CN102603571A - Preparation method of 2,4-dichloro-3-cyano-5-fluobenzoic acid - Google Patents
Preparation method of 2,4-dichloro-3-cyano-5-fluobenzoic acid Download PDFInfo
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Abstract
The invention relates to a preparation method of 2,4-dichloro-3-cyano-5-fluobenzoic acid, which comprises the following steps: reacting 2,6-dichloro-3-fluorbenzonitrile, which is used as a raw material, in a solvent concentrated sulfuric acid under the action of a bromization reagent to generate 2,6-dichloro-3-cyano-5-fluorobromobenzene; and preparing an alkane Grignard reagent, carrying out halogen-metal exchange reaction with 2,6-dichloro-3-cyano-5-fluorobromobenzene to prepare a 2,6-dichloro-3-cyano-5-fluorobromobenzene Grignard reagent, reacting with carbon dioxide, and carrying out after-treatment to obtain the target product 2,4-dichloro-3-cyano-5-fluobenzoic acid. Compared with the prior art, the invention has the advantages of simple steps, convenient operating procedure, high total yield, low cost, high safety, environmental protection and the like, is beneficial to industrial large-scale production, and has high implementation value and socioeconomic performance.
Description
(1) technical field
The present invention relates to a kind of 2, the preparation method of 4-two chloro-3-cyanic acid-5-fluorobenzoic acids, particularly a kind of with 2,6-two chloro-3-fluorobenzonitriles are feedstock production 2, the method for 4-two chloro-3-cyanic acid-5-fluorobenzoic acids.
(2) background technology
2,4-two chloro-3-cyanic acid-5-fluorobenzoic acids are key intermediates of the novel fluoroquinolone medicine Fei Nasha star finafloxacin hydrochloride of preparation (BAY35-3377), and this medicine is in clinical III stage phase at present, has good market outlook.Before the present invention provides, have 2 now, the compound method of 4-two chloro-3-cyanic acid-5-fluorobenzoic acids mainly contains two kinds: (1) US6229040 has reported 5-fluoro-1; 3-YLENE gets 2,4-two chloro-5-fluoro-1,3-YLENE with chlorine reaction under Louis acid catalysis; The back gets 2 with chlorine through free radical reaction, 4-two chloro-5-fluoro-3-dichloromethyl-1-benzenyl trichlorides, and hydrolysis gets 2 again; 4-two chloro-5-fluoro-3-formyl radical-phenylformic acid continue to get 2,4-two chloro-5-fluoro-3-N-hydroxyl imide base-phenylformic acid with azanol reaction; After dehydration reaction gets end product 2,4-two chloro-3-cyanic acid-5-fluorobenzoic acids.This route method steps is long, total recovery low (less than 30%), and operating procedure is comparatively complicated.(2) US4908366 is with 2, and 4-two chloro-5-fluorobenzoic acids are raw material, gets 2 through nitrated; 4-two chloro-3-nitro-5-fluorobenzoic acids, after reduce 2,4-two chloro-3-amino-5-fluorobenzoic acids; Get 2 through diazotization reaction and sandmeyer reaction again, 4-two chloro-3-cyanic acid-5-fluorobenzoic acids.One step of this method nitration reaction produces a large amount of acidified waste waters, and the sandmeyer reaction yield is not high and need use normal cuprous cyanide and normal highly toxic substance sodium cyanide more than three times, in suitability for industrialized production, will bring great potential safety hazard.
(3) summary of the invention
The purpose of this invention is to provide that a kind of reactions step is brief, product yield is high, green safety 2, the preparation method of 4-two chloro-3-cyanic acid-5-fluorobenzoic acids.
For solving the problems of the technologies described above, shown in the following reaction formula of technical thought of the present invention:
The technical scheme that the present invention adopts is:
A kind of 2, the preparation method of 4-two chloro-3-cyanic acid-5-fluorobenzoic acids comprises the steps:
(1), with 2,6-two chloro-3-fluorobenzonitriles, brominated reagent were dissolved in mass concentration 98% vitriol oil, in 0～50 ℃ of following insulation reaction 5～40 hours; Reaction solution slowly pours in the mixture of ice and water; Separate out white solid, the washing of suction filtration, filter cake, dry 2,6-two chloro-3-cyanic acid-5-bromofluorobenzenes;
(2), the halogenated alkane of C2～C4 is dissolved in the anhydrous diethyl ether, adds excessive magnesium powder stirring reaction and causes the back in 10～35 ℃ of reactions 1～24 hour down, is prepared into corresponding Grignard reagent;
(3), step (2) gained Grignard reagent diethyl ether solution is cooled to-10～-80 ℃, adds step (1) gained 2,6-two chloro-3-cyanic acid-5-bromofluorobenzene insulation reaction 0.5～1.5 hour begin to feed dry CO
2Gas slowly is warming up to-10～20 ℃ simultaneously, continues ventilatory response 0.5～1.5 hour, reacts the reaction solution that finishes and gets 2 through separation and purification, 4-two chloro-3-cyanic acid-5-fluorobenzoic acid product.
