CN101168495B - Method for synthesizing 1-bromo-2,4,5-trifluorobenzene - Google Patents
Method for synthesizing 1-bromo-2,4,5-trifluorobenzene Download PDFInfo
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- CN101168495B CN101168495B CN2007101569077A CN200710156907A CN101168495B CN 101168495 B CN101168495 B CN 101168495B CN 2007101569077 A CN2007101569077 A CN 2007101569077A CN 200710156907 A CN200710156907 A CN 200710156907A CN 101168495 B CN101168495 B CN 101168495B
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- trifluoro
- benzene
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- 238000000034 method Methods 0.000 title claims abstract description 11
- DVTULTINXNWGJY-UHFFFAOYSA-N 1-Bromo-2,4,5-trifluorobenzene Chemical compound FC1=CC(F)=C(Br)C=C1F DVTULTINXNWGJY-UHFFFAOYSA-N 0.000 title description 5
- 230000002194 synthesizing effect Effects 0.000 title 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 36
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 33
- 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
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 75
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 54
- 238000001035 drying Methods 0.000 claims description 46
- 238000010792 warming Methods 0.000 claims description 46
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 claims description 34
- 239000000706 filtrate Substances 0.000 claims description 31
- 239000012044 organic layer Substances 0.000 claims description 31
- 235000010265 sodium sulphite Nutrition 0.000 claims description 27
- 238000003756 stirring Methods 0.000 claims description 27
- 238000010189 synthetic method Methods 0.000 claims description 9
- 238000000746 purification Methods 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- 239000012141 concentrate Substances 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 125000001246 bromo group Chemical class Br* 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 abstract description 7
- 238000001308 synthesis method Methods 0.000 abstract 2
- 238000004448 titration Methods 0.000 description 42
- 239000006210 lotion Substances 0.000 description 23
- 239000000047 product Substances 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- 238000001816 cooling Methods 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 21
- 238000010907 mechanical stirring Methods 0.000 description 21
- 238000010992 reflux Methods 0.000 description 21
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a synthesis method of 1-bromine-2, 4, 5-trifluoro-benzene, which adds iron powder and 1, 2, 4-trifluoro-benzene into organic solvent, adds liquid bromine at 43-48DEG C in 3-4h, increases temperature to 62-68DEG C, adds azobisisobutyronitrile, mixes, reacts at 82-102DEG C completely to obtain reaction solution, to be purified to obtain 1-bromine-2, 4, 5-trifluoro-benzene. The mass ratio between the 1-bromine-2, 4, 5-trifluoro-benzene, liquid bromine, iron powder, and azobisisobutyronitrile is 1:0.5-1.5:0.025-0.050:0.002-0.006, the organic solvent is azobisisobutyronitrile or chloroform, of which the volume is 250-300ml/mol according to 1-bromine-2, 4, 5-trifluoro-benzene. Compared with prior synthesis method of 1-bromine-2, 4, 5-trifluoro-benzene, the invention has high yield, low cost, simple process and little environment pollution.
Description
(1) technical field
A kind of synthetic 1-bromo-2,4 of the present invention, the novel method of 5-trifluoro-benzene.
(2) background technology
1-bromo-2,4,5-trifluoro-benzene are the important intermediate of broad-spectrum antimicrobial quinolones, English name: 1-bromo-2,4,5-trifluorobenzene, these product are colourless transparent liquid, fusing point-19 ℃, 144 ℃ of boiling points, 55 ℃ of flash-points, refractive index 1.4860, proportion 1.758.About 1-bromo-2,4, the synthetic of 5-trifluoro-benzene is to utilize 1,2,4 at present, and 5-tetrabromo fluorobenzene carries out, but its cost of material is more expensive, the synthesis technique complexity, and products obtained therefrom purity is low, and not easily separated purification.
(3) summary of the invention
The object of the present invention is to provide a kind of low cost, oligosaprobic synthetic 1-bromo-2,4, the method for 5-trifluoro-benzene.
For reaching goal of the invention the technical solution used in the present invention be:
In organic solvent, add iron powder and 1,2, the 4-trifluoro-benzene in 43～48 ℃ of adding liquid bromines, slowly added in 3～4 hours, be warming up to 62～68 ℃ and add Diisopropyl azodicarboxylate, stir evenly, in 82～102 ℃ react completely reaction solution, after the reaction solution purification process, get 1-bromo-2,4,5-trifluoro-benzene, described 1,2,4-trifluoro-benzene: liquid bromine: iron powder: Diisopropyl azodicarboxylate amount of substance ratio is 1: 0.5～1.5: 0.025～0.050: 0.002～0.006, and described organic solvent is tetracol phenixin or chloroform, and described volume of organic solvent consumption is with 1-bromo-2,4, the 5-trifluoro-benzene is counted 250～300ml/mol.
