CN106397186A - Preparation method of ethyl bromodifluoroacetate - Google Patents
Preparation method of ethyl bromodifluoroacetate Download PDFInfo
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- CN106397186A CN106397186A CN201610793774.3A CN201610793774A CN106397186A CN 106397186 A CN106397186 A CN 106397186A CN 201610793774 A CN201610793774 A CN 201610793774A CN 106397186 A CN106397186 A CN 106397186A
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- Prior art keywords
- difluoro
- preparation
- ethyl bromide
- bromoacetonitrile
- reaction
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- IRSJDVYTJUCXRV-UHFFFAOYSA-N ethyl 2-bromo-2,2-difluoroacetate Chemical compound CCOC(=O)C(F)(F)Br IRSJDVYTJUCXRV-UHFFFAOYSA-N 0.000 title abstract 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- PWSYCGWXKUPFKT-UHFFFAOYSA-N 2-bromo-2,2-difluoroacetonitrile Chemical compound FC(F)(Br)C#N PWSYCGWXKUPFKT-UHFFFAOYSA-N 0.000 claims abstract description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 28
- -1 bromodifluoroacetyl halide Chemical class 0.000 claims abstract description 26
- 239000002994 raw material Substances 0.000 claims abstract description 12
- 238000006136 alcoholysis reaction Methods 0.000 claims abstract description 7
- 230000032050 esterification Effects 0.000 claims abstract description 6
- 238000005886 esterification reaction Methods 0.000 claims abstract description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 42
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 29
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 19
- 239000003054 catalyst Substances 0.000 claims description 16
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 7
- 239000004338 Dichlorodifluoromethane Substances 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 6
- YSSSPARMOAYJTE-UHFFFAOYSA-N dibenzo-18-crown-6 Chemical compound O1CCOCCOC2=CC=CC=C2OCCOCCOC2=CC=CC=C21 YSSSPARMOAYJTE-UHFFFAOYSA-N 0.000 claims description 6
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 6
- 235000019404 dichlorodifluoromethane Nutrition 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- LHNWMULAKLZVHJ-UHFFFAOYSA-N FBrF Chemical compound FBrF LHNWMULAKLZVHJ-UHFFFAOYSA-N 0.000 claims description 5
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical group [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 3
- 235000011149 sulphuric acid Nutrition 0.000 claims description 3
- 239000001117 sulphuric acid Substances 0.000 claims description 3
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 17
- 230000008569 process Effects 0.000 abstract description 12
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 239000007800 oxidant agent Substances 0.000 abstract description 8
- 230000001590 oxidative effect Effects 0.000 abstract description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 6
- 239000006227 byproduct Substances 0.000 abstract description 6
- 239000001301 oxygen Substances 0.000 abstract description 6
- 229910052760 oxygen Inorganic materials 0.000 abstract description 6
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 abstract description 5
- 230000007797 corrosion Effects 0.000 abstract description 5
- 238000005260 corrosion Methods 0.000 abstract description 5
- 239000000463 material Substances 0.000 abstract description 5
- LZCMQBRCQWOSHZ-UHFFFAOYSA-N 2-bromo-2,2-difluoroacetic acid Chemical compound OC(=O)C(F)(F)Br LZCMQBRCQWOSHZ-UHFFFAOYSA-N 0.000 abstract description 4
- 229910000039 hydrogen halide Inorganic materials 0.000 abstract description 4
- 239000012433 hydrogen halide Substances 0.000 abstract description 4
- 150000002978 peroxides Chemical class 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 229910052751 metal Inorganic materials 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 abstract 1
- 239000007864 aqueous solution Substances 0.000 abstract 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 abstract 1
- 238000005580 one pot reaction Methods 0.000 abstract 1
- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 abstract 1
- 231100000331 toxic Toxicity 0.000 abstract 1
- 230000002588 toxic effect Effects 0.000 abstract 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 18
- 229910052736 halogen Inorganic materials 0.000 description 16
- 239000000243 solution Substances 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 150000001263 acyl chlorides Chemical class 0.000 description 6
- 150000001265 acyl fluorides Chemical class 0.000 description 6