Further, the said brominated reagent of step of the present invention (1) is selected from N-bromo-succinimide (NBS), C5H6Br2N2O2, dibrominated tricyanic acid, bromo barbituric acid, is preferably N-bromo-succinimide (NBS); Said brominated reagent and 2, the proportional range of 6-two chloro-3-fluorobenzonitrile amount of substances is 0.6～1.5: 1, preferred 0.6～1.2: 1.
Further, the halogenated alkane of the said C2～C4 of step of the present invention (2) is the C2～C4 alkane of monochloro generation or single bromo.
The consumption of said mass concentration 98% vitriol oil is usually with 2, and the quality of 6-two chloro-3-fluorobenzonitriles is counted 2～5mL/g.
Further, step of the present invention (3) is used for preparing the halogenated alkane and 2 of the C2～C4 of said Grignard reagent, and the ratio of the amount of substance of 6-two chloro-3-fluorobenzonitriles is 1.1～1.5: 1.
Further, the said separation purification method of step of the present invention (3) is: reaction solution is regulated pH to 1～3, standing demix with 5wt% Hydrogen chloride; Getting ether layer strips with the 1M aqueous sodium hydroxide solution; The gained water layer is regulated pH to 1～3 with 5wt% Hydrogen chloride, and solid is separated out, suction filtration; Filter cake dry 2,4-two chloro-3-cyanic acid-5-fluorobenzoic acids.
Compared with prior art, method path step provided by the present invention is brief, operating procedure is easy, total recovery is higher than 70%, and product cost is low, has tangible economic advantages; And route has been got rid of the use of the harmful raw material of severe toxicity in the existing literature method, has the advantage of safety, environmental protection, is fit to commercial scale prodn, has obtained remarkable economical, social benefit.
(4) embodiment:
Below with specific embodiment technical scheme of the present invention is described, but protection scope of the present invention is not limited thereto:
Embodiment 1
2,6-two chloro-3-cyanic acid-5-bromofluorobenzenes synthetic
Add 38g (0.2mol) 2 in the 100mL vitriol oil, 6-two chloro-3-fluorobenzonitriles, 42.72g (0.24mol) N-bromo-succinimide, stirring at room reaction 30h; Reaction solution is slowly poured in the 200mL mixture of ice and water, and white solid is separated out, suction filtration; Filter cake washing, dry white solid product 52.8g, be 2; 6-two chloro-3-cyanic acid-5-bromofluorobenzenes, yield is 98%.m.p.122-124℃；
1H?NMR(400MHz，CDCl
3)δ：7.69(d，J＝7.6Hz，1H)；?
13C?NMR(100MHz，CDCl
3)δ：112.1(d，J＝3Hz)，116.5，122.1(d，J＝9Hz)，125.1(d，J＝20Hz)，125.2(d，J＝24Hz)，134.0(d，J＝4Hz)，156.0(d，J＝254Hz)；EI-MS(m/z)：269(M
+)。
Embodiment 2
2,6-two chloro-3-cyanic acid-5-bromofluorobenzenes synthetic
Add 38g (0.2mol) 2 in the 100mL vitriol oil, 6-two chloro-3-fluorobenzonitriles, 34.44g (0.12mol) dibrominated tricyanic acid, 0 ℃ of stirring reaction 40h; Reaction solution is slowly poured in the 200mL mixture of ice and water, and white solid is separated out, suction filtration; Filter cake washing, dry white solid product 52.8g, 2; 6-two chloro-3-cyanic acid-5-bromofluorobenzenes, yield is 96%, n.p.122.5-124 ℃.
