CN103172536A - Preparation method of 4-amino-2,6-dichloro-alpha-(4-chlorphenyl) benzyl cyanide - Google Patents
Preparation method of 4-amino-2,6-dichloro-alpha-(4-chlorphenyl) benzyl cyanide Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- YVPUHAUYKMGZAY-UHFFFAOYSA-N 2-(4-amino-2,6-dichlorophenyl)-2-(4-chlorophenyl)acetonitrile Chemical compound ClC1=CC(N)=CC(Cl)=C1C(C#N)C1=CC=C(Cl)C=C1 YVPUHAUYKMGZAY-UHFFFAOYSA-N 0.000 title abstract 3
- 238000006722 reduction reaction Methods 0.000 claims abstract description 15
- 238000006482 condensation reaction Methods 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 10
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 239000003880 polar aprotic solvent Substances 0.000 claims abstract description 5
- 239000003586 protic polar solvent Substances 0.000 claims abstract description 5
- DLJPNXLHWMRQIQ-UHFFFAOYSA-N 2-chloro-1-methoxy-4-nitrobenzene Chemical class COC1=CC=C([N+]([O-])=O)C=C1Cl DLJPNXLHWMRQIQ-UHFFFAOYSA-N 0.000 claims description 27
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 claims description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- QQVHQMAFAHWOOJ-UHFFFAOYSA-N C(C1=CC=CC=C1)#N.[Cl] Chemical compound C(C1=CC=CC=C1)#N.[Cl] QQVHQMAFAHWOOJ-UHFFFAOYSA-N 0.000 claims description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- 238000005457 optimization Methods 0.000 claims description 2
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 229960001866 silicon dioxide Drugs 0.000 claims description 2
- 235000012239 silicon dioxide Nutrition 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 3
- GJYVJKPFYCKNEC-UHFFFAOYSA-N 1,3-dichloro-2-methoxy-5-nitrobenzene Chemical compound COC1=C(Cl)C=C([N+]([O-])=O)C=C1Cl GJYVJKPFYCKNEC-UHFFFAOYSA-N 0.000 abstract 3
- WZSOEUAQKKEHFE-UHFFFAOYSA-N 2-chloro-2-phenylacetonitrile Chemical compound N#CC(Cl)C1=CC=CC=C1 WZSOEUAQKKEHFE-UHFFFAOYSA-N 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 239000012295 chemical reaction liquid Substances 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 7
- ZSZFUDFOPOMEET-UHFFFAOYSA-N 2-(4-chlorophenyl)-2-[2,6-dichloro-4-(3,5-dioxo-1,2,4-triazin-2-yl)phenyl]acetonitrile Chemical compound C1=CC(Cl)=CC=C1C(C#N)C1=C(Cl)C=C(N2C(NC(=O)C=N2)=O)C=C1Cl ZSZFUDFOPOMEET-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 229960000248 diclazuril Drugs 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- 0 *C*(CC1)=*1Cl Chemical compound *C*(CC1)=*1Cl 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000006193 diazotization reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 206010013786 Dry skin Diseases 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- BIXZHMJUSMUDOQ-UHFFFAOYSA-N dichloran Chemical compound NC1=C(Cl)C=C([N+]([O-])=O)C=C1Cl BIXZHMJUSMUDOQ-UHFFFAOYSA-N 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- JXIJUAWSDBACEB-UHFFFAOYSA-N 1-chloro-2-methoxy-4-nitrobenzene Chemical class COC1=CC([N+]([O-])=O)=CC=C1Cl JXIJUAWSDBACEB-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 241000272525 Anas platyrhynchos Species 0.000 description 1
- 241000272814 Anser sp. Species 0.000 description 1
- 241000224483 Coccidia Species 0.000 description 1
- 208000003495 Coccidiosis Diseases 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 206010023076 Isosporiasis Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- WPQZZIPKAKNGSF-UHFFFAOYSA-N acetonitrile;nitrobenzene Chemical compound CC#N.[O-][N+](=O)C1=CC=CC=C1 WPQZZIPKAKNGSF-UHFFFAOYSA-N 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000001165 anti-coccidial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000005649 metathesis reaction Methods 0.000 description 1
- 238000003359 percent control normalization Methods 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of 4-amino-2,6-dichloro-alpha-(4-chlorphenyl) benzyl cyanide, which comprises the following steps: by taking chlorobenzyl cyanide and 2,6-dichloro-4-nitroanisol as raw materials, in a polar aprotic solvent, under the action of a strong base and a phase transfer catalyst, condensing by controlling the reaction temperature to remove a water layer from obtained reaction liquid, and removing a solvent subjected to condensation reaction through distilling, thereby obtaining 2, 6-dichloro-4-nitroanisol; and placing the obtained 2, 6-dichloro-4-nitroanisol in the polar protic solvent through hydrazine hydrate, under the action of a catalyst and a carrier, carrying out reduction reaction by controlling the reaction temperature, finally, thereby obtaining required 4-amino-2,6-dichloro-alpha-(4-chlorphenyl) benzyl cyanide.
