile and sodium hydroxide through a solid material inlet of a hydrolysis reaction kettle, adding water through a second water metering tank, heating to reflux reaction for 6-8h, cooling to room temperature after the reaction is finished, adding hydrochloric acid through a hydrochloric acid metering tank to adjust the pH value to 3-4, continuously stirring and crystallizing at 0-5 ℃, filtering through a water dissociation centrifugal machine, washing filter cakes, and drying through a forced air drying box to obtain 2-methyl-4-aminobenzoic acid.
7. The system for producing 4-bromo-2-methylbenzoic acid as an intermediate in the production of f Lei Lana as claimed in claim 6, wherein said sandmeyer bromination reaction is:
adding 2-methyl-4-aminobenzoic acid into a bromination reaction kettle through a solid material inlet, adding hydrobromic acid and water through a hydrobromic acid metering tank and a third water metering tank, stirring to dissolve, cooling to 0-5 ℃, controlling the temperature to be 0-5 ℃, adding a sodium nitrite aqueous solution in batches through a sodium nitrite solution metering tank, continuously stirring for about 1h after the addition is finished, controlling the temperature to be 0-5 ℃, adding a copper bromide aqueous solution in batches through a copper bromide solution metering tank, heating to room temperature, stirring until the reaction is complete, filtering by a bromination centrifugal machine, washing a filter cake with water, and drying by a forced air drying oven to obtain a product.
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| CN101437804A (en) * | 2006-03-10 | 2009-05-20 | 辉瑞产品公司 | Dibenzyl amine compounds and derivatives |
| CN101500995A (en) * | 2006-03-17 | 2009-08-05 | 美国政府卫生与公共服务部 | 1-oxo-isoindoline compounds for the treatment of spinal muscular atrophy and other uses |
| CN109928890A (en) * | 2017-12-15 | 2019-06-25 | 重庆常捷医药有限公司 | A kind of preparation method of tolvaptan intermediate 2- methyl -4-N- (2- toluyl) benzoic acid |
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2022
- 2022-06-27 CN CN202210742159.5A patent/CN115141097A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101437804A (en) * | 2006-03-10 | 2009-05-20 | 辉瑞产品公司 | Dibenzyl amine compounds and derivatives |
| CN101500995A (en) * | 2006-03-17 | 2009-08-05 | 美国政府卫生与公共服务部 | 1-oxo-isoindoline compounds for the treatment of spinal muscular atrophy and other uses |
| CN109928890A (en) * | 2017-12-15 | 2019-06-25 | 重庆常捷医药有限公司 | A kind of preparation method of tolvaptan intermediate 2- methyl -4-N- (2- toluyl) benzoic acid |
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