CN103694137A - Production method of 2-fluorine-4-nitrobenzonitrile - Google Patents
Production method of 2-fluorine-4-nitrobenzonitrile Download PDFInfo
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Abstract
The invention discloses a production method of 2-fluorine-4-nitrobenzonitrile, and particularly relates to a cleaning production method for improving the 2-fluorine-4-nitrobenzonitrile capable of being used as a drug intermediate of a tyrosine kinase irreversible inhibitor and a protein kinase inhibitor at a diazotization bromination reaction stage. A few defects exist at the traditional diazotization bromination reaction stage; one defect is that the amount of waste liquor generated at the stage is relatively large, and 20-30 T of acid waste liquor can be concomitantly generated when every 1 T of 2-fluorine-4-nitrobenzonitrile is generated; one defect is that the reaction temperature needs to be controlled between 0 DEG C and 5 DEG C by using refrigeration equipment at the stage, and the production energy consumption is relatively high. The invention aims at providing the clean production method of 2-fluorine-4-nitrobenzonitrile. The cleaning production method disclosed by the invention can effectively reduce the amount of the waste liquor generated by reaction at the diazotization bromination reaction stage and can increase the reaction temperature at the stage from 0-5 DEG C to 40-80 DEG C, thereby reducing the reaction energy consumption.
Description
Technical field
The present invention relates to a kind of production method of 2-Fluoro-4-nitrobenzonitrile, relate in particular to a kind of pharmaceutical intermediate that can be used as tyrosine kinase irreversible inhibitor and kinases inhibitor 2-Fluoro-4-nitrobenzonitrile at diazotization bromo-reaction stage improved clean preparation method in addition.
Background technology
The English name of 2-Fluoro-4-nitrobenzonitrile is 2-Fluoro-4-nitrobenzonitrile, molecular formula is C7H3FN2O2, it is a kind of medicine intermediate, be a kind of pharmaceutical intermediate that can be used as tyrosine kinase irreversible inhibitor, this inhibitor can be used for treating the diseases such as cancer, atherosclerosis, restenosis, endometriosis or psoriasis.
At present about the several method of synthetic 2-Fluoro-4-nitrobenzonitrile, refer to the associated viscera in the synthetic method > > of invention disclosed patent < < on February 17th, 2010 2-Fluoro-4-nitrobenzonitrile (patent No. is ZL200910034970.2) such as Zhao Haoyu.
In above-mentioned patent, mentioning, is raw material by 3,4-difluoro nitrobenzene, through the synthetic 2-Fluoro-4-nitrobenzonitrile of ammonia solution, diazotization bromo and cyanogenation.Synthetic route is as follows:
Although this synthetic method has, main raw material is inexpensive, material toxicity is relatively low, and the purity of finished product 2-Fluoro-4-nitrobenzonitrile is high, and (content >=99.0%, HPLC) etc. advantage, exists some defects in the diazotization bromo-reaction stage.Main concentrated reflection is aspect following two:
The one, the waste liquid amount that this stage generates is larger, in the time of the fluoro-4-nitro of every generation 1T2-bromobenzene, can supervene the acid waste liquid of 20～30T, and so the waste liquid of quantity causes environmental protection pressure to make people worried;
The 2nd, in this stage, need to use refrigerating apparatus that temperature of reaction is controlled to 0～5 ℃, its production energy consumption is relatively high.
Summary of the invention
For above-mentioned shortcoming, the object of the present invention is to provide a kind of clean preparation method of 2-Fluoro-4-nitrobenzonitrile, the method can effectively be reduced in the waste liquid amount that diazotization bromo-reaction elementary reaction generates, thereby and the temperature of reaction in this stage can be promoted to 40～80 ℃ of energy consumptions that reduce reaction from 0～5 ℃.
