CN117049938A - Preparation method of 6-bromo-2, 3-difluorotoluene - Google Patents
Preparation method of 6-bromo-2, 3-difluorotoluene Download PDFInfo
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- CN117049938A CN117049938A CN202310733270.2A CN202310733270A CN117049938A CN 117049938 A CN117049938 A CN 117049938A CN 202310733270 A CN202310733270 A CN 202310733270A CN 117049938 A CN117049938 A CN 117049938A
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- nitrobenzene
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- YXTCBTSPHSNDHD-UHFFFAOYSA-N 1-bromo-3,4-difluoro-2-methylbenzene Chemical compound CC1=C(Br)C=CC(F)=C1F YXTCBTSPHSNDHD-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 63
- ODMLBEQUDLHJMW-UHFFFAOYSA-N 1,2-difluoro-3-methyl-4-nitrobenzene Chemical compound CC1=C(F)C(F)=CC=C1[N+]([O-])=O ODMLBEQUDLHJMW-UHFFFAOYSA-N 0.000 claims abstract description 18
- HYODOAMUBRENLA-UHFFFAOYSA-N 3,4-difluoro-2-methylaniline Chemical compound CC1=C(N)C=CC(F)=C1F HYODOAMUBRENLA-UHFFFAOYSA-N 0.000 claims abstract description 18
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 14
- ARCACZWMYGILNI-UHFFFAOYSA-N 1,2,3-trifluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C(F)=C1F ARCACZWMYGILNI-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 4
- 230000000911 decarboxylating effect Effects 0.000 claims abstract description 3
- 238000006722 reduction reaction Methods 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 9
- 239000012044 organic layer Substances 0.000 claims description 8
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims description 6
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 6
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 6
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 235000010288 sodium nitrite Nutrition 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000012434 nucleophilic reagent Substances 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 2
- 239000007868 Raney catalyst Substances 0.000 claims description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 2
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 2
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims description 2
- 150000001649 bromium compounds Chemical group 0.000 claims description 2
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 claims description 2
- NCPHGZWGGANCAY-UHFFFAOYSA-N methane;ruthenium Chemical compound C.[Ru] NCPHGZWGGANCAY-UHFFFAOYSA-N 0.000 claims description 2
- 238000003825 pressing Methods 0.000 claims description 2
- 239000012038 nucleophile Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000003638 chemical reducing agent Substances 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 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 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 206010022000 influenza Diseases 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- ZNEHIDGAPGVZSA-UHFFFAOYSA-N 1,2-difluoro-3-methylbenzene Chemical compound CC1=CC=CC(F)=C1F ZNEHIDGAPGVZSA-UHFFFAOYSA-N 0.000 description 2
- 102000004533 Endonucleases Human genes 0.000 description 2
- 108010042407 Endonucleases Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 241000712461 unidentified influenza virus Species 0.000 description 2
- YMQPKONILWWJQG-UHFFFAOYSA-N 4-bromo-1,2-difluorobenzene Chemical compound FC1=CC=C(Br)C=C1F YMQPKONILWWJQG-UHFFFAOYSA-N 0.000 description 1
- 208000029433 Herpesviridae infectious disease Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of medicines, and relates to a method for preparing 6-bromo-2, 3-difluorotoluene. The preparation method comprises the steps of (a) carrying out nucleophilic substitution reaction on 2,3, 4-trifluoro nitrobenzene to obtain diethyl 2- (2, 3-difluoro-6-nitrobenzene) malonate; (b) Decarboxylating diethyl 2- (2, 3-difluoro-6-nitrobenzene) malonate obtained in the step (a) to obtain 1, 2-difluoro-3-methyl-4-nitrobenzene; (c) Carrying out a reduction reaction on the 1, 2-difluoro-3-methyl-4-nitrobenzene obtained in the step (b) in a reducing agent to obtain 3, 4-difluoro-2-methylaniline; (d) Diazotizing the 3, 4-difluoro-2-methylaniline obtained in the step (c) to obtain 6-bromo-2, 3-difluorotoluene. The method has the advantages of strong reaction selectivity and high reaction safety, and can realize industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a method for preparing 6-bromo-2, 3-difluorotoluene.