Embodiment 3
2,6-two chloro-3-cyanic acid-5-bromofluorobenzenes synthetic
Add 38g (0.2mol) 2 in the 100mL vitriol oil, 6-two chloro-3-fluorobenzonitriles, 34.2g (0.12mol) bromo barbituric acid, 50 ℃ of stirring at room reaction 5h; Reaction solution is slowly poured in the 200mL mixture of ice and water, and white solid is separated out, suction filtration; The filter cake washing; Dry white solid product 50.6g, 2,6-two chloro-3-cyanic acid-5-bromofluorobenzene yield is 94%.n.p.122-124℃
Embodiment 4
2,6-two chloro-3-cyanic acid-5-bromofluorobenzenes synthetic
Add 38g (0.2mol) 2 in the 100mL vitriol oil, 6-two chloro-3-fluorobenzonitriles, 34.32g (0.12mol) C5H6Br2N2O2, stirring at room reaction 25h; Reaction solution is slowly poured in the 200mL mixture of ice and water, and white solid is separated out, suction filtration; Filter cake washing, dry white solid product 50.0g, 2; 6-two chloro-3-cyanic acid-5-bromofluorobenzenes, yield is 93%, n.p.122-124 ℃.
Embodiment 5
2,4-two chloro-3-cyanic acid-5-fluorobenzoic acids synthetic
In the dry reaction device; Add 3.12g (0.13mol) magnesium powder, the diethyl ether solution that is added dropwise to a little monochloroethane stirs under the room temperature to covering the magnesium powder; Reaction initiation back control room temperature slowly is added dropwise to remaining monochloroethane diethyl ether solution and (adds monochloroethane 7.74g (0.12mol) altogether; Ether 150mL), dropwises, continue insulation reaction 12h.Reaction finishes, and filtering residual magnesium powder, prepared ethylmagnesium chloride diethyl ether solution are cooled to-30 ℃, adds the 26.9g (0.1mol) 2 that embodiment 1 makes; 6-two chloro-3-cyanic acid-5-bromofluorobenzenes, reaction 0.5h, beginning slowly feeds dry dioxide gas, and slowly is warming up to-5 ℃; Continue to feed carbon dioxide gas precursor reactant 1h, 5wt% Hydrogen chloride is regulated pH to 1～3, divides the water-yielding stratum reject, gets ether layer and strips 2 times with 40mL (2x20mL) the 1M NaOH aqueous solution; Behind the combining water layer, 5wt% Hydrogen chloride is regulated pH to 1～3, and solid is separated out; Suction filtration, filter cake dry pale yellow powder solid product 19.2g, yield is 82%.m.p.204-206℃；
1H?NMR(DMSO-d
6)δ：8.18(d，J＝9.2Hz，1H)，14.23(brs，1H)；
13C?NMR(DMSO-d
6)δ：112.8(d，J＝3Hz)，116.1，122.5(d，J＝24Hz)，126.6(d，J＝21Hz)，130.7(d，J＝3Hz)，134.1(d，J＝6Hz)，155.7(d，J＝248Hz)，163.9；ESI-MS(m/z)：233([M-H]
-)。(moving phase is methyl alcohol to HPLC purity: water=70: 30): 99.5%
Embodiment 6
2,4-two chloro-3-cyanic acid-5-fluorobenzoic acids synthetic
In the dry reaction device; Add 3.12g (0.13mol) magnesium powder, the diethyl ether solution that is added dropwise to a little isopropyl chloride stirs under the room temperature to covering the magnesium powder; Reaction initiation back control room temperature slowly is added dropwise to remaining isopropyl chloride diethyl ether solution and (adds isopropyl chloride 9.42g (0.12mol) altogether; Ether 150mL), dropwises, continue insulation reaction 24h.Reaction finishes, and filtering residual magnesium powder, prepared isopropylmagnesium chloride diethyl ether solution are cooled to-50 ℃, adds the 26.9g (0.1mol) 2 that embodiment 2 makes; 6-two chloro-3-cyanic acid-5-bromofluorobenzenes, reaction 0.5h, beginning slowly feeds dry dioxide gas, and slowly is warming up to-10 ℃; Continue to feed carbon dioxide gas precursor reactant 1h, the 5wt% dilute hydrochloric acid solution is regulated pH to 1～3, divides the water-yielding stratum reject; Get ether layer and strip 2 times with 40mL (2x20mL) the 1M NaOH aqueous solution, behind the combining water layer, 5wt% Hydrogen chloride is regulated pH to 1～3; Solid is separated out, suction filtration, filter cake dry pale yellow powder solid product 19.9g; Yield is 85%, and m.p.204-206 ℃, (moving phase is methyl alcohol to HPLC purity: water=70: 30): 99.0%.