- AZSZCFSOHXEJQE-UHFFFAOYSA-N dibromodifluoromethane Chemical compound FC(F)(Br)Br AZSZCFSOHXEJQE-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 150000001262 acyl bromides Chemical class 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- WGIRTDAEWOUFQR-UHFFFAOYSA-N 1,1-dibromo-1-chloro-2,2,2-trifluoroethane Chemical compound FC(F)(F)C(Cl)(Br)Br WGIRTDAEWOUFQR-UHFFFAOYSA-N 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 231100000614 poison Toxicity 0.000 description 4
- 230000007096 poisonous effect Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 210000003298 dental enamel Anatomy 0.000 description 3
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 150000002730 mercury Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229960002523 mercuric chloride Drugs 0.000 description 2
- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical compound Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 description 2
- 229910000474 mercury oxide Inorganic materials 0.000 description 2
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- ZXUJWPHOPHHZLR-UHFFFAOYSA-N 1,1,1-trichloro-2-fluoroethane Chemical compound FCC(Cl)(Cl)Cl ZXUJWPHOPHHZLR-UHFFFAOYSA-N 0.000 description 1
- QMSVNDSDEZTYAS-UHFFFAOYSA-N 1-bromo-1-chloroethane Chemical compound CC(Cl)Br QMSVNDSDEZTYAS-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- INYGCQMOMATNOD-UHFFFAOYSA-N BrCC(=O)O.[F] Chemical compound BrCC(=O)O.[F] INYGCQMOMATNOD-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- XAVQSYRCKUWPLF-UHFFFAOYSA-M C(C)O.[F-].[K+] Chemical compound C(C)O.[F-].[K+] XAVQSYRCKUWPLF-UHFFFAOYSA-M 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- PRPAGESBURMWTI-UHFFFAOYSA-N [C].[F] Chemical compound [C].[F] PRPAGESBURMWTI-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- UQXKXGWGFRWILX-UHFFFAOYSA-N ethylene glycol dinitrate Chemical compound O=N(=O)OCCON(=O)=O UQXKXGWGFRWILX-UHFFFAOYSA-N 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Toxicology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of organic synthesis and discloses a preparation method of ethyl bromodifluoroacetate. Difluorobromoacetonitrile is taken as a raw material, and prepared through a one-pot method and subjected to alcoholysis and esterification in ethanol aqueous solution to obtain ethyl bromodifluoroacetate. According to the method provided by the invention, difluorobromoacetonitrile is taken as the raw material and then bromodifluoroacetic acid is subjected to the alcoholysis and esterification after directly hydrolyzed, without generating a toxic bromodifluoroacetyl halide intermediate, and the use of fuming sulfuric acid as an oxidant and bad in operating environments and maximum in pollution, or peroxide or ozone, or oxygen in a high pressure system to result in poor selectivity and very low yield is avoided. Furthermore, the existence of by-products with extremely strong hydrogen halide corrosion of hydrogen fluoride and the like which both have extremely large corrosion to metal and glass-lined materials is avoided in the process, so that the requirements for production reaction equipment are lowered, and the preparation of ethyl bromodifluoroacetate can be carried out in the ordinary glass-lined reaction device.
Description
Technical field
The invention belongs to organic synthesis field is and in particular to a kind of preparation method of ethyl bromide difluoride.
Background technology
Ethyl bromide difluoride compound is a kind of intermediate of synthetic drug and high energy material.Disclosed prepare this chemical combination
Ethanol and difluoro acetyl bromide halogen reaction are prepared ethyl bromide difluoride by thing, and its chemical equation is as follows：
Wherein, X can be F, Cl or Br, and difluoro acetyl bromide halogen can prepare difluoro bromine second according to various different process methods
Carboxylic acid halides (acyl chlorides, acylbromide and acyl fluorides).
In numerous open source literatures and patent, it is itemized in various different processes, but basic core technology
The technology of preparing of difluoro acetyl bromide halogen, substantially with the bromo- halothane of the fluoro- 1- of 1,1- bis- for raw material, in oxidant [O] and
Under catalyst [C] effect, by preparing the required approach of intermediate difluoro acetyl bromide halogen, obtain difluoro bromine reacting with ethanol
Ethyl acetate, the technology of preparing route of its difluoro acetyl bromide halogen is as follows：
Wherein, X1, X2, X3：Can difference can also be identical, they are F respectively, and any one of Cl or Br, X can be
F, Cl or Br.
As Zhao, Jingwei et al. (Chinese Journal of Chemistry, 27 (6), 1163-1168；2009)
Report by the bromo- 2- ethyl chloride of 1,1,2- tri- fluoro- 1,2- bis- under oleum and catalyst Mercury oxide black. act on, at 80 DEG C plus
Heat 3 hours, obtains ethyl bromide difluoride in potassium fluoride ethanol solution.