Background
Balofluo Sha Weizhi (baloxaverboxil) is a selective inhibitor of influenza virus cap-dependent endonucleases. The drug has been shown to be therapeutically active in preclinical models of influenza a and b virus infections, including strains resistant to current antiviral agents. Balo Sha Weizhi, which was approved by the FDA for marketing in 2018, is a novel anti-chemical book influenza drug with a novel mechanism of action that can selectively inhibit cap-dependent endonucleases and prevent polymerase function and influenza virus mRNA replication. Balo Sha Wei was developed from salt wild pharmacy and signed a protocol for co-global development and commercialization of balo Sha Wei with roche corporation, including roche corporation, U.S. gene tek, and currently salt wild/roche is developing influenza phase 3 clinic of balo Sha Weizhi in China.
6-bromo-2, 3-difluorotoluene is a key intermediate in the preparation of baluo Sha Weizhi (baloxovirmarboxil), and there are mainly 2 routes in the current state of the art: 1. WO2020/146682 reports that 6-bromo-2, 3-difluorotoluene is obtained by bromination of 2, 3-difluorotoluene, but the 2, 3-difluorotoluene is not commercially produced, and the production requirements of the 6-bromo-2, 3-difluorotoluene cannot be met. 2. CN112062750a reports methylation from 1-bromo-3, 4-difluorobenzene, but requires a low temperature of-70 ℃ for the reaction, which is a safety risk for production.
Disclosure of Invention
The invention aims to provide a preparation method of 6-bromo-2, 3-difluorotoluene, which is simple, safe and easy for mass production, and the specific technical scheme is as follows:
a method for preparing 6-bromo-2, 3-difluorotoluene, comprising the following steps:
(a) Nucleophilic substitution reaction is carried out on 2,3, 4-trifluoro nitrobenzene to obtain diethyl 2- (2, 3-difluoro-6-nitrobenzene) malonate;
(b) Decarboxylating diethyl 2- (2, 3-difluoro-6-nitrobenzene) malonate obtained in the step (a) to obtain 1, 2-difluoro-3-methyl-4-nitrobenzene;
(c) Carrying out reduction reaction on the 1, 2-difluoro-3-methyl-4-nitrobenzene obtained in the step (b) to obtain 3, 4-difluoro-2-methylaniline;
(d) Diazotizing the 3, 4-difluoro-2-methylaniline obtained in the step (c) to obtain 6-bromo-2, 3-difluorotoluene.
Further, the specific steps of the step (a) are as follows:
(1) Toluene and nucleophilic reagent are added into a reaction bottle, the temperature is reduced to 0 ℃, sodium tert-butoxide is slowly added in batches, and the mixture is stirred for standby;
(2) Adding toluene and 2,3, 4-trifluoro nitrobenzene into another reaction bottle, and cooling to 0 ℃;
(3) Dropwise adding the solution obtained in the step (1) into the solution obtained in the step (2), controlling the temperature, and stirring for 2h after the dropwise adding is finished;
(4) Adding water into the solution obtained in the step (3), separating the solution, and concentrating the organic phase under reduced pressure to obtain diethyl 2- (2, 3-difluoro-6-nitrobenzene) malonate.
Further, the nucleophilic reagent used in the nucleophilic substitution reaction in the step (a) is one or more of dimethyl malonate, diethyl malonate and dicarboxylic malonate; diethyl malonate is preferred;
the reaction temperature of the step (1) and the step (3) is-10-30 ℃; preferably-5 to 5 ℃;
the stirring time of the step (1) and the step (3) is 1-5 hours; preferably 2 to 3 hours;
the molar ratio of the 2,3, 4-trifluoro nitrobenzene to the nucleophilic reagent is 1:1-1:2; preferably 1:1 to 1:1.05.
