CN114773149A - Efficient synthesis method of medicine intermediate 2,4, 5-trifluorobromobenzyl - Google Patents
Efficient synthesis method of medicine intermediate 2,4, 5-trifluorobromobenzyl Download PDFInfo
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- CN114773149A CN114773149A CN202210500326.5A CN202210500326A CN114773149A CN 114773149 A CN114773149 A CN 114773149A CN 202210500326 A CN202210500326 A CN 202210500326A CN 114773149 A CN114773149 A CN 114773149A
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- -1 2,4, 5-trifluorobromobenzyl Chemical group 0.000 title claims abstract description 23
- 238000001308 synthesis method Methods 0.000 title claims abstract description 14
- 239000003814 drug Substances 0.000 title description 3
- 239000003054 catalyst Substances 0.000 claims abstract description 39
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims abstract description 38
- PEBWOGPSYUIOBP-UHFFFAOYSA-N 1,2,4-trifluorobenzene Chemical compound FC1=CC=C(F)C(F)=C1 PEBWOGPSYUIOBP-UHFFFAOYSA-N 0.000 claims abstract description 29
- CEPCPXLLFXPZGW-UHFFFAOYSA-N 2,4-difluoroaniline Chemical compound NC1=CC=C(F)C=C1F CEPCPXLLFXPZGW-UHFFFAOYSA-N 0.000 claims abstract description 25
- 229930040373 Paraformaldehyde Natural products 0.000 claims abstract description 20
- 229920002866 paraformaldehyde Polymers 0.000 claims abstract description 20
- RJXOVESYJFXCGI-UHFFFAOYSA-N 2,4-difluoro-1-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C=C1F RJXOVESYJFXCGI-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000005979 thermal decomposition reaction Methods 0.000 claims abstract description 14
- 238000006193 diazotization reaction Methods 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 100
- 238000010438 heat treatment Methods 0.000 claims description 46
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 34
- 239000000047 product Substances 0.000 claims description 28
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 27
- 239000007864 aqueous solution Substances 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 238000004321 preservation Methods 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 claims description 20
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 20
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 18
- 238000004132 cross linking Methods 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 18
- 235000010288 sodium nitrite Nutrition 0.000 claims description 17
- 239000002077 nanosphere Substances 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 16
- 238000001914 filtration Methods 0.000 claims description 15
- 239000007789 gas Substances 0.000 claims description 15
- 239000000543 intermediate Substances 0.000 claims description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 14
- 229920006037 cross link polymer Polymers 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 14
- 239000012044 organic layer Substances 0.000 claims description 14
- 239000000843 powder Substances 0.000 claims description 14
- 238000004821 distillation Methods 0.000 claims description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 9
- 238000000944 Soxhlet extraction Methods 0.000 claims description 9
- MQRWBMAEBQOWAF-UHFFFAOYSA-N acetic acid;nickel Chemical compound [Ni].CC(O)=O.CC(O)=O MQRWBMAEBQOWAF-UHFFFAOYSA-N 0.000 claims description 9
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 9
- 229940078494 nickel acetate Drugs 0.000 claims description 9
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 9
- RILZRCJGXSFXNE-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]ethanol Chemical compound OCCC1=CC=C(OC(F)(F)F)C=C1 RILZRCJGXSFXNE-UHFFFAOYSA-N 0.000 claims description 8
- 239000012954 diazonium Substances 0.000 claims description 8
- 150000001989 diazonium salts Chemical class 0.000 claims description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 239000003431 cross linking reagent Substances 0.000 claims description 7
- 239000008367 deionised water Substances 0.000 claims description 7
- 229910021641 deionized water Inorganic materials 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 239000005457 ice water Substances 0.000 claims description 7
- 239000010410 layer Substances 0.000 claims description 7
- 239000011259 mixed solution Substances 0.000 claims description 7
- 230000007935 neutral effect Effects 0.000 claims description 7
- 239000012450 pharmaceutical intermediate Substances 0.000 claims description 7
- 239000002244 precipitate Substances 0.000 claims description 7
- 238000001291 vacuum drying Methods 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 239000013315 hypercross-linked polymer Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- GAUXEYCSWSMMFZ-UHFFFAOYSA-N 1-(bromomethyl)-2,4,5-trifluorobenzene Chemical compound FC1=CC(F)=C(CBr)C=C1F GAUXEYCSWSMMFZ-UHFFFAOYSA-N 0.000 claims description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 2
- 238000003763 carbonization Methods 0.000 claims description 2
- 238000010000 carbonizing Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 238000005984 hydrogenation reaction Methods 0.000 abstract 1
- 239000002253 acid Substances 0.000 description 5
- DVTULTINXNWGJY-UHFFFAOYSA-N 1-Bromo-2,4,5-trifluorobenzene Chemical compound FC1=CC(F)=C(Br)C=C1F DVTULTINXNWGJY-UHFFFAOYSA-N 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000197 pyrolysis Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
- C07C17/32—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by introduction of halogenated alkyl groups into ring compounds
-
- 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
- B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
- B01J27/24—Nitrogen compounds
-
- 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
- B01J35/00—Catalysts, in general, characterised by their form or physical properties