Purification process of the present invention is, the reaction solution cold filtration is got filtrate, and gained filtrate is the washings of 15～25% sodium sulfite solution with concentration, the volumetric usage of described sodium sulfite solution is with 1-bromo-2,4, and the 5-trifluoro-benzene is counted 250～350ml/mol, stir layering, isolate organic layer, organic layer is 7-9 with 5～20% sodium hydroxide solution lotion to pH value, use the siccative drying, filter, filtrate concentrates, promptly get 1-bromo-2,4, the 5-trifluoro-benzene, described siccative is preferably anhydrous MgSO
4
Of the present invention 1,2,4-trifluoro-benzene: liquid bromine: iron powder: Diisopropyl azodicarboxylate amount of substance ratio is preferably 1: 0.75～and 1.25: 0.029～0.045: 0.003～0.005, more preferably 1: 1: 0.036: 0.004.
Organic solvent of the present invention is preferably tetracol phenixin.
The method of the invention is preferably: add iron powder and 1 in organic solvent, 2, the 4-trifluoro-benzene in 43～48 ℃ of adding liquid bromines, added in 3～4 hours, be warming up to 62～68 ℃ and add Diisopropyl azodicarboxylate stirring 1-4 hour, got reaction solution fully in 3～5 hours in 82～102 ℃ of reactions, the reaction solution purification process gets 1-bromo-2,4,5-trifluoro-benzene, described organic solvent are tetracol phenixin or chloroform.
The present invention recommends described method specifically to may further comprise the steps: add iron powder and 1 in tetracol phenixin, 2, the 4-trifluoro-benzene, in 45 ℃ with adding the liquid bromine in 4 hours, adding Diisopropyl azodicarboxylate (AIBN) in 65 ℃ stirred 2 hours, in 90～95 ℃ of reactions 4 hours, cold filtration, gained filtrate is washed with 20% sodium sulfite solution, and described sodium sulfite solution volumetric usage is with 1-bromo-2,4, the 5-trifluoro-benzene is counted 300ml/mol, isolate organic layer, organic layer is 7-9 with 10% sodium hydroxide lotion to pH value, gets the anhydrous MgSO of organic layer
4Drying is filtered, and filtrate concentrates, and promptly gets 1-bromo-2,4, the 5-trifluoro-benzene; Described 1,2,4-trifluoro-benzene: liquid bromine: iron powder: Diisopropyl azodicarboxylate amount of substance ratio is 1: 1: 0.036: 0.004; The volumetric usage of described tetracol phenixin is with 1-bromo-2,4, and the 5-trifluoro-benzene is counted 300ml/mol.
The beneficial effect of the relative prior art of the present invention is that yield is higher, cost is low, flow process is simple, and environmental pollution is little.
(4) embodiment
The invention will be further described below in conjunction with embodiment, but protection scope of the present invention is not limited to this.
Embodiment 1.
1,2,4-trifluoro-benzene 13.2g (100mmol), CCl
425ml, iron powder 0.16g (2.857mmol), mechanical stirring is heated to 45 ℃, on reflux condensing tube, add constant voltage titration funnel, load onto drying tube on the constant voltage titration funnel, slowly dropping liquid bromine 12.0g (75mmol) dripped off in 4 hours, be warming up to 65 ℃ and add Diisopropyl azodicarboxylate 49mg (0.298mmol), stirred 2 hours, and be warming up to 82 ℃, reacted 3 hours.Cooling adds 20% sodium sulfite solution 30ml, stirs 10 minutes, tells organic layer, the sodium hydroxide lotion with 10%, and being washed till pH value is 8, uses anhydrous MgSO
4Drying is filtered, and filtrate is concentrated, and gets product 12.1g, and detecting purity through HPLC is 99.2%, 1H-NMR (CDCl
3) δ: 7.38 (Ar-H), 7.02 (m, H Ar-H), are 1-bromo-2,4, and 5-trifluoro-benzene, yield are 57% for m, H.
Embodiment 2.