Technology contents of the present invention is, a kind of clean preparation method of 2-Fluoro-4-nitrobenzonitrile, and its step is as follows:
(1), in reactor, drop into Hydrogen bromide and copper powder, the mol ratio of Hydrogen bromide and copper powder is 5.0:1～15.0:1, stirring is warming up to 95～105 ℃, be incubated again 2～5h, then be cooled to 40～80 ℃, under stirring in this solution, add respectively the fluoro-4-N-methyl-p-nitroaniline of 2-, water and ethylene dichloride, the add-on of the fluoro-4-N-methyl-p-nitroaniline of 2-and hydrobromic mol ratio are 1:2.2～1:10.7, the mol ratio of the fluoro-4-N-methyl-p-nitroaniline of 2-and water is 1:5.0～1:20.5, the mol ratio of the fluoro-4-N-methyl-p-nitroaniline of 2-and ethylene dichloride is respectively 1:2.0～1:7.5, after adding, at 40～80 ℃, be incubated 0.5～5h, and then slowly drip the NaNO2 solution that 1.0～5.5 times of concentration of 2-fluoro-4-N-methyl-p-nitroaniline molar weight are 10.0～37.0 % by weight in this mixing solutions, and keeping temperature of reaction is 40～80 ℃, drip off rear insulation and stir 0.5～5h, then standing rear profit layering, water layer extracts rear and oil reservoir merging with the ethylene dichloride of 1.0～7.5 times of consumptions of 2-fluoro-4-N-methyl-p-nitroaniline molar weight, solvent ethylene dichloride is removed in drying and underpressure distillation, gained crude product carries out recrystallization with the toluene of 1.0～8.5 times of consumptions of the fluoro-4-N-methyl-p-nitroaniline of 2-molar weight again, obtains content > 99.0%(GC) the fluoro-4-nitro of brown color crystal 2-bromobenzene,
(2) under the condition that is, solvent by the 2-fluoro-4-nitro bromobenzene making in step (1) and cuprous cyanide at NMP (N-Methyl pyrrolidone), there is cyanogenation and generate finished product 2-Fluoro-4-nitrobenzonitrile.
In the clean preparation method of above-mentioned a kind of 2-Fluoro-4-nitrobenzonitrile, under the condition that 2-fluoro-4-nitro bromobenzene and cuprous cyanide are solvent at NMP, there is the process that cyanogenation generates 2-Fluoro-4-nitrobenzonitrile, with reference in the synthetic method > > (patent No. is ZL200910034970.2) of a patent of invention < < 2-Fluoro-4-nitrobenzonitrile about the associated viscera of synthetic 2-Fluoro-4-nitrobenzonitrile, it is: cuprous cyanide is dissolved in the solution of toluene and NMP mixing, cuprous cyanide, the mol ratio of toluene and NMP is 1:1.3～3.0:3.0～4.5, stir and entirely with water segregator, to slough moisture content and toluene after being warmed up to 155～165 ℃ after molten, then cool to 140～150 ℃ and drop into the fluoro-4-nitro of the 2-bromobenzene making in step (2), the mol ratio of the fluoro-4-nitro of cuprous cyanide and 2-bromobenzene is 1:0.75～0.85, after adding 150～160 ℃ of insulation reaction 3～7 hours, GC detect to the fluoro-4-nitro of 2-bromobenzene without, be down to room temperature, under agitation solution is poured in the vinyl acetic monomer aqueous solution that 5.0～7.5 times of concentration of crude product molar weight of the fluoro-4-p-nitrile of 2-are 40～50 % by weight, filter and remove mantoquita, the vinyl acetic monomer washing extraction of 2.3～3.3 times of the molar weights of 2-fluoro-4-p-nitrile for filter cake, merge oil reservoir, wash again oil reservoir with water, finally with negative pressure precipitation after anhydrous magnesium sulfate drying, obtain the fluoro-4-p-nitrile of the 2-crude product of brown color, with the toluene of 1.5～3.5 times of the crude product molar weights of the fluoro-4-p-nitrile of 2-, carry out recrystallization again, finally obtain the fluoro-4-p-nitrile of yellow crystals shape product 2-.
In the clean preparation method of above-mentioned a kind of 2-Fluoro-4-nitrobenzonitrile, solvent ethylene dichloride and toluene can be by underpressure distillation recoveries; The water layer separating after reaction is after bipolar membrane electrodialysis method is isolated Sodium Bromide wherein, and water layer spent acid is recyclable applying mechanically also.
In the clean preparation method of above-mentioned a kind of 2-Fluoro-4-nitrobenzonitrile, preparation method about the fluoro-4-N-methyl-p-nitroaniline of main raw material 2-, equally also about preparing the associated viscera of the fluoro-4-N-methyl-p-nitroaniline of 2-in the synthetic method > > (patent No. is ZL20091 0034970.2) with reference to a patent of invention < < 2-Fluoro-4-nitrobenzonitrile, it is: by 3, 4-difluoro nitrobenzene, Red copper oxide, industrial spirit and concentration are that the ammonia soln of 25～29 % by weight drops in reactor, wherein 3, 4-difluoro nitrobenzene, Red copper oxide, the mol ratio of industrial spirit and ammoniacal liquor is 1:0.10～0.12:6～10:10～15, mix above material, be warmed up to 120～130 ℃, control the pressure of reactor at 1.2～1.8MPa, insulation reaction 18～20 hours, GC follows the tracks of reaction and substantially finishes, after cooling, material is pressed in water, separates out the fluoro-4-N-methyl-p-nitroaniline of yellow solid 2-, leach washing, the dry fluoro-4-N-methyl-p-nitroaniline of 2-making, its content > 99.0%(GC), in this preparation method, use Red copper oxide as catalyzer, solvent without sherwood oil as washing directly just carries out drying and processing but wash filter cake with water later.