- B01J35/50—Catalysts, in general, characterised by their form or physical properties characterised by their shape or configuration
- B01J35/56—Foraminous structures having flow-through passages or channels, e.g. grids or three-dimensional monoliths
-
- 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
- B01J37/00—Processes, in general, for preparing catalysts; Processes, in general, for activation of catalysts
- B01J37/02—Impregnation, coating or precipitation
- B01J37/0201—Impregnation
-
- 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
- B01J37/00—Processes, in general, for preparing catalysts; Processes, in general, for activation of catalysts
- B01J37/16—Reducing
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/35—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/30—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds
- C07C209/32—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups
- C07C209/36—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups by reduction of nitro groups bound to carbon atoms of six-membered aromatic rings in presence of hydrogen-containing gases and a catalyst
- C07C209/365—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups by reduction of nitro groups bound to carbon atoms of six-membered aromatic rings in presence of hydrogen-containing gases and a catalyst by reduction with preservation of halogen-atoms in compounds containing nitro groups and halogen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
- C07C245/20—Diazonium compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
The invention discloses a high-efficiency synthesis method of a medical intermediate 2,4, 5-trifluorobromobenzyl, which comprises the following steps: preparing a honeycomb supported catalyst; 2, 4-difluoronitrobenzene is taken as a raw material, and hydrogenation reduction is carried out under the catalysis of a honeycomb supported catalyst to prepare 2, 4-difluoroaniline; 2, 4-difluoroaniline is used as a raw material, diazotization reaction is firstly carried out, and then thermal decomposition reaction is carried out to prepare 1,2, 4-trifluorobenzene; reacting 1,2, 4-trifluorobenzene with sodium bromide and paraformaldehyde to obtain the target product 2,4, 5-trifluorobromobenzyl. The method provided by the invention is simple to operate, and the prepared target product has high purity and high yield.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a high-efficiency synthesis method of a medical intermediate 2,4, 5-trifluorobromobenzyl.
Background
2,4, 5-trifluorobromobenzene is transparent liquid, is an important medical intermediate, is often used for synthesis of various medicines, but the research on the synthetic route is less and not mature at present, and the application of the 2,4, 5-trifluorobromobenzene is greatly limited.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: aiming at the defects in the prior art, the method for efficiently synthesizing the pharmaceutical intermediate 2,4, 5-trifluorobromobenzene is provided, 2, 4-difluoronitrobenzene is used as a raw material, and the target product is prepared by sequentially carrying out catalytic hydrogenation, diazotization and pyrolysis and finally reacting with sodium bromide and paraformaldehyde.
In order to solve the technical problem, the technical scheme of the invention is as follows:
a high-efficiency synthesis method of a medical intermediate 2,4, 5-trifluorobromobenzyl comprises the following steps:
(1) adding carbazole and benzylamine into 1, 2-dichloroethane, stirring, adding anhydrous ferric trichloride as a catalyst, formaldehyde dimethyl ether as a cross-linking agent, slowly heating to perform a pre-crosslinking reaction, continuously heating to perform a crosslinking reaction, filtering after the reaction is finished, performing Soxhlet extraction on a filtered precipitate by using methanol and water, and performing vacuum drying on an extracted product to prepare a nitrogen-doped super-crosslinked polymer nanosphere;
(2) mixing a mixed solution of palladium acetate and nickel acetate with the prepared nitrogen-doped super-crosslinked polymer nanospheres, drying, carbonizing the dried powder, putting the carbonized powder into a hydrogen peroxide solution, stirring, and drying to obtain a honeycomb supported catalyst;
(3) adding the prepared honeycomb supported catalyst into a reactor, adding 2, 4-difluoronitrobenzene, introducing hydrogen to replace air in the reactor, heating for reaction, filtering to remove the catalyst after the reaction is finished, distilling the filtrate under reduced pressure, and collecting fractions to obtain 2, 4-difluoroaniline;
(4) dropwise adding sodium fluoborate into the prepared 2, 4-difluoroaniline for dissolving in water, quickly cooling after dropwise adding, then dropwise adding a sodium nitrite aqueous solution, keeping the temperature for reaction after dropwise adding, allowing the diazonium salt intermediate prepared after the reaction to enter a thermal decomposer for thermal decomposition reaction to prepare 1,2, 4-trifluorobenzene, and absorbing the gas obtained by thermal decomposition by using the aqueous solution and reusing the gas in the diazotization reaction;
(5) adding paraformaldehyde and sodium bromide into a reaction bottle filled with a sulfuric acid solution respectively, then slowly adding the prepared 1,2, 4-trifluorobenzene, heating for reaction, quickly cooling the reaction solution after the reaction is finished, then adding ice water into the reaction system for hydrolysis, standing for layering, washing the water layer of the organic layer with deionized water to be neutral, and then carrying out reduced pressure distillation on the organic layer to obtain the target product 2,4, 5-trifluorobenzyl bromide.