1,2,4-trifluoro-benzene 13.2g (100mmol), CCl
425ml, iron powder 0.2g (3.571mmol), mechanical stirring is heated to 45 ℃, on reflux condensing tube, add constant voltage titration funnel, load onto drying tube on the constant voltage titration funnel, slowly dropping liquid bromine 12.0g (75mmol) dripped off in 4 hours, be warming up to 65 ℃ and add Diisopropyl azodicarboxylate 66mg (0.402mmol), stirred 2 hours, and be warming up to 92 ℃, reacted 4 hours.Cooling adds 20% sodium sulfite solution 30ml, stirs 10 minutes, tells organic layer, the sodium hydroxide lotion with 10%, and being washed till pH value is 8, uses MgSO
4Drying is filtered, and filtrate is concentrated, and gets product 13.9g, and detecting purity through HPLC is 99.2%, 1H-NMR (CDCl
3) δ: 7.38 (Ar-H), 7.02 (m, H Ar-H), are 1-bromo-2,4, and 5-trifluoro-benzene, yield are 66% for m, H.
Embodiment 3.
1,2,4-trifluoro-benzene 13.2g (100mmol), CCl
425ml, iron powder 0.25g (4.464mmol), mechanical stirring is heated to 45 ℃, on reflux condensing tube, add constant voltage titration funnel, load onto drying tube on the constant voltage titration funnel, slowly dropping liquid bromine 12.0g (75mmol) dripped off in 4 hours, be warming up to 65 ℃ and add Diisopropyl azodicarboxylate 82mg (0.499mmol), stirred 2 hours, and be warming up to 102 ℃, reacted 5 hours.Cooling adds 20% sodium sulfite solution 30ml, stirs 10 minutes, tells organic layer, the sodium hydroxide lotion with 10%, and being washed till pH value is 8, uses anhydrous MgSO
4Drying is filtered, and filtrate is concentrated, and gets product 13.4g, and detecting purity through HPLC is 99.2%, 1H-NMR (CDCl
3) δ: 7.38 (Ar-H), 7.02 (m, H Ar-H), are 1-bromo-2,4, and 5-trifluoro-benzene, yield are 64% for m, H.
Embodiment 4.
1,2,4-trifluoro-benzene 13.2g (100mmol), CCl
425ml, iron powder 0.16g (2.857mmol), mechanical stirring is heated to 45 ℃, on reflux condensing tube, add constant voltage titration funnel, load onto drying tube on the constant voltage titration funnel, slowly dropping liquid bromine 16.0g (100mmol) dripped off in 4 hours, be warming up to 65 ℃ and add Diisopropyl azodicarboxylate 49mg (0.298mmol), stirred 2 hours, and be warming up to 82 ℃, reacted 3 hours.Cooling adds 20% sodium bisulfite 30ml, stirs 10 minutes, tells organic layer, the sodium hydroxide lotion with 10%, and being washed till pH value is 8, uses anhydrous MgSO
4Drying is filtered, and filtrate is concentrated, and gets product 12.8g, and detecting purity through HPLC is 99.2%, 1H-NMR (CDCl
3) δ: 7.38 (Ar-H), 7.02 (m, H Ar-H), are 1-bromo-2,4, and 5-trifluoro-benzene, yield are 61% for m, H.
Embodiment 5.
1,2,4-trifluoro-benzene 13.2g (100mmol), CCl
425ml, iron powder 0.2g (3.571mmol), mechanical stirring is heated to 45 ℃, on reflux condensing tube, add constant voltage titration funnel, load onto drying tube on the constant voltage titration funnel, slowly dropping liquid bromine 16.0g (100mmol) dripped off in 4 hours, be warming up to 65 ℃ and add Diisopropyl azodicarboxylate 66mg (0.402mmol), stirred 2 hours, and be warming up to 92 ℃, reacted 4 hours.Cooling adds 20% sodium sulfite solution 30ml, stirs 10 minutes, tells organic layer, the sodium hydroxide lotion with 10%, and being washed till pH value is 8, uses anhydrous MgSO
4Drying is filtered, and filtrate is concentrated, and gets product 14.7g, and detecting purity through HPLC is 99.2%, 1H-NMR (CDCl
3) δ: 7.38 (Ar-H), 7.02 (m, H Ar-H), are 1-bromo-2,4, and 5-trifluoro-benzene, yield are 70% for m, H.