It is raw material that the fluoro-4-N-methyl-p-nitroaniline of 2-is take in the present invention, in the diazotization bromo-reaction stage, utilize Hydrogen bromide, copper powder and Sodium Nitrite etc. under the raw material condition that is solvent at ethylene dichloride, in the fluoro-4-N-methyl-p-nitroaniline of 2--change into-Br of NH2 generated the fluoro-4-nitro of 2-bromobenzene; The fluoro-4-N-methyl-p-nitroaniline of 2-can be that raw material obtains by ammonia solution with 3,4-difluoro nitrobenzene; The fluoro-4-nitro of the 2-bromobenzene generating be take NMP and can be obtained finished product 2-Fluoro-4-nitrobenzonitrile as generation cyanogenations such as solvent and CuCN; This technique, owing to possessing the features such as energy-conservation and environmental protection, is conducive to suitability for industrialized production.
The present invention is by being improved in the diazotization bromo-reaction stage, the waste liquid amount that the 2-Fluoro-4-nitrobenzonitrile diazotization bromo-reaction stage in process of production generates is lowered greatly, and can adopt this part waste liquid of method recovery of membrane sepn, thereby the temperature of reaction in diazotization bromo-reaction stage can be promoted to 40～80 ℃ of energy consumptions that reduce reaction from 0～5 ℃ simultaneously; The fluoro-4-nitro of the diazotization bromo-reaction intermediate 2-bromobenzene that adopts the present invention to generate can guarantee its purity and the former patent of invention (patent No.: ZL200910034970.2) suitable, and molar yield also suitably promotes to some extent, the energy-saving and environmental protection characteristic that this technique possesses, makes it be conducive to suitability for industrialized production.
Reaction equation of the present invention is as follows:
The advantage that the present invention compared with prior art had is as follows:
1, the present invention is promoted to 40～80 ℃ by the temperature of reaction in diazotization bromo stage in original production technique by 0～5 ℃, has saved and has produced required energy consumption;
2, the present invention merges into " one kettle way " by the two step operations in diazotization bromo stage in original production technique, has saved the running cost of production equipment and plant personnel;
3, the waste liquid amount that the present invention produces the fluoro-4-nitro of the 2-bromobenzene of every generation 1T in original production technique is down to 15.5～22.7T by 20～30T;
4, the present invention has used the bipolar membrane electrodialysis method separating heavy nitrogenize bromo-reaction stage to produce the Sodium Bromide in waste liquid, to reach the object of this acid waste liquid energy recovery;
5, the fluoro-4-nitro of the prepared intermediate 2-of the present invention bromobenzene is brown color crystal, content >=99.0%(GC), using it as raw material, to do the prepared finished product 2-Fluoro-4-nitrobenzonitrile of cyanogenation is yellow crystals, content >=99.0%(HPLC).
Embodiment
Below in conjunction with embodiment, further describe the present invention, but be not limited to lifted embodiment.In example below, related chemical is technical grade salable product.
The preparation of example 1, the fluoro-4-N-methyl-p-nitroaniline of 2-
In autoclave, drop into the industrial spirit of 300L, the ammoniacal liquor of 187.5L28%, 6.8Kg Red copper oxide and 120Kg 3,4-difluoro nitrobenzene, mixes above material, is warmed up to the pressure of 120 ℃ of control reactors at 1.7MPa, insulation reaction 18 hours, GC follows the tracks of reaction and substantially finishes; After cooling, material is pressed in water, separates out the fluoro-4-N-methyl-p-nitroaniline of yellow solid 2-crude product 113.0Kg, filter cake washing, dry rear standby, detecting its content is 99.61%(GC).