Embodiment 7
2,4-two chloro-3-cyanic acid-5-fluorobenzoic acids synthetic
In the dry reaction device; Add 3.36g (0.14mol) magnesium powder, the diethyl ether solution that is added dropwise to a little isopropyl bromide stirs under the room temperature to covering the magnesium powder; Keep slight boiling condition slowly to be added dropwise to remaining isopropyl bromide diethyl ether solution after reaction causes and (add isopropyl bromide 14.76g (0.12mol) altogether; Ether 150mL), dropwises, keep 35 ℃ to continue reaction 1h.Reaction finishes, filtering residual magnesium powder, and prepared sec.-propyl bromination magnesium diethyl ether solution is cooled to-20 ℃, adds the 26.9g (0.1mol) 2 that embodiment 3 makes; 6-two chloro-3-cyanic acid-5-bromofluorobenzenes, reaction 1.5h, beginning slowly feeds dry dioxide gas, and slowly is warming up to 0 ℃; Continue to feed carbon dioxide gas precursor reactant 1h, the 5wt% dilute hydrochloric acid solution is regulated pH to 1～3, divides the water-yielding stratum reject; Get ether layer and strip 2 times with 40mL (2x20mL) the 1M NaOH aqueous solution, behind the combining water layer, 5wt% Hydrogen chloride is regulated pH to 1～3; Solid is separated out, suction filtration, filter cake dry pale yellow powder solid product 17.6g; Yield is 75%, and m.p.204-206 ℃, (moving phase is methyl alcohol to HPLC purity: water=70: 30): 99.0%.
Embodiment 8
2,4-two chloro-3-cyanic acid-5-fluorobenzoic acids synthetic
In the dry reaction device; Add 3.36g (0.14mol) magnesium powder, the diethyl ether solution that is added dropwise to a little n-butyl chloride stirs under the room temperature to covering the magnesium powder; Keep slight boiling condition slowly to be added dropwise to remaining n-butyl chloride diethyl ether solution after reaction causes and (add n-butyl chloride 11.1g (0.12mol) altogether; Ether 150mL), dropwises, keep 35 ℃ of reaction 5h.React the filtering residual magnesium powder that finishes, prepared normal-butyl chlorination magnesium diethyl ether solution is cooled to-30 ℃, adds the 26.9g (0.1mol) 2 that embodiment 4 makes, 6-two chloro-3-cyanic acid-5-bromofluorobenzenes; Reaction 0.5h, beginning slowly feeds dry dioxide gas, and slowly is warming up to-5 ℃; Continue to feed carbon dioxide gas precursor reactant 1h, the 5wt% dilute hydrochloric acid solution is regulated pH to 1～3, divides the water-yielding stratum reject; Get ether layer and strip 2 times with 40mL (2x20mL) the 1M NaOH aqueous solution, behind the combining water layer, 5wt% Hydrogen chloride is regulated pH to 1～3; Solid is separated out, suction filtration, filter cake dry pale yellow powder solid product 19.2g; Yield is 82%, and m.p.204-206 ℃, (moving phase is methyl alcohol to HPLC purity: water=70: 30): 99.0%.
Embodiment 9
2,4-two chloro-3-cyanic acid-5-fluorobenzoic acids synthetic
In the dry reaction device; Add 3.36g (0.14mol) magnesium powder, the diethyl ether solution that is added dropwise to a little tert.-butyl bromide stirs under the room temperature to covering the magnesium powder; Keep slight boiling condition slowly to be added dropwise to remaining tert.-butyl bromide diethyl ether solution after reaction causes and (add tert.-butyl bromide 16.44g (0.12mol) altogether; Ether 150mL), dropwises, keep 35 ℃ of reaction 2h.Reaction finishes, filtering residual magnesium powder, and prepared tertiary butyl bromination magnesium diethyl ether solution is cooled to-40 ℃, adds the 26.9g (0.1mol) 2 that embodiment 1 makes; 6-two chloro-3-cyanic acid-5-bromofluorobenzenes, reaction 0.5h feeds dry dioxide gas, and slowly is warming up to-5 ℃; Continue to feed carbon dioxide gas precursor reactant 1h, the 5wt% dilute hydrochloric acid solution is regulated pH to 1～3, divides the water-yielding stratum reject; Get ether layer and strip 2 times with 40mL (2x20mL) the 1M NaOH aqueous solution, behind the combining water layer, 5wt% Hydrogen chloride is regulated pH to 1～3; Solid is separated out, suction filtration, filter cake dry pale yellow powder solid product 19.6g; Yield is 84%, and m.p.204-206 ℃, (moving phase is methyl alcohol to HPLC purity: water=70: 30): 99.0%.