Embodiment 6
1,2,4-trifluoro-benzene 13.2g (100mmol), CCl
425ml, iron powder 0.25g (4.464mmol), mechanical stirring is heated to 45 ℃, adds constant voltage titration funnel on reflux condensing tube, load onto drying tube on the constant voltage titration funnel, slowly dropping liquid bromine 16.0g (100mmol) dripped off in 4 hours, was warming up to 65 ℃ and added Diisopropyl azodicarboxylate 82mg (0.50mmol) stirring 2 hours, be warming up to 102 ℃, reacted 5 hours.Cooling adds 20% sodium sulfite solution 30ml, stirs 10 minutes, tells organic layer, the sodium hydroxide lotion with 10%, and being washed till pH value is 8, uses anhydrous MgSO
4Drying is filtered, and filtrate is concentrated, and gets product 14.3g, and detecting purity through HPLC is 99.2%, 1H-NMR (CDCl
3) δ: 7.38 (Ar-H), 7.02 (m, H Ar-H), are 1-bromo-2,4, and 5-trifluoro-benzene, yield are 68% for m, H.
Embodiment 7.
1,2,4-trifluoro-benzene 13.2g (100mmol), CCl
425ml, iron powder 0.16g (2.857mmol), mechanical stirring is heated to 45 ℃, on reflux condensing tube, add constant voltage titration funnel, load onto drying tube on the constant voltage titration funnel, slowly dropping liquid bromine 20.0g (125mmol) dripped off in 4 hours, be warming up to 65 ℃ and add Diisopropyl azodicarboxylate 49mg (0.298mol), stirred 2 hours, and be warming up to 82 ℃, reacted 3 hours.Cooling adds 20% sodium sulfite solution 30ml, stirs 10 minutes, tells organic layer, the sodium hydroxide lotion with 10%, and being washed till pH value is 8, uses anhydrous MgSO
4Drying is filtered, and filtrate is concentrated, and gets product 12.2g, and detecting purity through HPLC is 99.2%, 1H-NMR (CDCl
3) δ: 7.38 (Ar-H), 7.02 (m, H Ar-H), are 1-bromo-2,4, and 5-trifluoro-benzene, yield are 58% for m, H.
Embodiment 8.
1,2,4-trifluoro-benzene 13.2g (100mmol), CCl
425ml, iron powder 0.2g_ (3.571mmol), mechanical stirring is heated to 45 ℃, on reflux condensing tube, add constant voltage titration funnel, load onto drying tube on the constant voltage titration funnel, slowly dropping liquid bromine 20.0g (125mmol) dripped off in 4 hours, be warming up to 65 ℃ and add Diisopropyl azodicarboxylate 66mg (0.402mmol), stirred 2 hours, and be warming up to 92 ℃, reacted 4 hours.Cooling adds 20% sodium bisulfite 30ml, stirs 10 minutes, tells organic layer, the sodium hydroxide lotion with 10%, and being washed till pH value is 8, uses MgSO
4Drying is filtered, and filtrate is concentrated, and gets product 13.9g, and detecting purity through HPLC is 99.2%, 1H-NMR (CDCl
3) δ: 7.38 (Ar-H), 7.02 (m, H Ar-H), are 1-bromo-2,4, and 5-trifluoro-benzene, yield are 66% for m, H.
Embodiment 9
1,2,4-trifluoro-benzene 13.2g (100mmol), CCl
425ml, iron powder 0.2g (3.571mmol), mechanical stirring is heated to 45 ℃, on reflux condensing tube, add constant voltage titration funnel, load onto drying tube on the constant voltage titration funnel, slowly dropping liquid bromine 20.0g (125mmol) dripped off in 4 hours, be warming up to 65 ℃ and add Diisopropyl azodicarboxylate 82mg (0.499mmol), stirred 2 hours, and be warming up to 102 ℃, reacted 5 hours.Cooling adds 20% sodium sulfite solution 30ml, stirs 10 minutes, tells organic layer, the sodium hydroxide lotion with 10%, and being washed till pH value is 8, uses anhydrous MgSO
4Drying is filtered, and filtrate is concentrated, and gets product 12.6g, and detecting purity through HPLC is 99.2%, 1H-NMR (CDCl
3) δ: 7.38 (Ar-H), 7.02 (m, H Ar-H), are 1-bromo-2,4, and 5-trifluoro-benzene, yield are 60% for m, H.