Further, the preparation step of the step (b) comprises the following steps:
adding diethyl 2- (2, 3-difluoro-6-nitrobenzene) malonate obtained in the step (a) into a reaction bottle, adding water and concentrated sulfuric acid, heating, stirring for reaction, cooling to normal temperature after the reaction is finished, adding ethyl acetate for separating liquid, drying an organic layer, and concentrating to obtain the product 1, 2-difluoro-3-methyl-4-nitrobenzene.
Further, the reaction temperature in step (b) is 70 to 120 ℃, preferably 90 to 100 ℃;
the stirring reaction time is 10 to 24 hours, preferably 10 to 12 hours.
Further, the preparation method of the step (c) comprises the following steps:
adding the 1, 2-difluoro-3-methyl-4-nitrobenzene obtained in the step (b), a reducing agent and a solvent into a reaction bottle, pressing hydrogen after nitrogen replacement, heating, controlling pressure, stirring for reaction, filtering after the reaction is finished, and concentrating to obtain the product 3, 4-difluoro-2-methylaniline.
Further, the catalyst is one of palladium carbon, ruthenium carbon, platinum carbon and Raney nickel, and the solvent is methanol or hydrochloric acid; preferably, the reducing agent is palladium carbon, and the solvent is methanol; the reaction pressure is 0-3 MPa, preferably 0.3-0.6 MPa; the reaction temperature is 20-60 ℃, preferably 40-50 ℃; the reaction time is 6 to 12 hours, preferably 5 to 6 hours.
Further, the preparation method of the step (d) comprises the following steps:
adding the 3, 4-difluoro-2-methylaniline obtained in the step (c) into a reaction bottle, adding water and diazotizing acid, cooling to 0 ℃, adding sodium nitrite, stirring, adding brominating reagent in batches, stirring for reaction, adding ethyl acetate after the reaction is finished, separating liquid, drying an organic layer, concentrating, and distilling under reduced pressure to obtain the product 6-bromo-2, 3-difluorotoluene.
Further, the diazotized acid is hydrobromic, hydrochloric or sulfuric acid, preferably hydrobromic acid;
the molar ratio of 3, 4-difluoro-2-methylaniline to hydrobromic acid is 1:1-1:10, preferably 1:8-1:9;
the reaction temperature is-10 to 20 ℃, preferably 0 to 5 ℃;
the brominating reagent is bromide such as potassium bromide, sodium bromide, cuprous bromide and the like, preferably cuprous bromide;
stirring for 1-2 h after adding sodium nitrite; the stirring reaction time is 1 to 10 hours, preferably 4 to 6 hours.
Advantageous effects
1) The invention has mild reaction conditions and is easy to operate and control;
2) The comprehensive yield of the reaction steps is high;
3) The invention has strong reaction selectivity and high reaction safety;
4) The production process can realize industrial production, has low cost and has commercial advantage.
Drawings
FIG. 1 shows HNMR spectra of the product obtained in step (b) of the present invention;
FIG. 2 shows HNMR spectra of the product obtained in step (c) of the present invention;
FIG. 3 shows HNMR spectra of the product obtained in step (d) of the present invention.
Detailed Description
The above-described aspects of the present invention will be described in further detail with reference to the following embodiments. It should not be construed that the scope of the above subject matter of the present invention is limited to the following examples.