Example 2, (1), in the reactor of 1000L, drop into the Hydrogen bromide of 250.0L and the copper powder of 13.0Kg, stir and be warming up to 100 ℃, then be incubated 3h, be then cooled to 55 ℃, under stirring, add respectively the water of 75.0L, the fluoro-4-N-methyl-p-nitroaniline of prepared 2-in 56.2Kg example 1, and the ethylene dichloride of 100.0L, after adding, at 55 ℃, be incubated 2h, and then to the aqueous solution of the 70.0L of the Sodium Nitrite of this mixed solution and dripping 38.0Kg, control temperature of reaction at 55 ℃, drip off rear insulation and stir 2h, then standing rear profit layering, water layer extracts rear and oil reservoir merging with the ethylene dichloride of 150.0L, gained crude product carries out recrystallization with the toluene of 60.0L again, obtain content > 99.0%(GC) the fluoro-4-nitro of brown color crystal 2-bromobenzene 58.7Kg, molar yield is that 74.1%(is in the fluoro-4-N-methyl-p-nitroaniline of 2-), melting range is 91.0～93.3 ℃ of (literature values: 92～94 ℃, 99%).
1hNMR(CDCl
3), δ: 7.79(s, 1H, Ar-H), 8.00(s, 2H, Ar-H); MS, m/Z:219(molecular ion peak), 173,140,94.Above-mentioned got oil reservoir drying and vacuum distillation recovered solvent ethylene dichloride 210.7L, recrystallization reclaims toluene 48.1L with mother liquor through underpressure distillation;
Get above-mentioned water layer waste liquid successively by decolouring system, purification system and membrane filtration system, part waste back-cycling reactive system recovery, remaining waste liquid, after reclaiming Sodium Bromide, is processed through biochemical system, and COD reduces to 200mgL
-1qualified discharge.
(2), in the reactor of 500L, dropping into the toluene of 50L and the concentration of 120Kg is the nmp solution of the cuprous cyanide of 20 % by weight, stir and heat up, being warmed up to 160 ℃ sloughs after moisture content and toluene, cool to 150 ℃ of crude products that drop into the fluoro-4-nitro of the 2-bromobenzene making in 50.0Kg step (1), add 155 ℃ of insulation reaction 7 hours, GC detect to the fluoro-4-nitro of 2-bromobenzene without, now the content of the fluoro-4-p-nitrile of product 2-is 93.3%(GC); Be down to room temperature, stir in downhill reaction still and drop into the vinyl acetic monomer aqueous solution that 240Kg concentration is 45 % by weight, filter and remove mantoquita collection oil reservoir, filter cake is with merging oil reservoir after vinyl acetic monomer washing and washing, then dry rear negative pressure precipitation, obtains the fluoro-4-p-nitrile of brown color crude product 2-30.1Kg; With the toluene of 50L, the fluoro-4-p-nitrile of crude product 2-is carried out to recrystallization, obtain the fluoro-4-p-nitrile of yellow crystals 2-19.4Kg, content is 99.1%(HPLC), molar yield is that 51.4%(is in the fluoro-4-nitro of 2-bromobenzene), melting range is 69.3～71.5 ℃ (literature values: 70～71 ℃, 98%).
1hNMR(CDCl
3), δ: 7.58(m, 1H,, Ar-H), 8.01(m, 1H, Ar-H), 8.09(m, 1H, Ar-H); MS, m/Z:166(molecular ion peak), 120,100,93,75.）
Example 3, (1), in the reactor of 1000L, drop into the Hydrogen bromide of 200.0L and the copper powder of 15.0Kg, stir and be warming up to 100 ℃, then be incubated 5h, be then cooled to 55 ℃, under stirring, add respectively the water of 75.0L, the fluoro-4-N-methyl-p-nitroaniline of prepared 2-in 56.2Kg example 1, and the ethylene dichloride of 150.0L, after adding, at 55 ℃, be incubated 2h, and then to the aqueous solution of the 70.0L of the Sodium Nitrite of this mixed solution and dripping 43.0Kg, control temperature of reaction at 55 ℃, drip off rear insulation and stir 2h, then standing rear profit layering, water layer extracts rear and oil reservoir merging with the ethylene dichloride of 120.0L, gained crude product carries out recrystallization with the toluene of 45.0L again, obtain content > 99.0%(GC) the fluoro-4-nitro of brown color crystal 2-bromobenzene 62.0Kg, molar yield is that 78.3%(is in the fluoro-4-N-methyl-p-nitroaniline of 2-), melting range is 91.4～92.7 ℃ of (literature values: 92～94 ℃, 99%).