Embodiment 10
1,2,4-trifluoro-benzene 13.2g (100mmol), CCl
425ml, iron powder 0.16g (2.857mmol), mechanical stirring, be heated to 45 ℃, on reflux condensing tube, add constant voltage titration funnel, load onto drying tube on the constant voltage titration funnel, slowly dropping liquid bromine 16.0g, (100mmol), dripped off in 4 hours, and be warming up to 65 ℃ and add Diisopropyl azodicarboxylate 66mg (0.402mmol), stirred 2 hours, be warming up to 92 ℃, reacted 5 hours.Cooling adds 20% sodium sulfite solution 30ml, stirs 10 minutes, tells organic layer, the sodium hydroxide lotion with 10%, and being washed till pH value is 8, uses anhydrous MgSO
4Drying is filtered, and filtrate is concentrated, and gets product 14.5g, and detecting purity through HPLC is 99.2%, 1H-NMR (CDCl
3) δ: 7.38 (Ar-H), 7.02 (m, H Ar-H), are 1-bromo-2,4, and 5-trifluoro-benzene, yield are 69% for m, H.
Embodiment 11
1,2,4-trifluoro-benzene 13.2g (100mmol), CCl
425ml, iron powder 0.25g (4.464mmol), mechanical stirring is heated to 45 ℃, on reflux condensing tube, add constant voltage titration funnel, load onto drying tube on the constant voltage titration funnel, slowly dropping liquid bromine 16.0g (100mmol) dripped off in 4 hours, be warming up to 65 ℃ and add Diisopropyl azodicarboxylate 49mg (0.298mmol), stirred 2 hours, and be warming up to 82 ℃, reacted 3 hours.Cooling adds 20% sodium sulfite solution 30ml, stirs 10 minutes, tells organic layer, the sodium hydroxide lotion with 10%, and being washed till pH value is 8, uses anhydrous MgSO
4Drying is filtered, and filtrate is concentrated, and gets product 13.7g, and detecting purity through HPLC is 99.2%, 1H-NMR (CDCl
3) δ: 7.38 (Ar-H), 7.02 (m, H Ar-H), are 1-bromo-2,4, and 5-trifluoro-benzene, yield are 65% for m, H.
Embodiment 12.
1,2,4-trifluoro-benzene 13.2g (100mmol), CCl
425ml, iron powder 0.2g (3.571mmol), mechanical stirring is heated to 45 ℃, on reflux condensing tube, add constant voltage titration funnel, load onto drying tube on the constant voltage titration funnel, slowly dropping liquid bromine 12.0g (75mmol) dripped off in 4 hours, be warming up to 65 ℃ and add Diisopropyl azodicarboxylate 49mg (0.298mmol), stirred 2 hours, and be warming up to 92 ℃, reacted 3 hours.Cooling adds 20% sodium sulfite solution 30ml, stirs 10 minutes, tells organic layer, the sodium hydroxide lotion with 10%, and being washed till pH value is 8, uses anhydrous MgSO
4Drying is filtered, and filtrate is concentrated, and gets product 13.0g, and detecting purity through HPLC is 99.2%, 1H-NMR (CDCl
3) δ: 7.38 (Ar-H), 7.02 (m, H Ar-H), are 1-bromo-2,4, and 5-trifluoro-benzene, yield are 62% for m, H.
Embodiment 13.
1,2,4-trifluoro-benzene 13.2g (100mmol), CCl
427ml, iron powder 0.14g (2.450mmol), mechanical stirring is heated to 43 ℃, on reflux condensing tube, add constant voltage titration funnel, load onto drying tube on the constant voltage titration funnel, slowly dropping liquid bromine 8.0g (50mmol) dripped off in 4 hours, be warming up to 68 ℃ and add Diisopropyl azodicarboxylate 98mg (0.608mmol), stirred 1 hour, and be warming up to 82 ℃, reacted 3 hours.Cooling adds 15% sodium sulfite solution 30ml, stirs 10 minutes, tells organic layer, the sodium hydroxide lotion with 20%, and being washed till pH value is 8, uses anhydrous MgSO
4Drying is filtered, and filtrate is concentrated, and gets product 12.5g, and detecting purity through HPLC is 99.2%, 1H-NMR (CDCl
3) δ: 7.38 (Ar-H), 7.02 (m, H Ar-H), are 1-bromo-2,4, and 5-trifluoro-benzene, yield are 59% for m, H.
Embodiment 14.