Description
Technical field
The present invention relates to the medicine intermediate field, specifically relate to 4-amino-2, the preparation method of 6-two chloro-α-(4-chloro-phenyl-) benzyl cyanide.
Background technology
Diclazuril is the efficient anticoccidial drug of latest generation, is developed by Belgian Yang Sen company the eighties in 20th century, goes on the market in Europe in 1992.This medicine has good prevention effect to various coccidias such as chicken, duck, goose, rabbits, and feed per ton adds the 1g diclazuril, can 100% controls the outburst of coccidiosis.Therefore, the study on the synthesis of diclazuril has been subject to extensive concern both domestic and external in recent years.
Wherein, 4-amino-2,6-two chloro-α-(4-chloro-phenyl-) benzyl cyanide is an important intermediate for the synthesis of diclazuril.Mainly contain US Patent No. 4631278 and Chinese patent CN1158248 about its synthetic report, wherein, US4631278 mainly is expressed as: with to chlorine cyanobenzene (2) and 1,2,3-three chloro-5-oil of mirbane (3) are raw material, condensation under the 50%NaOH effect, and crystallization first obtains intermediate 2 in isopropyl ether, 6-two chloro-α-(4-chloro-phenyl-)-4-nitrobenzene ethane nitrile (4); This intermediate obtains 4-amino-2,6-two chloro-α-(4-chloro-phenyl-) benzyl cyanide (1) through iron powder/ammonium chloride reduction; In addition, Chinese patent CN1158248 and Cao Wei (" Zhejiang chemical industry ", 2004(2), 12) introduced raw material 1,2, the preparation method of 3-three chloro-5-oil of mirbane (3), 2,6-Dichloro-4-nitroaniline (5) is through diazotization reaction, then carries out the halogen replacement(metathesis)reaction and obtain 1,2,3-, three chloro-5-oil of mirbane (3); In addition, and Cao Wei (" Zhejiang chemical industry ", 2004(2), 12) also reported the catalytic hydrogenation that adopts 5%Pt/C to intermediate 2, the method that 6-two chloro-α-(4-chloro-phenyl-)-the 4-nitrobenzene ethane nitrile reduces.The reaction scheme of aforesaid method is as follows:
Aforesaid method has the preparation of following drawback: 1,2,3-three chloro-5-oil of mirbane to adopt diazotization reaction, and danger is larger, and is higher to equipment and operational requirement; Intermediate 2,6-two chloro-α-(4-chloro-phenyl-)-4-nitrobenzene ethane nitrile adopt the iron powder reducing method, produce a large amount of waste water and iron mud, pollutes larger, or the Pt metal catalytic hydro-reduction of employing costliness, cost is high, and higher to equipment requirements.
Summary of the invention
For the deficiencies in the prior art, the invention provides that a kind of to need not cost low, free of contamination 4-is amino-2, the preparation method of 6-two chloro-α-(4-chloro-phenyl-) benzyl cyanide.
For achieving the above object, the present invention adopts following technical scheme to realize:
4-amino-2, the preparation method of 6-two chloro-α-(4-chloro-phenyl-) benzyl cyanide is characterized in that, comprises the steps:
A, condensation reaction: with chlorine cyanobenzene and 2,6-two chloro-4-Nitroanisoles are raw material, in polar aprotic solvent, under highly basic and phase-transfer catalyst effect, control temperature of reaction and carry out condensation in 40～60 ℃ of scopes, with the reaction solution branch vibration layer that obtains, boil off the solvent of condensation reaction, obtain 2,6-, two chloro-4-Nitroanisoles; Mole proportioning of described chlorine cyanobenzene and 2,6-, two chloro-4-Nitroanisoles is 1～1.2:1.