In the preferable embodiment, in the step (1), the mass ratio of carbazole, benzylamine, anhydrous ferric chloride, and formaldehyde dimethyl ether is 1: (0.5-0.7): 5.35: (3-4).
Preferably, in the step (1), the temperature of the pre-crosslinking reaction is 40-50 ℃ and the time is 4-5 h; the temperature of the crosslinking reaction is 75-85 ℃, and the time is 15-20 h; the Soxhlet extraction time is 45-50 h.
Preferably, in the step (2), the mass ratio of the palladium acetate, the nickel acetate and the nitrogen-doped super cross-linked polymer nanospheres is 5: (3-5): 10; the volume concentration of the hydrogen peroxide solution is 30 percent, the stirring treatment time is 3-5h, and the rotating speed of the stirring treatment is 500-800 r/m.
Preferably, in the step (2), the temperature of the mixing treatment is normal temperature, and the treatment time is 20-25 h; the carbonization treatment conditions are as follows: heating to 500 deg.C at a rate of 3-5 deg.C/min, and holding for 1-2 h.
Preferably, in the step (3), the usage ratio of the 2, 4-difluoronitrobenzene to the honeycomb supported catalyst is 0.1 mol: (0.1-0.13) g; the temperature rise reaction is carried out at 50 ℃, the reaction pressure is 0.1MPa, and the reaction time is 2 h.
Preferably, in the step (4), the concentration of the sodium nitrite solution is 25 wt%, the concentration of the fluoroboric acid aqueous solution is 30 wt%, and the molar ratio of the 2, 4-difluoroaniline, the fluoroboric acid and the sodium nitrite is 1 (3-5): (1-1.2).
Preferably, in the step (4), the dropping temperature of the fluoroboric acid aqueous solution is 10-25 ℃, the temperature of the heat preservation reaction is-20-5 ℃, and the time of the heat preservation reaction is 3-5 h. During thermal decomposition, the temperature is firstly increased to 110 ℃ at the speed of 3-5 ℃/min, the temperature is maintained for 1h, then the temperature is increased to 180 ℃ at the speed of 10 ℃/min, and the temperature is maintained for 2-5 h.
Preferably, in the step (5), the molar ratio of the paraformaldehyde to the sodium bromide to the 1,2, 4-trifluorobenzene is 0.7: (0.7-0.8): (0.3-0.4).
Preferably, in the step (5), the temperature of the reaction system is kept at 20 +/-5 ℃ when the paraformaldehyde and the sodium bromide are added, the 1,2, 4-trifluorobenzene is added, the temperature is raised to 40 +/-2 ℃ after the 1,2, 4-trifluorobenzene is added, the reaction time is 8-12 hours, and the temperature is rapidly reduced to-5-0 ℃ after the reaction is finished.
Due to the adoption of the technical scheme, the invention has the beneficial effects that:
the invention firstly uses 2, 4-difluoronitrobenzene as a raw material to synthesize 2, 4-difluoroaniline under the action of a self-made supported catalyst, then the 2, 4-difluoroaniline is mixed with fluoboric acid to prepare fluoborate, diazotization reaction is carried out under the action of sodium nitrite to prepare fluoboric acid diazonium salt, thermal decomposition reaction is carried out to prepare 1,2, 4-trifluorobenzene, and finally, the 1,2, 4-trifluorobenzene reacts with paraformaldehyde under the action of sodium bromide to prepare the target product.
According to the invention, a template-free method is adopted, carbazole and benzylamine are taken as monomers to synthesize a super-crosslinked polymer, and then an in-situ impregnation-reduction method is adopted to embed catalytic active components palladium and nickel into a formed nitrogen-doped porous carbon skeleton, so that the prepared supported catalyst has high catalytic activity and good stability. The invention recycles the boron trifluoride gas generated after thermal decomposition, thereby effectively reducing the preparation cost of the product. After the reaction of the 1,2, 4-trifluorobenzene and the paraformaldehyde, the temperature is quickly reduced, so that the generation of byproducts can be effectively avoided, and the yield and the purity of the product can be effectively improved.