1,2,4-trifluoro-benzene 13.2g (100mmol), CCl
427ml, iron powder 0.14g (2.450mmol), mechanical stirring is heated to 43 ℃, on reflux condensing tube, add constant voltage titration funnel, load onto drying tube on the constant voltage titration funnel, slowly dropping liquid bromine 8.0g (50mmol) dripped off in 4 hours, be warming up to 65 ℃ and add Diisopropyl azodicarboxylate 98mg (0.608mmol), stirred 3 hours, and be warming up to 95 ℃, reacted 3 hours.Cooling adds 15% sodium sulfite solution 30ml, stirs 10 minutes, tells organic layer, the sodium hydroxide lotion with 5%, and being washed till pH value is 8, uses anhydrous MgSO
4Drying is filtered, and filtrate is concentrated, and gets product 13.2g, and detecting purity through HPLC is 99.2%, 1H-NMR (CDCl
3) δ: 7.38 (Ar-H), 7.02 (m, H Ar-H), are 1-bromo-2,4, and 5-trifluoro-benzene, yield are 63% for m, H.
Embodiment 15.
1,2,4-trifluoro-benzene 13.2g (100mmol), CCl
425ml, iron powder 0.14g (2.450mmol), mechanical stirring is heated to 43 ℃, on reflux condensing tube, add constant voltage titration funnel, load onto drying tube on the constant voltage titration funnel, slowly dropping liquid bromine 8.0g (50mmol) dripped off in 4 hours, be warming up to 62 ℃ and add Diisopropyl azodicarboxylate 32mg (0.201mmol), stirred 2 hours, and be warming up to 90 ℃, reacted 4 hours.Cooling adds 25% sodium sulfite solution 30ml, stirs 10 minutes, tells organic layer, the sodium hydroxide lotion with 20%, and being washed till pH value is 8, uses anhydrous MgSO
4Drying is filtered, and filtrate is concentrated, and gets product 13.4g, and detecting purity through HPLC is 99.2%, 1H-NMR (CDCl
3) δ: 7.38 (Ar-H), 7.02 (m, H Ar-H), are 1-bromo-2,4, and 5-trifluoro-benzene, yield are 64% for m, H.
Embodiment 16.
1,2,4-trifluoro-benzene 13.2g (100mmol), CCl
430ml, iron powder 0.28g (5.013mmol), mechanical stirring is heated to 43 ℃, on reflux condensing tube, add constant voltage titration funnel, load onto drying tube on the constant voltage titration funnel, slowly dropping liquid bromine 24.0g (150mmol) dripped off in 4 hours, be warming up to 68 ℃ and add Diisopropyl azodicarboxylate 49mg (0.298mmol), stirred 1 hour, and be warming up to 82 ℃, reacted 5 hours.Cooling adds 15% sodium sulfite solution 30ml, stirs 10 minutes, tells organic layer, the sodium hydroxide lotion with 20%, and being washed till pH value is 8, uses anhydrous MgSO
4Drying is filtered, and filtrate is concentrated, and gets product 12.6g, and detecting purity through HPLC is 99.2%, 1H-NMR (CDCl
3) δ: 7.38 (Ar-H), 7.02 (m, H Ar-H), are 1-bromo-2,4, and 5-trifluoro-benzene, yield are 60% for m, H.
Embodiment 17.
1,2,4-trifluoro-benzene 13.2g (100mmol), CHCl
327ml, iron powder 0.14g (2.450mmol), mechanical stirring is heated to 43 ℃, on reflux condensing tube, add constant voltage titration funnel, load onto drying tube on the constant voltage titration funnel, slowly dropping liquid bromine 8.0g (50mmol) dripped off in 4 hours, be warming up to 68 ℃ and add Diisopropyl azodicarboxylate 98mg (0.608mmol), stirred 1 hour, and be warming up to 82 ℃, reacted 3 hours.Cooling adds 15% sodium sulfite solution 30ml, stirs 10 minutes, tells organic layer, the sodium hydroxide lotion with 20%, and being washed till pH value is 8, uses anhydrous MgSO
4Drying is filtered, and filtrate is concentrated, and gets product 12.5g, and detecting purity through HPLC is 99.2%, 1H-NMR (CDCl
3) δ: 7.38 (Ar-H), 7.02 (m, H Ar-H), are 1-bromo-2,4, and 5-trifluoro-benzene, yield are 59% for m, H.
Embodiment 18.