B, with obtain in step a 2,6-two chloro-4-Nitroanisoles through hydrazine hydrate in the polar protic solvent, under catalyzer and carrier function, control temperature of reaction and carry out reduction reaction in 60-80 ℃ of scope, finally obtain required 4-amino-2,6-two chloro-α-(4-chloro-phenyl-) benzyl cyanide; Mole proportioning of described hydrazine hydrate and 2,6-, two chloro-4-Nitroanisoles is 1.5～4:1;
In step a, the preferred temperature of condensation reaction is controlled at 45～55 ℃;
In step a, the required polar aprotic solvent of condensation reaction is selected: a kind of in tetrahydrofuran (THF), 2-methyltetrahydrofuran or dioxane, and the mass ratio of described solvent and 2,6-, two chloro-4-Nitroanisoles is 2～8:1;
In step a, the required highly basic of condensation reaction is selected: potassium hydroxide, and sodium hydroxide, sodium methylate, a kind of in sodium ethylate, mole proportioning of described highly basic and 2,6-, two chloro-4-Nitroanisoles is 2～4:1;
In step a, the required phase-transfer catalyst of condensation reaction is selected: benzyl triethyl ammonium bromide, benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, a kind of in tetrabutylammonium chloride, described phase-transfer catalyst is 0.5%～5.0%:1 with mass ratio with 2,6-, two chloro-4-Nitroanisoles;
In step b, the required polar protic solvent of reduction reaction is selected: methyl alcohol, and a kind of in ethanol or Virahol, the mass ratio of described solvent and 2,6-, two chloro-4-Nitroanisoles is 2～8:1;
In step b, the required catalyzer of reduction reaction is selected: iron trichloride, and the mass ratio of described catalyzer and 2,6-, two chloro-4-Nitroanisoles is 2%～5%:1;
In step b, the required carrier of reduction reaction is selected: a kind of in gac, aluminum oxide or silicon-dioxide, and the mass ratio of described carrier and 2,6-, two chloro-4-Nitroanisoles is 5%～10%:1;
In step b, mole proportion optimization of reduction reaction hydrazine hydrate and 2,6-, two chloro-4-Nitroanisoles is 2～3:1.
Adopt technical scheme provided by the invention, possess following beneficial effect:
1, the first step condensation is raw material with 2,6-, two chloro-4-Nitroanisoles, replaces 1,2,3-, three chloro-5-Nitroanisoles, has avoided diazotization reaction.
2, intermediate 2, and 6-two chloro-α-(4-chloro-phenyl-)-4-nitrobenzene ethane nitrile does not separate, and directly enters next step reduction, simplifies the operation.
3, the hydrazine hydrate method is adopted in reduction, pollutes few, low for equipment requirements, dangerous low.
Embodiment
Below by specific embodiment, the present invention is done detailed description:
Embodiment 1:
Drop into chlorine cyanobenzene 47.8g(0.315mol in the four-hole boiling flask of the 500ml of a drying), 2,6-two chloro-4-Nitroanisole 66.6g(0.30mol), benzyl triethyl ammonium bromide 0.6g and 2-methyltetrahydrofuran 290g, slowly add 50%NaOH solution 48.0g(0.60mol), approximately 5 minutes.Slowly be warming up to 45 ℃, insulated and stirred 6 hours.Reaction finishes, and stops stirring, and separatory divides and removes the bottom water layer.The organic layer underpressure distillation obtains yellow liquid until steam without cut.Add methyl alcohol 300g, gac 5.0g, iron trichloride 2.0g is warming up to backflow.Slowly drip hydrazine hydrate 45.0g(0.6375mol under reflux state), approximately 2 hours.Drip and finish, continue to reflux 30 minutes.Be cooled to 60 ℃, remove by filter gac.The mother liquor distillation boils off approximately 280g of solvent.Slowly add entry 300ml, faint yellow crystallization is arranged in process.Be cooled to room temperature, suction filtration, filter cake are washed to pH and are about 8.60 ℃ of successive dryings get faint yellow solid 74.5g, yield 79.7%, purity (HPLC) 98.6%.