Detailed Description
The invention is further illustrated by the following examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Example 1
(1) Adding 5g of carbazole and 2.5g of benzylamine into 100ml of 1, 2-dichloroethane, stirring, adding 26.75g of anhydrous ferric trichloride as a catalyst, taking 15g of formaldehyde dimethyl ether as a cross-linking agent, slowly heating to 40 ℃ to perform pre-crosslinking reaction for 4 hours, then continuously heating to 75 ℃ to perform crosslinking reaction for 15 hours, filtering after the reaction is finished, performing Soxhlet extraction on the filtered precipitate by adopting methanol and water for 48 hours, and then performing vacuum drying on the extracted product to prepare the nitrogen-doped hypercrosslinked polymer nanosphere;
(2) mixing a mixed solution containing 5g of palladium acetate and 3g of nickel acetate with 10g of the prepared nitrogen-doped super-crosslinked polymer nanosphere at normal temperature for 20 hours, drying, placing the dried powder in a muffle furnace, heating to 500 ℃ at the speed of 3 ℃/min, carrying out heat preservation for 1 hour, placing the carbonized powder in a hydrogen peroxide solution with the volume concentration of 30%, stirring for 3 hours at the rotating speed of 500 rpm, and drying to prepare a honeycomb supported catalyst;
(3) adding the prepared honeycomb supported catalyst into a reactor, adding 2, 4-difluoronitrobenzene, introducing hydrogen to replace air in the reactor, and controlling the dosage ratio of the 2, 4-difluoronitrobenzene to the honeycomb supported catalyst to be 0.1 mol: 0.1 g; then heating to 50 ℃, controlling the reaction pressure to be 0.1MPa, reacting for 2h, filtering to remove the catalyst after the reaction is finished, then carrying out reduced pressure distillation on the filtrate, and collecting fractions to obtain 2, 4-difluoroaniline;
(4) dropwise adding a sodium fluoroborate aqueous solution with the concentration of 30 wt% into the prepared 2, 4-difluoroaniline at the temperature of 10 ℃, after dropwise adding, rapidly cooling to 0 ℃, then dropwise adding a sodium nitrite aqueous solution with the concentration of 25 wt%, and controlling the molar ratio of the 2, 4-difluoroaniline, the fluoroboric acid and the sodium nitrite to be 1: 3: 1; after the dropwise addition is finished, performing heat preservation reaction for 3-5h, enabling a diazonium salt intermediate prepared after the reaction to enter a thermal decomposer, firstly heating to 110 ℃ at the speed of 3 ℃/min, preserving heat for 1h, then heating to 180 ℃ at the speed of 10 ℃/min, preserving heat for 2h to prepare 1,2, 4-trifluorobenzene, and absorbing gas obtained by thermal decomposition by adopting an aqueous solution and then reusing the gas in the diazotization reaction;
(5) adding paraformaldehyde and sodium bromide into a reaction bottle filled with 50ml of 98 wt% sulfuric acid solution at normal temperature respectively, and then slowly adding the prepared 1,2, 4-trifluorobenzene, wherein the molar ratio of the paraformaldehyde to the sodium bromide to the 1,2, 4-trifluorobenzene is controlled to be 0.7: 0.7: 0.3, heating to 40 ℃ for reaction for 10 hours, after the reaction is finished, quickly cooling the reaction solution to-5 ℃, then adding ice water into the reaction system for hydrolysis, standing for layering, washing the water layer of the organic layer by deionized water to be neutral, and then carrying out reduced pressure distillation on the organic layer to obtain the target product 2,4, 5-trifluorobromobenzyl, wherein the product purity is 99.8%, and the product yield is 85.5%.