1,2,4-trifluoro-benzene 13.2g (100mmol), CHCl
327ml, iron powder 0.14g (2.450mmol), mechanical stirring is heated to 43 ℃, on reflux condensing tube, add constant voltage titration funnel, load onto drying tube on the constant voltage titration funnel, slowly dropping liquid bromine 8.0g (50mmol) dripped off in 4 hours, be warming up to 65 ℃ and add Diisopropyl azodicarboxylate 98mg (0.608mmol), stirred 3 hours, and be warming up to 95 ℃, reacted 3 hours.Cooling adds 15% sodium sulfite solution 25ml, stirs 10 minutes, tells organic layer, the sodium hydroxide lotion with 5%, and being washed till pH value is 8, uses anhydrous MgSO
4Drying is filtered, and filtrate is concentrated, and gets product 13.0g, and detecting purity through HPLC is 99.2%, 1H-NMR (CDCl
3) δ: 7.38 (Ar-H), 7.02 (m, H Ar-H), are 1-bromo-2,4, and 5-trifluoro-benzene, yield are 62% for m, H.
Embodiment 19.
1,2,4-trifluoro-benzene 13.2g (100mmol), CHCl
325ml, iron powder 0.14g (2.450mmol), mechanical stirring is heated to 43 ℃, on reflux condensing tube, add constant voltage titration funnel, load onto drying tube on the constant voltage titration funnel, slowly dropping liquid bromine 8.0g (50mmol) dripped off in 4 hours, be warming up to 62 ℃ and add Diisopropyl azodicarboxylate 32mg (0.201mmol), stirred 2 hours, and be warming up to 90 ℃, reacted 4 hours.Cooling adds 25% sodium sulfite solution 28ml, stirs 10 minutes, tells organic layer, the sodium hydroxide lotion with 20%, and being washed till pH value is 8, uses anhydrous MgSO
4Drying is filtered, and filtrate is concentrated, and gets product 13.6g, and detecting purity through HPLC is 99.2%, 1H-NMR (CDCl
3) δ: 7.38 (Ar-H), 7.02 (m, H Ar-H), are 1-bromo-2,4, and 5-trifluoro-benzene, yield are 64% for m, H.
Embodiment 20.
1,2,4-trifluoro-benzene 13.2g (100mmol), CHCl
330ml, iron powder 0.28g (5.013mmol), mechanical stirring is heated to 43 ℃, on reflux condensing tube, add constant voltage titration funnel, load onto drying tube on the constant voltage titration funnel, slowly dropping liquid bromine 24.0g (150mmol) dripped off in 4 hours, be warming up to 68 ℃ and add Diisopropyl azodicarboxylate 49mg (0.298mmol), stirred 1 hour, and be warming up to 82 ℃, reacted 5 hours.Cooling adds 15% sodium sulfite solution 25ml, stirs 10 minutes, tells organic layer, the sodium hydroxide lotion with 20%, and being washed till pH value is 8, uses anhydrous MgSO
4Drying is filtered, and filtrate is concentrated, and gets product 12.3g, and detecting purity through HPLC is 99.2%, 1H-NMR (CDCl
3) δ: 7.38 (Ar-H), 7.02 (m, H Ar-H), are 1-bromo-2,4, and 5-trifluoro-benzene, yield are 58% for m, H.
Embodiment 20.
1,2,4-trifluoro-benzene 13.2g (100mmol), CHCl
330ml, iron powder 0.21g (3.601mmol), mechanical stirring is heated to 43 ℃, on reflux condensing tube, add constant voltage titration funnel, load onto drying tube on the constant voltage titration funnel, slowly dropping liquid bromine 16.0g (100mmol) dripped off in 4 hours, be warming up to 68 ℃ and add Diisopropyl azodicarboxylate 66mg (0.402mmol), stirred 1 hour, and be warming up to 82 ℃, reacted 3 hours.Cooling adds 15% sodium sulfite solution 30ml, stirs 10 minutes, tells organic layer, the sodium hydroxide lotion with 20%, and being washed till pH value is 8, uses anhydrous MgSO
4Drying is filtered, and filtrate is concentrated, and gets product 12.7g, and detecting purity through HPLC is 99.2%, 1H-NMR (CDCl
3) δ: 7.38 (Ar-H), 7.02 (m, H Ar-H), are 1-bromo-2,4, and 5-trifluoro-benzene, yield are 60% for m, H.