HPLC condition: moving phase: A:0.1%, W/V ammonium acetate solution, B: acetonitrile; Flow velocity: 1.5ml/min; Temperature: room temperature; Sampling volume: 5 μ l; Detector: wavelength 230nm
Embodiment 2:
Drop into chlorine cyanobenzene 33.3g(0.22mol in the four-hole boiling flask of the 500ml of a drying), 2,6-two chloro-4-Nitroanisole 44.4g(0.20mol), benzyl triethyl ammonium bromide 0.4g and tetrahydrofuran (THF) 250g.Slowly add 50%NaOH solution 48.0g(0.60mol), approximately 5 minutes.Slowly be warming up to 45 ℃, insulated and stirred 6 hours.Reaction finishes, and stops stirring, and separatory divides and removes the bottom water layer.Organic layer distillation obtains yellow liquid until steam without cut.Add methyl alcohol 160g, gac 3.5g, iron trichloride 1.5g is warming up to backflow.Slowly drip hydrazine hydrate 33.0g(0.4675mol under reflux state), approximately 1 hour 40 minutes.Drip and finish, continue to reflux 30 minutes.Be cooled to 60 ℃, remove by filter gac.The mother liquor distillation boils off approximately 150g of solvent.Slowly add entry 200ml, faint yellow crystallization is arranged in process.Be cooled to room temperature, suction filtration, filter cake are washed to pH and are about 8.60 ℃ of successive dryings get faint yellow solid 48.2g, yield 77.4%, purity (HPLC) 98.8%
Claims (9)
1.4-amino-2, the preparation method of 6-two chloro-α-(4-chloro-phenyl-) benzyl cyanide is characterized in that, comprises the steps:
A, condensation reaction: with chlorine cyanobenzene and 2,6-two chloro-4-Nitroanisoles are raw material, in polar aprotic solvent, under highly basic and phase-transfer catalyst effect, control temperature of reaction and carry out condensation in 40～60 ℃ of scopes, with the reaction solution branch vibration layer that obtains, boil off the solvent of condensation reaction, obtain 2,6-, two chloro-4-Nitroanisoles; Mole proportioning of described chlorine cyanobenzene and 2,6-, two chloro-4-Nitroanisoles is 1～1.2:1.
B, with obtain in step a 2,6-two chloro-4-Nitroanisoles through hydrazine hydrate in the polar protic solvent, under catalyzer and carrier function, control temperature of reaction and carry out reduction reaction in 60-80 ℃ of scope, finally obtain required 4-amino-2,6-two chloro-α-(4-chloro-phenyl-) benzyl cyanide; Mole proportioning of described hydrazine hydrate and 2,6-, two chloro-4-Nitroanisoles is 1.5～4:1.
2. 4-according to claim 1 is amino-2, and the preparation method of 6-two chloro-α-(4-chloro-phenyl-) benzyl cyanide is characterized in that: in step a, the preferred temperature of condensation reaction is controlled at 45～55 ℃.
3. 4-according to claim 1 amino-2, the preparation method of 6-two chloro-α-(4-chloro-phenyl-) benzyl cyanide, it is characterized in that: in step a, the required polar aprotic solvent of condensation reaction is selected: a kind of in tetrahydrofuran (THF), 2-methyltetrahydrofuran or dioxane; The mass ratio of described solvent and 2,6-, two chloro-4-Nitroanisoles is 2～8:1.
4. 4-according to claim 1 is amino-2, and the preparation method of 6-two chloro-α-(4-chloro-phenyl-) benzyl cyanide is characterized in that: in step a, the required highly basic of condensation reaction is selected: potassium hydroxide, sodium hydroxide, sodium methylate, a kind of in sodium ethylate; Mole proportioning of described highly basic and 2,6-, two chloro-4-Nitroanisoles is 2～4:1.
5. 4-according to claim 1 amino-2, the preparation method of 6-two chloro-α-(4-chloro-phenyl-) benzyl cyanide, it is characterized in that: in step a, the required phase-transfer catalyst of condensation reaction is selected: benzyl triethyl ammonium bromide, benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, a kind of in tetrabutylammonium chloride; Described phase-transfer catalyst with the mass ratio of 2,6-, two chloro-4-Nitroanisoles be 0.5%～5.0%:1.
6. 4-according to claim 1 is amino-2, and the preparation method of 6-two chloro-α-(4-chloro-phenyl-) benzyl cyanide is characterized in that: in step b, the required polar protic solvent of reduction reaction is selected: methyl alcohol, a kind of in ethanol or Virahol; The mass ratio of described solvent and 2,6-, two chloro-4-Nitroanisoles is 2～8:1.