Example 1:
a method for preparing 6-bromo-2, 3-difluorotoluene, comprising the following steps:
step (a): preparation of diethyl 2- (2, 3-difluoro-6-nitrobenzene) malonate
Toluene (5L) and diethyl malonate (0.9 kg,5.65 mol) are added into a reaction bottle, the temperature is reduced to 0 ℃, sodium tert-butoxide (0.54 kg,5.6 mol) is slowly added in batches, and the mixture is stirred for 2 hours at the temperature of 0-5 ℃ for later use; toluene (5L), 2,3, 4-trifluoro nitrobenzene (1.0 kg,5.65 mol) is added into another reaction bottle, the temperature is reduced to 0 ℃, the solution is dripped, the temperature is controlled to be 0-5 ℃, the dripping is completed, the stirring is carried out for 2 hours at the temperature of 0-5 ℃, water (3L) is added after the reaction is completed, the liquid is separated, and the organic phase is decompressed and concentrated to obtain 2- (2, 3-difluoro-6-nitrobenzene) diethyl malonate, 1.7kg, the yield: 94.9%.
Step (b): preparation of 1, 2-difluoro-3-methyl-4-nitrobenzene
Diethyl 2- (2, 3-difluoro-6-nitrobenzene) malonate (1.5 kg,4.73 mol) was added into a reaction flask, water (2.5 kg), concentrated sulfuric acid (2.5 kg) was added, the temperature was raised to 90 ℃ and stirred for reaction, after the reaction was completed, ethyl acetate (15L) was added, the solution was separated, and the organic layer was dried and concentrated to obtain the product 1, 2-difluoro-3-methyl-4-nitrobenzene, 800g, yield: 97.7%.
Step (c): preparation of 3, 4-difluoro-2-methylaniline
1, 2-difluoro-3-methyl-4-nitrobenzene (0.7 kg,4.04 mol), 10% palladium carbon (0.1 kg), methanol (5L) are added into a reaction bottle, hydrogen is pressed in after nitrogen replacement, the temperature is raised to 40 ℃, the pressure is controlled to 0.3MPa, stirring reaction is carried out, after the reaction is finished, filtration and concentration are carried out, and the product 3, 4-difluoro-2-methylaniline is obtained, 550g, the yield is obtained: 95%.
1H NMR(400MHz,25℃,DMSO-d6)：2.00(3H,s),5.01(2H,s),6.38(1H,m)，6.90(1H,dd)。
Step (d): preparation of 1, 2-difluoro-3-methyl-4-nitrobenzene
3, 4-difluoro-2-methylaniline (0.5 kg,3.49 mol) is added into a reaction bottle, water (2.5 kg) and hydrobromic acid (2.26 kg) are added, the temperature is reduced to 0 ℃, sodium nitrite (0.29 kg,4.2 mol) is added, stirring is carried out for 1h, cuprous bromide (0.526 kg,3.66 mol) is added in batches, stirring reaction is carried out, ethyl acetate (5L) is added after the reaction is finished, liquid separation, an organic layer is dried, concentrated and distilled under reduced pressure, thus obtaining the product 6-bromo-2, 3-difluorotoluene, 650g, yield: 90%.
1H NMR(400MHz,CDCl3)d 7.36-7.42(m,1H),7.19(dd,1H),2.22(s,3H)ppm。
Example 2:
step (a): preparation of diethyl 2- (2, 3-difluoro-6-nitrobenzene) malonate
In a reaction bottle, adding dimethylbenzene (5L), diethyl malonate (0.9 kg,5.65 mol), cooling to 0 ℃, slowly adding potassium tert-butoxide (0.63 kg,5.6 mol) in batches, and stirring at 0-5 ℃ for 2h for later use; in another reaction flask, xylene (5L), 2,3, 4-trifluoronitrobenzene (1.0 kg,5.65 mol) is added, the temperature is reduced to 5 ℃, the solution is added dropwise, the temperature is controlled to be 0-5 ℃, the mixture is stirred for 2 hours at the temperature of 0-5 ℃, water (3L) is added after the reaction is finished, the liquid is separated, and the organic phase is concentrated under reduced pressure to obtain diethyl 2- (2, 3-difluoro-6-nitrobenzene) malonate, 1.67kg, the yield: 93.1%.