Claims (8)
1.1-bromo-2,4, the synthetic method of 5-trifluoro-benzene, it is characterized in that described method is: in organic solvent, add iron powder and 1,2,4-trifluoro-benzene, add the liquid bromine in 43～48 ℃, added in 3～4 hours, and be warming up to 62～68 ℃ and add Diisopropyl azodicarboxylate, stir evenly, in 82～102 ℃ react completely reaction solution, the reaction solution purification process gets 1-bromo-2,4, the 5-trifluoro-benzene, described 1,2,4-trifluoro-benzene: liquid bromine: iron powder: Diisopropyl azodicarboxylate amount of substance ratio is 1: 0.5～1.5: 0.025～0.050: 0.002～0.006, described organic solvent is tetracol phenixin or chloroform, described volume of organic solvent consumption is with 1-bromo-2,4, and the 5-trifluoro-benzene is counted 250～300ml/mol.
2. 1-bromo-2 as claimed in claim 1,4, the synthetic method of 5-trifluoro-benzene, it is characterized in that described purification process is, the reaction solution cold filtration is got filtrate, it is the washings of 15～25% sodium sulfite solution that gained filtrate adds concentration, the volumetric usage of described sodium sulfite solution is with 1-bromo-2,4, the 5-trifluoro-benzene is counted 250～350ml/mol, stirs layering, isolate organic layer, organic layer with 5～20% sodium hydroxide solution wash to pH value be 7-9, use the siccative drying, filter, filtrate concentrates, promptly get 1-bromo-2,4, the 5-trifluoro-benzene.
3. 1-bromo-2,4 as claimed in claim 2, the synthetic method of 5-trifluoro-benzene is characterized in that described siccative is anhydrous MgSO
4
4. 1-bromo-2,4 as claimed in claim 1, the synthetic method of 5-trifluoro-benzene is characterized in that describedly 1,2,4-trifluoro-benzene: liquid bromine: iron powder: Diisopropyl azodicarboxylate amount of substance ratio is 1: 0.75～1.25: 0.029～0.045: 0.003～0.005.
5. synthetic method as claimed in claim 4 is characterized in that describedly 1,2, and 4-trifluoro-benzene: liquid bromine: iron powder: Diisopropyl azodicarboxylate amount of substance ratio is 1: 1: 0.036: 0.004.
6. synthetic method as claimed in claim 1 is characterized in that described organic solvent is a tetracol phenixin.
7. synthetic method as claimed in claim 1 is characterized in that described method is: add iron powder and 1,2 in organic solvent, the 4-trifluoro-benzene, in 43～48 ℃ of adding liquid bromines, added in 3～4 hours, be warming up to 62～68 ℃, adding Diisopropyl azodicarboxylate stirred 1～4 hour, got reaction solution in 3～5 hours fully in 82～102 ℃ of reactions, the reaction solution purification process gets 1-bromo-2,4, the 5-trifluoro-benzene.
8. synthetic method as claimed in claim 1, it is characterized in that described method is: in tetracol phenixin, add iron powder and 1,2, the 4-trifluoro-benzene, in 45 ℃ with adding the liquid bromine in 4 hours, adding Diisopropyl azodicarboxylate in 65 ℃ stirred 2 hours, in 90～95 ℃ of reactions 4 hours, cold filtration, it is the washing of 20% sodium sulfite solution that gained filtrate adds concentration, described sodium sulfite solution volumetric usage is with 1-bromo-2,4, the 5-trifluoro-benzene is counted 300ml/mol, isolates organic layer, organic layer with 10% sodium hydroxide solution wash to pH value be 8, get the anhydrous MgSO of organic layer
4Drying is filtered, and filtrate concentrates, and promptly gets 1-bromo-2,4, the 5-trifluoro-benzene; Described 1,2,4-trifluoro-benzene: liquid bromine: iron powder: Diisopropyl azodicarboxylate amount of substance ratio is 1: 1: 0.036: 0.004; Described tetracol phenixin volumetric usage is with 1-bromo-2,4, and the 5-trifluoro-benzene is counted 300ml/mol.
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| US4351974A (en) * | 1980-03-04 | 1982-09-28 | Bayer Aktiengesellschaft | Preparation of 3-bromo-4-fluorotoluene |
| CN1944361A (en) * | 2006-10-30 | 2007-04-11 | 温州医学院 | Process for preparing fluconazole intermediate 2,4-difluror bromo-benzene |
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| US4351974A (en) * | 1980-03-04 | 1982-09-28 | Bayer Aktiengesellschaft | Preparation of 3-bromo-4-fluorotoluene |
| CN1944361A (en) * | 2006-10-30 | 2007-04-11 | 温州医学院 | Process for preparing fluconazole intermediate 2,4-difluror bromo-benzene |
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