1hNMR(CDCl
3), δ: 7.79(s, 1H, Ar-H), 8.00(s, 2H, Ar-H); MS, m/Z:219(molecular ion peak), 173,140,94.Above-mentioned got oil reservoir drying and vacuum distillation recovered solvent ethylene dichloride 242.5.7L, recrystallization reclaims toluene 37.3L with mother liquor through underpressure distillation;
Get above-mentioned water layer waste liquid successively by decolouring system, purification system and membrane filtration system, part waste back-cycling reactive system recovery, remaining waste liquid, after reclaiming Sodium Bromide, is processed through biochemical system, and COD reduces to 160mgL
-1qualified discharge.
(2), drop into the toluene of 50L in dropping in the reactor of 500L and the concentration of 120Kg is the nmp solution of the cuprous cyanide of 20 % by weight, stir and heat up, being warmed up to 160 ℃ sloughs after moisture content and toluene, cool to 150 ℃ of crude products that drop into the fluoro-4-nitro of the 2-bromobenzene making in 50.0Kg step (1), add 150 ℃ of insulation reaction 5 hours, GC detect to the fluoro-4-nitro of 2-bromobenzene without, now the content of the fluoro-4-p-nitrile of product 2-is 92.7%(GC); Be down to room temperature, stir in downhill reaction still and drop into the vinyl acetic monomer aqueous solution that 200Kg concentration is 45 % by weight, filter and remove mantoquita collection oil reservoir, filter cake is with merging oil reservoir after vinyl acetic monomer washing and washing, then dry rear negative pressure precipitation, obtains the fluoro-4-p-nitrile of brown color crude product 2-27.8Kg; With the toluene of 45L, the fluoro-4-p-nitrile of crude product 2-is carried out to recrystallization, obtain the fluoro-4-p-nitrile of yellow crystals 2-18.1Kg, content is 99.2%(HPLC), molar yield is that 47.9%(is in the fluoro-4-nitro of 2-bromobenzene), melting range is 69.4～71.3 ℃ (literature values: 70～71 ℃, 98%).
1hNMR(CDCl
3), δ: 7.58(m, 1H,, Ar-H), 8.01(m, 1H, Ar-H), 8.09(m, 1H, Ar-H); MS, m/Z:166(molecular ion peak), 120,100,93,75.）。
Claims (1)
1. a clean preparation method for 2-Fluoro-4-nitrobenzonitrile, its step is as follows:
(1), in reactor, drop into Hydrogen bromide and copper powder, the mol ratio of Hydrogen bromide and copper powder is 5.0:1～15.0:1, stirring is warming up to 95～105 ℃, be incubated again 2～5h, then be cooled to 40～80 ℃, under stirring in this solution, add respectively the fluoro-4-N-methyl-p-nitroaniline of 2-, water and ethylene dichloride, the add-on of the fluoro-4-N-methyl-p-nitroaniline of 2-and hydrobromic mol ratio are 1: 2.2～1: 10.7, the mol ratio of the fluoro-4-N-methyl-p-nitroaniline of 2-and water is 1: 5.0～1: 20.5, the mol ratio of the fluoro-4-N-methyl-p-nitroaniline of 2-and ethylene dichloride is respectively 1: 2.0～1: 7.5, after adding, at 40～80 ℃, be incubated 0.5～5 h, and then slowly drip the NaNO that 1.0～5.5 times of concentration of 2-fluoro-4-N-methyl-p-nitroaniline molar weight are 10.0～37.0 % by weight in this mixing solutions
2solution, and to keep temperature of reaction be 40～80 ℃, drips off rear insulation and stir 0.5～5 h, then standing rear profit layering, water layer extracts rear and oil reservoir merging with the ethylene dichloride of 1.0～7.5 times of consumptions of 2-fluoro-4-N-methyl-p-nitroaniline molar weight, solvent ethylene dichloride is removed in drying and underpressure distillation, gained crude product carries out recrystallization with the toluene of 1.0～8.5 times of consumptions of the fluoro-4-N-methyl-p-nitroaniline of 2-molar weight again, obtains content > 99.0%(GC) the fluoro-4-nitro of brown color crystal 2-bromobenzene,
(2) under the condition that is, solvent by the 2-fluoro-4-nitro bromobenzene making in step (1) and cuprous cyanide at NMP (N-Methyl pyrrolidone), there is cyanogenation and generate finished product 2-Fluoro-4-nitrobenzonitrile.
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| CN109487297A (en) * | 2018-11-12 | 2019-03-19 | 新乡市珺隆生物科技有限公司 | The electrochemical applications of trimethoxy-benzene synthesis |
| CN115093344A (en) * | 2022-06-14 | 2022-09-23 | 绍兴市上虞金冠化工有限公司 | Preparation method of cyano-containing azo disperse dye or intermediate |
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Application publication date: 20140402 |