Claims (7)
1. one kind 2, the preparation method of 4-two chloro-3-cyanic acid-5-fluorobenzoic acids is characterized in that comprising the steps:
(1), with 2,6-two chloro-3-fluorobenzonitriles, brominated reagent were dissolved in mass concentration 98% vitriol oil, in 0～50 ℃ of following insulation reaction 5～40 hours; Reaction solution slowly pours in the mixture of ice and water; Separate out white solid, the washing of suction filtration, filter cake, dry 2,6-two chloro-3-cyanic acid-5-bromofluorobenzenes;
(2), the halogenated alkane of C2～C4 is dissolved in the anhydrous diethyl ether, adds excessive magnesium powder stirring reaction and causes the back in 10～35 ℃ of reactions 1～24 hour down, is prepared into corresponding Grignard reagent diethyl ether solution;
(3), step (2) gained Grignard reagent diethyl ether solution is cooled to-10～-80 ℃, adds step (1) gained 2,6-two chloro-3-cyanic acid-5-bromofluorobenzene insulation reaction 0.5～1.5 hour begin to feed dry CO
2Gas slowly is warming up to-10～20 ℃ simultaneously, continues ventilatory response 0.5～1.5 hour, reacts the reaction solution that finishes and gets 2 through separation and purification, 4-two chloro-3-cyanic acid-5-fluorobenzoic acid product.
2. as claimed in claim 12, the preparation method of 4-two chloro-3-cyanic acid-5-fluorobenzoic acids is characterized in that said brominated reagent is selected from N-bromo-succinimide, C5H6Br2N2O2, dibrominated tricyanic acid or bromo barbituric acid.
3. as claimed in claim 12, the preparation method of 4-two chloro-3-cyanic acid-5-fluorobenzoic acids is characterized in that said brominated reagent is the N-bromo-succinimide.
4. as claimed in claim 12, the preparation method of 4-two chloro-3-cyanic acid-5-fluorobenzoic acids is characterized in that said brominated reagent and 2, and the ratio of the amount of substance of 6-two chloro-3-fluorobenzonitriles is 0.6～1.5: 1.
5. as claimed in claim 12, the preparation method of 4-two chloro-3-cyanic acid-5-fluorobenzoic acids, the halogenated alkane that it is characterized in that the said C2～C4 of step in the claim 1 (2) is the C2～C4 alkane of monochloro generation or single bromo.
6. as claimed in claim 12; The preparation method of 4-two chloro-3-cyanic acid-5-fluorobenzoic acids; It is characterized in that step in the claim 1 (3) is used for preparing the halogenated alkane and 2 of the C2～C4 of said Grignard reagent, the ratio of the amount of substance of 6-two chloro-3-fluorobenzonitriles is 1.1～1.5: 1.
7. as claimed in claim 12, the preparation method of 4-two chloro-3-cyanic acid-5-fluorobenzoic acids is characterized in that the said separation purification method of step in the claim 1 (3) is: reaction solution is regulated pH to 1～3 with 5wt% Hydrogen chloride; Static layering is got ether layer and is stripped with the 1M aqueous sodium hydroxide solution, and the gained water layer is regulated pH to 1～3 with 5wt% Hydrogen chloride; Separate out solid; Suction filtration, filter cake dry 2,4-two chloro-3-cyanic acid-5-fluorobenzoic acids.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104744305A (en) * | 2015-03-13 | 2015-07-01 | 浙江中欣化工股份有限公司 | Synthesis method of 2,4-dichloro-3-cyan-5-fluorobenzoic acid |
| CN109232450A (en) * | 2018-10-25 | 2019-01-18 | 山东润博生物科技有限公司 | A kind of synthetic method of sulfentrazone |
| CN110156637A (en) * | 2019-06-18 | 2019-08-23 | 宁波美诺华药业股份有限公司 | A kind of preparation method of the chloro- 3- cyano -5- fluobenzoic acid of 2,4- bis- |
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| CN1436771A (en) * | 1997-04-24 | 2003-08-20 | 拜尔公司 | 3-Cyan-2,4,5-trifluoro-benzene formyl fluorine and intermediate produced therefor |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104744305A (en) * | 2015-03-13 | 2015-07-01 | 浙江中欣化工股份有限公司 | Synthesis method of 2,4-dichloro-3-cyan-5-fluorobenzoic acid |
| CN109232450A (en) * | 2018-10-25 | 2019-01-18 | 山东润博生物科技有限公司 | A kind of synthetic method of sulfentrazone |
| CN109232450B (en) * | 2018-10-25 | 2022-01-25 | 山东润博生物科技有限公司 | Synthetic method of sulfentrazone |
| CN110156637A (en) * | 2019-06-18 | 2019-08-23 | 宁波美诺华药业股份有限公司 | A kind of preparation method of the chloro- 3- cyano -5- fluobenzoic acid of 2,4- bis- |
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| CN102603571B (en) | 2014-08-06 |
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