7. 4-according to claim 1 is amino-2, and the preparation method of 6-two chloro-α-(4-chloro-phenyl-) benzyl cyanide is characterized in that: in step b, the required catalyzer of reduction reaction is selected: iron trichloride; The mass ratio of described catalyzer and 2,6-, two chloro-4-Nitroanisoles is 2%～5%:1.
8. 4-according to claim 1 is amino-2, and the preparation method of 6-two chloro-α-(4-chloro-phenyl-) benzyl cyanide is characterized in that: in step b, the required carrier of reduction reaction is selected: gac, aluminum oxide or silicon-dioxide; The mass ratio of described carrier and 2,6-, two chloro-4-Nitroanisoles is 5%～10%:1.
9. 4-according to claim 1 is amino-2, and the preparation method of 6-two chloro-α-(4-chloro-phenyl-) benzyl cyanide is characterized in that: in step b, mole proportion optimization of reduction reaction hydrazine hydrate and 2,6-, two chloro-4-Nitroanisoles is 2～3:1
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106883148A (en) * | 2017-03-29 | 2017-06-23 | 浙江国邦药业有限公司 | A kind of restoring method of (2,6 dichloro-4,4 amido) a (4 ' chlorphenyl) benzene acetonitrile |
| CN113999139A (en) * | 2021-12-03 | 2022-02-01 | 杭州臻峰科技有限公司 | Method for preparing 2, 6-dichloro-alpha- (4-chlorophenyl) -4-nitrophenylacetonitrile |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1537929A (en) * | 1975-03-18 | 1979-01-10 | Janssen Pharmaceutica Nv | Salicylanilide derivatives |
| US4631278A (en) * | 1984-08-01 | 1986-12-23 | Janssen Pharmaceutica N.V. | Anti-protozoal α-aryl-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-benzeneacetonitrile derivatives, pharmaceutical compositions, and method of use therefor |
| CN1485315A (en) * | 2002-09-26 | 2004-03-31 | 上海化学试剂研究所 | 3, the preparation method of 4'-diaminodiphenyl ether |
| CN101265238A (en) * | 2007-12-12 | 2008-09-17 | 重庆天极旅业有限公司 | Method for synthesizing triazine ring derivatives |
| CN102285927A (en) * | 2011-06-29 | 2011-12-21 | 青岛康地恩药业股份有限公司 | Method for preparing ponazuril serving as anticoccidiosis medicament |
-
2013
- 2013-03-19 CN CN2013100889514A patent/CN103172536A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1537929A (en) * | 1975-03-18 | 1979-01-10 | Janssen Pharmaceutica Nv | Salicylanilide derivatives |
| US4631278A (en) * | 1984-08-01 | 1986-12-23 | Janssen Pharmaceutica N.V. | Anti-protozoal α-aryl-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-benzeneacetonitrile derivatives, pharmaceutical compositions, and method of use therefor |
| CN1485315A (en) * | 2002-09-26 | 2004-03-31 | 上海化学试剂研究所 | 3, the preparation method of 4'-diaminodiphenyl ether |
| CN101265238A (en) * | 2007-12-12 | 2008-09-17 | 重庆天极旅业有限公司 | Method for synthesizing triazine ring derivatives |
| CN102285927A (en) * | 2011-06-29 | 2011-12-21 | 青岛康地恩药业股份有限公司 | Method for preparing ponazuril serving as anticoccidiosis medicament |
Non-Patent Citations (3)
| Title |
|---|
| 朱建民 等: "广谱驱虫药非班太尔的合成", 《浙江化工》 * |
| 邢锦娟: "水合肼法还原芳香硝基化合物制备方案的技术进展", 《化学工业与工程技术》 * |
| 黄培 等: "硝基化合物还原制备芳香胺", 《南京工业大学学报》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106883148A (en) * | 2017-03-29 | 2017-06-23 | 浙江国邦药业有限公司 | A kind of restoring method of (2,6 dichloro-4,4 amido) a (4 ' chlorphenyl) benzene acetonitrile |
| CN113999139A (en) * | 2021-12-03 | 2022-02-01 | 杭州臻峰科技有限公司 | Method for preparing 2, 6-dichloro-alpha- (4-chlorophenyl) -4-nitrophenylacetonitrile |
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