Step (b): preparation of 1, 2-difluoro-3-methyl-4-nitrobenzene
Diethyl 2- (2, 3-difluoro-6-nitrobenzene) malonate (1.5 kg,4.73 mol) is added into a reaction bottle, water (2.5 kg) and phosphoric acid (9 kg) are added, the temperature is raised to 90 ℃, the reaction is stirred, the temperature is reduced after the reaction is finished, dichloromethane (15L) is added, the liquid is separated, the organic layer is dried, concentrated and rectified to obtain the product 1, 2-difluoro-3-methyl-4-nitrobenzene, 671g, yield: 82%.
1H NMR(400MHz,25℃,DMSO-d6)：2.45(3H,s),7.56(1H,dd),7.95(1H,m)。
Step (c): preparation of 3, 4-difluoro-2-methylaniline
1, 2-difluoro-3-methyl-4-nitrobenzene (0.7 kg,4.04 mol), 5% palladium carbon (0.1 kg), tetrahydrofuran (5L) were added into a reaction flask, nitrogen was replaced, hydrogen was pressed in, the temperature was raised to 30 ℃, 0.3-0.5MPa was maintained, the reaction was stirred, the reaction was completed, filtration and concentration were carried out, and 3, 4-difluoro-2-methylaniline was obtained as a product, 538g, yield: 95%.
1H NMR(400MHz,25℃,DMSO-d6)：2.00(3H,s),5.01(2H,s),6.38(1H,m)，6.90(1H,dd)。
Step (d): preparation of 1, 2-difluoro-3-methyl-4-nitrobenzene
3, 4-difluoro-2-methylaniline (0.5 kg,3.49 mol) is added into a reaction bottle, water (2.5 kg) and hydrochloric acid (1.5L) are added, the temperature is reduced to 0 ℃, sodium nitrite (0.29 kg,4.2 mol) is added, stirring is carried out for 1h, cuprous bromide (0.526 kg,3.66 mol) is added in batches, stirring reaction is carried out, ethyl acetate (5L) is added after the reaction is finished, liquid separation, an organic layer is dried, concentrated and distilled under reduced pressure, thus obtaining the product 6-bromo-2, 3-difluorotoluene, 585g, yield: 81%.
1 H NMR(400MHz,CDCl 3 )d 7.36-7.42(m,1H),7.19(dd,1H),2.22(s,3H)ppm。
Claims (9)
1. A method for preparing 6-bromo-2, 3-difluorotoluene, comprising the following steps:
(a) Nucleophilic substitution reaction is carried out on 2,3, 4-trifluoro nitrobenzene to obtain diethyl 2- (2, 3-difluoro-6-nitrobenzene) malonate;
(b) Decarboxylating diethyl 2- (2, 3-difluoro-6-nitrobenzene) malonate obtained in the step (a) to obtain 1, 2-difluoro-3-methyl-4-nitrobenzene;
(c) Carrying out reduction reaction on the 1, 2-difluoro-3-methyl-4-nitrobenzene obtained in the step (b) to obtain 3, 4-difluoro-2-methylaniline;
(d) Diazotizing the 3, 4-difluoro-2-methylaniline obtained in the step (c) to obtain 6-bromo-2, 3-difluorotoluene.
2. The method for preparing 6-bromo-2, 3-difluorotoluene according to claim 1, wherein the specific steps of step (a) are as follows:
(1) Toluene and nucleophilic reagent are added into a reaction bottle, the temperature is reduced to 0 ℃, sodium tert-butoxide is slowly added in batches, and the mixture is stirred for standby;
(2) Adding toluene and 2,3, 4-trifluoro nitrobenzene into another reaction bottle, and cooling to 0 ℃;
(3) Dropwise adding the solution obtained in the step (1) into the solution obtained in the step (2), controlling the temperature, and stirring for 2h after the dropwise adding is finished;
(4) Adding water into the solution obtained in the step (3), separating the solution, and concentrating the organic phase under reduced pressure to obtain diethyl 2- (2, 3-difluoro-6-nitrobenzene) malonate.