Example 2
(1) Adding 5g of carbazole and 3.5g of benzylamine into 100ml of 1, 2-dichloroethane, stirring, adding 26.75g of anhydrous ferric trichloride as a catalyst, using 20g of formaldehyde dimethyl ether as a cross-linking agent, slowly heating to 40 ℃ to perform pre-crosslinking reaction for 5 hours, then continuously heating to 85 ℃ to perform crosslinking reaction for 20 hours, filtering after the reaction is finished, performing Soxhlet extraction on the filtered precipitate by using methanol and water for 50 hours, and then performing vacuum drying on the extracted product to prepare the nitrogen-doped hypercrosslinked polymer nanosphere;
(2) mixing a mixed solution containing 5g of palladium acetate and 5g of nickel acetate with 10g of the prepared nitrogen-doped super-crosslinked polymer nanosphere at normal temperature for 25 hours, drying, placing the dried powder in a muffle furnace, heating to 500 ℃ at the speed of 5 ℃/min, carrying out heat preservation for 2 hours, placing the carbonized powder in a hydrogen peroxide solution with the volume concentration of 30%, stirring at the rotating speed of 800 rpm for 5 hours, and drying to prepare a honeycomb supported catalyst;
(3) adding the prepared honeycomb supported catalyst into a reactor, adding 2, 4-difluoronitrobenzene, introducing hydrogen to replace air in the reactor, and controlling the dosage ratio of the 2, 4-difluoronitrobenzene to the honeycomb supported catalyst to be 0.1 mol: 0.13 g; then heating to 50 ℃, controlling the reaction pressure to be 0.1MPa, reacting for 2 hours, filtering to remove the catalyst after the reaction is finished, then carrying out reduced pressure distillation on the filtrate, and collecting fractions to obtain 2, 4-difluoroaniline;
(4) dropwise adding a sodium fluoroborate aqueous solution with the concentration of 30 wt% into the prepared 2, 4-difluoroaniline at 25 ℃, after dropwise adding, rapidly cooling to 5 ℃, then dropwise adding a sodium nitrite aqueous solution with the concentration of 25 wt%, and controlling the molar ratio of the 2, 4-difluoroaniline, the fluoroboric acid and the sodium nitrite to be 1: 5: 1.2; after the dropwise addition is finished, carrying out heat preservation reaction for 5h, enabling the prepared diazonium salt intermediate to enter a thermal decomposer after the reaction is finished, firstly heating to 110 ℃ at the speed of 5 ℃/min, carrying out heat preservation for 1h, then heating to 180 ℃ at the speed of 10 ℃/min, carrying out heat preservation for 5h to prepare 1,2, 4-trifluorobenzene, and absorbing the gas obtained by thermal decomposition by adopting an aqueous solution and then reusing the gas in the diazotization reaction;
(5) adding paraformaldehyde and sodium bromide into a reaction bottle filled with 50ml of 98 wt% sulfuric acid solution at normal temperature respectively, and then slowly adding the prepared 1,2, 4-trifluorobenzene, wherein the molar ratio of the paraformaldehyde to the sodium bromide to the 1,2, 4-trifluorobenzene is controlled to be 0.7: 0.8: 0.4, heating to 40 ℃ for reaction for 10 hours, after the reaction is finished, quickly cooling the reaction solution to-0 ℃, then adding ice water into the reaction system for hydrolysis, then standing for layering, washing the water layer of the organic layer by deionized water to be neutral, and then carrying out reduced pressure distillation on the organic layer to obtain the target product 2,4, 5-trifluorobromobenzyl, wherein the product purity is 99.5%, and the product yield is 85.6%.
Example 3
(1) Adding 5g of carbazole and 3g of benzylamine into 100ml of 1, 2-dichloroethane, stirring, adding 26.75g of anhydrous ferric trichloride as a catalyst and 18g of formaldehyde dimethyl ether as a cross-linking agent, slowly heating to 40 ℃ to perform pre-crosslinking reaction for 4 hours, then continuously heating to 80 ℃ to perform crosslinking reaction for 16 hours, filtering after the reaction is finished, performing Soxhlet extraction on the filtered precipitate by adopting methanol and water for 48 hours, and then performing vacuum drying on the extracted product to prepare the nitrogen-doped super-crosslinked polymer nanospheres;
(2) mixing a mixed solution containing 5g of palladium acetate and 3.5g of nickel acetate with 10g of the prepared nitrogen-doped super-crosslinked polymer nanosphere at normal temperature for 20 hours, drying, putting the dried powder into a muffle furnace, heating to 500 ℃ at the speed of 4 ℃/min, carrying out heat preservation for 1 hour, putting the carbonized powder into a hydrogen peroxide solution with the volume concentration of 30%, stirring at the rotating speed of 600 rpm for 4 hours, and drying to prepare a honeycomb supported catalyst;
(3) adding the prepared honeycomb supported catalyst into a reactor, then adding 2, 4-difluoronitrobenzene, introducing hydrogen to replace air in the reactor, and controlling the dosage ratio of the 2, 4-difluoronitrobenzene to the honeycomb supported catalyst to be 0.1 mol: 0.11 g; then heating to 50 ℃, controlling the reaction pressure to be 0.1MPa, reacting for 2 hours, filtering to remove the catalyst after the reaction is finished, then carrying out reduced pressure distillation on the filtrate, and collecting fractions to obtain 2, 4-difluoroaniline;
(4) dropwise adding a 30 wt% sodium fluoborate aqueous solution into the prepared 2, 4-difluoroaniline at the temperature of 20 ℃, after dropwise adding, rapidly cooling to-5 ℃, then dropwise adding a 25 wt% sodium nitrite aqueous solution, and controlling the molar ratio of the 2, 4-difluoroaniline to the fluoboric acid to the sodium nitrite to be 1: 3.5: 1.1; after the dropwise addition is finished, carrying out heat preservation reaction for 4h, enabling the diazonium salt intermediate prepared after the reaction to enter a thermal decomposer, firstly heating to 110 ℃ at the speed of 4 ℃/min, carrying out heat preservation for 1h, then heating to 180 ℃ at the speed of 10 ℃/min, carrying out heat preservation for 3h to prepare 1,2, 4-trifluorobenzene, and absorbing the gas obtained by thermal decomposition by adopting an aqueous solution and then reusing the gas in the diazotization reaction;
(5) adding paraformaldehyde and sodium bromide into a reaction bottle filled with 50ml of 98 wt% sulfuric acid solution at normal temperature respectively, and then slowly adding the prepared 1,2, 4-trifluorobenzene, wherein the molar ratio of the paraformaldehyde to the sodium bromide to the 1,2, 4-trifluorobenzene is controlled to be 0.7: 0.75: 0.35, heating to 40 ℃ for reaction for 10 hours, after the reaction is finished, quickly cooling the reaction solution to-5 ℃, adding ice water into the reaction system for hydrolysis, standing for layering, washing an organic layer with deionized water to make the water layer neutral, and then carrying out reduced pressure distillation on the organic layer to obtain the target product 2,4, 5-trifluorobromobenzyl, wherein the product purity is 99.8%, and the product yield is 85.7%.
Example 4
(1) Adding 5g of carbazole and 3g of benzylamine into 100ml of 1, 2-dichloroethane, stirring, adding 26.75g of anhydrous ferric trichloride as a catalyst and 15g of formaldehyde dimethyl ether as a cross-linking agent, slowly heating to 40 ℃ to perform pre-crosslinking reaction for 4 hours, then continuously heating to 75 ℃ to perform crosslinking reaction for 18 hours, filtering after the reaction is finished, performing Soxhlet extraction on the filtered precipitate by adopting methanol and water for 48 hours, and then performing vacuum drying on the extracted product to prepare the nitrogen-doped super-crosslinked polymer nanospheres;
(2) mixing a mixed solution containing 5g of palladium acetate and 4g of nickel acetate with 10g of the prepared nitrogen-doped super-crosslinked polymer nanosphere at normal temperature for 24 hours, drying, placing the dried powder in a muffle furnace, heating to 500 ℃ at the speed of 4 ℃/min, carrying out heat preservation for 2 hours, placing the carbonized powder in a hydrogen peroxide solution with the volume concentration of 30%, stirring at the rotating speed of 700 rpm for 4 hours, and drying to prepare a honeycomb supported catalyst;
(3) adding the prepared honeycomb supported catalyst into a reactor, adding 2, 4-difluoronitrobenzene, introducing hydrogen to replace air in the reactor, and controlling the dosage ratio of the 2, 4-difluoronitrobenzene to the honeycomb supported catalyst to be 0.1 mol: 0.12 g; then heating to 50 ℃, controlling the reaction pressure to be 0.1MPa, reacting for 2 hours, filtering to remove the catalyst after the reaction is finished, then carrying out reduced pressure distillation on the filtrate, and collecting fractions to obtain 2, 4-difluoroaniline;
(4) dropwise adding a sodium fluoborate aqueous solution with the concentration of 30 wt% into the prepared 2, 4-difluoroaniline at the temperature of 20 ℃, after dropwise adding, rapidly cooling to-10 ℃, then dropwise adding a sodium nitrite aqueous solution with the concentration of 25 wt%, and controlling the molar ratio of the 2, 4-difluoroaniline, the fluoboric acid and the sodium nitrite to be 1: 4: 1.1; after the dropwise addition is finished, carrying out heat preservation reaction for 4h, enabling the diazonium salt intermediate prepared after the reaction to enter a thermal decomposer, firstly heating to 110 ℃ at the speed of 5 ℃/min, carrying out heat preservation for 1h, then heating to 180 ℃ at the speed of 10 ℃/min, carrying out heat preservation for 4h to prepare 1,2, 4-trifluorobenzene, and absorbing the gas obtained by thermal decomposition by adopting an aqueous solution and then reusing the gas in the diazotization reaction;
(5) adding paraformaldehyde and sodium bromide into a reaction bottle filled with 50ml of 98 wt% sulfuric acid solution at normal temperature respectively, and then slowly adding the prepared 1,2, 4-trifluorobenzene, wherein the molar ratio of the paraformaldehyde to the sodium bromide to the 1,2, 4-trifluorobenzene is controlled to be 0.7: 0.77: 0.35, heating to 40 ℃ for reaction for 10h, quickly cooling the reaction solution to-5 ℃ after the reaction is finished, adding ice water into the reaction system for hydrolysis, standing for layering, washing an organic layer with deionized water to make the water layer neutral, and then carrying out reduced pressure distillation on the organic layer to obtain the target product 2,4, 5-trifluorobromobenzyl, wherein the product purity is 99.7%, and the product yield is 85.6%.