3. The method for preparing 6-bromo-2, 3-difluorotoluene according to claim 2, wherein the nucleophile in step (a) is one or more of dimethyl malonate, diethyl malonate, and dicarboxylic malonate; diethyl malonate is preferred;
the reaction temperature of the step (1) and the step (3) is-10-30 ℃; preferably-5 to 5 ℃;
the stirring time of the step (1) and the step (3) is 1-5 hours; preferably 2 to 3 hours;
the molar ratio of the 2,3, 4-trifluoro nitrobenzene to the nucleophilic reagent is 1:1-1:2; preferably 1:1 to 1:1.05.
4. The process for producing 6-bromo-2, 3-difluorotoluene according to claim 1, wherein,
the preparation step of the step (b) comprises the following steps:
adding diethyl 2- (2, 3-difluoro-6-nitrobenzene) malonate obtained in the step (a) into a reaction bottle, adding water and concentrated sulfuric acid, heating, stirring for reaction, cooling to normal temperature after the reaction is finished, adding ethyl acetate for separating liquid, drying an organic layer, and concentrating to obtain the product 1, 2-difluoro-3-methyl-4-nitrobenzene.
5. The process for the preparation of 6-bromo-2, 3-difluorotoluene according to claim 1, wherein the reaction temperature in step (b) is from 70 to 120 ℃, preferably from 90 to 100 ℃;
the stirring reaction time is 10 to 24 hours, preferably 10 to 12 hours.
6. The process for producing 6-bromo-2, 3-difluorotoluene according to claim 1, wherein,
the preparation method of the step (c) comprises the following steps:
adding the 1, 2-difluoro-3-methyl-4-nitrobenzene obtained in the step (b), a catalyst and a solvent into a reaction bottle, pressing hydrogen after nitrogen replacement, heating, controlling pressure, stirring for reaction, filtering after the reaction is finished, and concentrating to obtain the product 3, 4-difluoro-2-methylaniline.
7. The method for preparing 6-bromo-2, 3-difluorotoluene according to claim 6, wherein the catalyst is one of palladium carbon, ruthenium carbon, platinum carbon and raney nickel, and the solvent is methanol or hydrochloric acid; preferably, the catalyst is palladium carbon, and the solvent is methanol; the reaction pressure is 0-3 MPa, preferably 0.3-0.6 MPa; the reaction temperature is 20-60 ℃, preferably 40-50 ℃; the reaction time is 6 to 12 hours, preferably 5 to 6 hours.
8. The process for producing 6-bromo-2, 3-difluorotoluene according to claim 1, wherein,
the preparation method of the step (d) comprises the following steps:
adding the 3, 4-difluoro-2-methylaniline obtained in the step (c) into a reaction bottle, adding water and diazotizing acid, cooling to 0 ℃, adding sodium nitrite, stirring, adding brominating reagent in batches, stirring for reaction, adding ethyl acetate after the reaction is finished, separating liquid, drying an organic layer, concentrating, and distilling under reduced pressure to obtain the product 6-bromo-2, 3-difluorotoluene.
9. The process for the preparation of 6-bromo-2, 3-difluorotoluene according to claim 8, wherein said diazotising acid is hydrobromic, hydrochloric or sulfuric acid, preferably hydrobromic acid;
the molar ratio of 3, 4-difluoro-2-methylaniline to hydrobromic acid is 1:1-1:10, preferably 1:8-1:9;
the reaction temperature is-10 to 20 ℃, preferably 0 to 5 ℃;
the brominating reagent is bromide such as potassium bromide, sodium bromide, cuprous bromide and the like, preferably cuprous bromide;
stirring for 1-2 h after adding sodium nitrite; the stirring reaction time is 1 to 10 hours, preferably 4 to 6 hours.
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