Example 5
(1) Adding 5g of carbazole and 3g of benzylamine into 100ml of 1, 2-dichloroethane, stirring, adding 26.75g of anhydrous ferric trichloride as a catalyst and 17g of formaldehyde dimethyl ether as a cross-linking agent, slowly heating to 45 ℃ to perform pre-crosslinking reaction for 5 hours, then continuously heating to 80 ℃ to perform crosslinking reaction for 20 hours, filtering after the reaction is finished, performing Soxhlet extraction on the filtered precipitate by adopting methanol and water for 48 hours, and then performing vacuum drying on the extracted product to prepare the nitrogen-doped super-crosslinked polymer nanospheres;
(2) mixing a mixed solution containing 5g of palladium acetate and 5g of nickel acetate with 10g of the prepared nitrogen-doped super-crosslinked polymer nanosphere at normal temperature for 24 hours, drying, putting the dried powder into a muffle furnace, heating to 500 ℃ at the speed of 4 ℃/min, carrying out heat preservation for 1 hour, putting the carbonized powder into a hydrogen peroxide solution with the volume concentration of 30%, stirring at the rotating speed of 800 rpm for 3 hours, and drying to prepare a honeycomb supported catalyst;
(3) adding the prepared honeycomb supported catalyst into a reactor, then adding 2, 4-difluoronitrobenzene, introducing hydrogen to replace air in the reactor, and controlling the dosage ratio of the 2, 4-difluoronitrobenzene to the honeycomb supported catalyst to be 0.1 mol: 0.13 g; then heating to 50 ℃, controlling the reaction pressure to be 0.1MPa, reacting for 2h, filtering to remove the catalyst after the reaction is finished, then carrying out reduced pressure distillation on the filtrate, and collecting fractions to obtain 2, 4-difluoroaniline;
(4) dropwise adding a sodium fluoborate aqueous solution with the concentration of 30 wt% into the prepared 2, 4-difluoroaniline at 25 ℃, after dropwise adding, rapidly cooling to-5 ℃, then dropwise adding a sodium nitrite aqueous solution with the concentration of 25 wt%, and controlling the molar ratio of the 2, 4-difluoroaniline, the fluoboric acid and the sodium nitrite to be 1: 4: 1.1; after the dropwise addition is finished, carrying out heat preservation reaction for 4h, enabling the diazonium salt intermediate prepared after the reaction to enter a thermal decomposer, firstly heating to 110 ℃ at the speed of 3 ℃/min, carrying out heat preservation for 1h, then heating to 180 ℃ at the speed of 10 ℃/min, carrying out heat preservation for 4h to prepare 1,2, 4-trifluorobenzene, and absorbing the gas obtained by thermal decomposition by adopting an aqueous solution and then reusing the gas in the diazotization reaction;
(5) adding paraformaldehyde and sodium bromide into a reaction bottle filled with 50ml of 98 wt% sulfuric acid solution at normal temperature respectively, and then slowly adding the prepared 1,2, 4-trifluorobenzene, wherein the molar ratio of the paraformaldehyde to the sodium bromide to the 1,2, 4-trifluorobenzene is controlled to be 0.7: 0.7: 0.3, heating to 40 ℃ for reaction for 10 hours, after the reaction is finished, rapidly cooling the reaction solution to-3 ℃, then adding ice water into the reaction system for hydrolysis, then standing for layering, washing the water layer of the organic layer by deionized water to be neutral, and then carrying out reduced pressure distillation on the organic layer to obtain the target product 2,4, 5-trifluorobromobenzyl, wherein the product purity is 99.7%, and the product yield is 85.6%.
Further, it should be understood that various changes or modifications of the present invention can be made by those skilled in the art after reading the teaching of the present invention, and these equivalents also fall within the scope of the claims appended to the present application.
Claims (10)
1. A high-efficiency synthesis method of a medical intermediate 2,4, 5-trifluorobromobenzyl is characterized by comprising the following steps:
(1) adding carbazole and benzylamine into 1, 2-dichloroethane, stirring, adding anhydrous ferric trichloride as a catalyst, formaldehyde dimethyl ether as a cross-linking agent, slowly heating to perform a pre-crosslinking reaction, continuously heating to perform a crosslinking reaction, filtering after the reaction is finished, performing Soxhlet extraction on a precipitate obtained by filtering by adopting methanol and water, and then performing vacuum drying on the extracted product to obtain a nitrogen-doped super-crosslinked polymer nanosphere;
(2) mixing a mixed solution of palladium acetate and nickel acetate with the prepared nitrogen-doped super-crosslinked polymer nanospheres, drying, carbonizing the dried powder, stirring the carbonized powder in a hydrogen peroxide solution, and drying to prepare a honeycomb-shaped supported catalyst;
(3) adding the prepared honeycomb supported catalyst into a reactor, then adding 2, 4-difluoronitrobenzene, introducing hydrogen to replace air in the reactor, then heating to react, filtering to remove the catalyst after the reaction is finished, then distilling the filtrate under reduced pressure, and collecting fractions to prepare 2, 4-difluoroaniline;
(4) dropwise adding sodium fluoborate into the prepared 2, 4-difluoroaniline for dissolving in water, quickly cooling after dropwise adding, then dropwise adding a sodium nitrite aqueous solution, keeping the temperature for reaction after dropwise adding, allowing the diazonium salt intermediate prepared after the reaction to enter a thermal decomposer for thermal decomposition reaction to prepare 1,2, 4-trifluorobenzene, and absorbing the gas obtained by thermal decomposition by using the aqueous solution and reusing the gas in the diazotization reaction;
(5) adding paraformaldehyde and sodium bromide into a reaction bottle filled with a sulfuric acid solution respectively, then slowly adding the prepared 1,2, 4-trifluorobenzene, heating for reaction, quickly cooling the reaction solution after the reaction is finished, then adding ice water into the reaction system for hydrolysis, standing for layering, washing the water layer of the organic layer with deionized water to be neutral, and then carrying out reduced pressure distillation on the organic layer to obtain the target product 2,4, 5-trifluorobenzyl bromide.
2. The method for efficiently synthesizing 2,4, 5-trifluorobromobenzyl as a pharmaceutical intermediate according to claim 1, wherein in step (1), the preferable technical scheme is that the mass ratio of carbazole, benzylamine, anhydrous ferric chloride and formaldehyde dimethyl ether is 1: (0.5-0.7): 5.35: (3-4).
3. The efficient synthesis method of the pharmaceutical intermediate 2,4, 5-trifluorobromobenzyl according to claim 1, wherein in step (1), the temperature of the pre-crosslinking reaction is 40-50 ℃ and the time is 4-5 h; the temperature of the cross-linking reaction is 75-85 ℃, and the time is 15-20 h; the Soxhlet extraction time is 45-50 h.
4. The efficient synthesis method of the pharmaceutical intermediate 2,4, 5-trifluorobromobenzyl according to claim 1, wherein in step (2), the mass ratio of the palladium acetate, the nickel acetate and the nitrogen-doped hypercrosslinked polymer nanospheres is 5: (3-5): 10; the volume concentration of the hydrogen peroxide solution is 30 percent, the stirring treatment time is 3-5h, and the rotation speed of the stirring treatment is 800 revolutions per minute.
5. The efficient synthesis method of the pharmaceutical intermediate 2,4, 5-trifluorobromobenzyl according to claim 1, wherein in step (2), the temperature of the mixing treatment is normal temperature, and the treatment time is 20-25 h; the carbonization treatment conditions are as follows: heating to 500 deg.C at a rate of 3-5 deg.C/min, and maintaining for 1-2 h.
6. The efficient synthesis method of 2,4, 5-trifluorobromobenzyl as a medical intermediate according to claim 1, wherein in step (3), the dosage ratio of 2, 4-difluoronitrobenzene to honeycomb-shaped supported catalyst is 0.1 mol: (0.1-0.13) g; the temperature of the heating reaction is 50 ℃, the reaction pressure is 0.1MPa, and the reaction time is 2 h.
7. The efficient synthesis method of 2,4, 5-trifluorobromobenzyl as a pharmaceutical intermediate according to claim 1, wherein in step (4), the concentration of the sodium nitrite solution is 25 wt%, the concentration of the fluoroboric acid aqueous solution is 30 wt%, and the molar ratio of 2, 4-difluoroaniline, fluoroboric acid and sodium nitrite is 1 (3-5): (1-1.2).
8. The efficient synthesis method of the medical intermediate 2,4, 5-trifluorobromobenzyl according to claim 1, wherein in step (4), the dropping temperature of the fluoroboric acid aqueous solution is 10-25 ℃, the temperature of the heat preservation reaction is-20 ℃ to 5 ℃, and the time of the heat preservation reaction is 3-5 h. During thermal decomposition, firstly, the temperature is increased to 110 ℃ at the speed of 3-5 ℃/min, the temperature is kept for 1h, then the temperature is increased to 180 ℃ at the speed of 10 ℃/min, and the temperature is kept for 2-5 h.
9. The efficient synthesis method of 2,4, 5-trifluorobromobenzyl as a pharmaceutical intermediate of claim 1, wherein in the step (5), the molar ratio of the paraformaldehyde to the sodium bromide to the 1,2, 4-trifluorobenzene is 0.7: (0.7-0.8): (0.3-0.4).
10. The efficient synthesis method of the medical intermediate 2,4, 5-trifluorobromobenzyl according to claim 1, wherein in step (5), paraformaldehyde and sodium bromide are added while keeping the temperature of the reaction system at 20 ± 5 ℃, 1,2, 4-trifluorobenzene is added, the temperature is raised to 40 ± 2 ℃ for 8-12 hours, and the temperature is rapidly lowered to-5-0 ℃ after the reaction is finished.
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