Drivon, Gilles et al. (Eur.Pat.Appl., 1270540,02Jan 2003) report by 1,1,2,2- tetra-
Fluoro- glycol dibromide, under oleum effect, is obtained difluoro acetyl bromide fluorine, is followed by obtained difluoro bromoacetic acid with ethanol synthesis
Ethyl ester；
Sato, Shiro et al. (Japanese patent application, 11-80084,23Mar 1999) report by 1,1,2- tri- fluoro- 1,
2- Bromofume, under oleum and catalyst iron sesquioxide act on, obtains difluoro acetyl bromide fluorine, followed by with ethanol synthesis
Obtain ethyl bromide difluoride.
Gillet, Jean-Philippe and Ruppin, Christophe (Eur.Pat.Appl., 810197,03Dec
1997) it was recently reported that by bromo- 2, the 2- dichloroethanes of fluoro- 1, the 2- bis- of 1,1- bis- under oxygen and catalyst azodiisobutyronitrile act on,
Obtain difluoro acetyl bromide fluorine, followed by obtain ethyl bromide difluoride with ethanol synthesis.
Si, Linxu et al. (CN102746150,24Oct 2012) report and are existed by the fluoro- 2,2,2- trichloroethane of 1,2- bis-
Under oxygen effect, under the conditions of 0.5Mpa, 120 DEG C are heated 6 hours, obtain difluoro acetyl bromide fluorine, followed by obtain with ethanol synthesis
Ethyl bromide difluoride.
Report a lot of processes at G. Delhi Feng et al. (CN1239458C), substantially by the bromo- halogen of the fluoro- 1- of 1,1- bis-
It is raw material for ethane, under the effect of different oxidants, obtain difluoro acetyl bromide halogen, then occurred with ethanol by difluoro acetyl bromide halogen
Reaction, prepare ethyl bromide difluoride, the oxidant that these processes are adopted be mainly oleum, peroxide,
Oxygen or ozone etc., and obtain difluoro acetyl bromide halogen under poisonous mercury salt (as mercury oxide, mercuric chloride etc.) catalysis.
In sum, all technical processs are all based on first obtaining difluoro acetyl bromide halogen (acyl fluorides, acyl chlorides and acylbromide at present
Deng), obtaining ethyl bromide difluoride with ethanol synthesis, simultaneously with the by-product life that the hydrogen halide corrosions such as fluohydric acid gas are extremely strong
Produce.These processes are main to have following problem：
The bromo- halothane of the fluoro- 1- of (1) 1,1- bis- is raw material, and substantially oxidant effect and poisonous mercury salt are (as aoxidized
Hydrargyrum, mercuric chloride etc.) under catalysis, prepare difluoro acetyl bromide halogen (acyl fluorides, acyl chlorides and acylbromide etc.), the oxidant that this process adopts
It is oleum, its severe operational environment, pollution is greatly；Using peroxide, oxygen or ozone, or high pressure system
In, but poor selectivity, yield is extremely low, and cost is high；
(2), in this technical process, intermediate difluoro acetyl bromide halogen is with the raw one-tenth of the form of gas in hot conditionss,
Need to collect in strong cool condition, obtain volatile liquid at normal temperatures, collect in process and esterification process, easily hydrolyze, lead to
Yield is extremely low.
(3) during obtaining difluoro acetyl bromide halogen (acyl fluorides, acyl chlorides and acylbromide etc.), simultaneously with hydrogen halides such as fluohydric acid gas
The extremely strong by-product of corrosivity, all can have great corrosivity to metal and enamel material, thus will to producing consersion unit
Ask high.
Additionally, being raising 1, the oxidation of the bromo- halothane of the fluoro- 1- of 1- bis- obtains difluoro acetyl bromide halogen (acyl fluorides, acyl chlorides and acyl
Bromine etc.), mostly using the heavy metal mercury salt (catalyst) to environmental hazard, irreversible destruction may be produced to environment.
Content of the invention
The weak point existing for this area, it is an object of the invention to provide a kind of preparation of ethyl bromide difluoride
Method, it is to be directly obtained by the hydrolysis of difluoro bromoacetonitrile, need not separate and directly react and prepare difluoro bromine second with ethyl ester
Acetoacetic ester.
It is that the technical scheme of anthology goal of the invention is；
A kind of preparation method of ethyl bromide difluoride, with difluoro bromoacetonitrile as raw material, is prepared by one kettle way, difluoro bromine
Acetonitrile alcoholysis esterification in ethanol water, obtains ethyl bromide difluoride.Reaction equation is：
BrF2CCN→BrF2CCOOH→BrF2CCOOC2H5(1)
The initiation material difluoro bromoacetonitrile that the present invention adopts can be prepared with Cupricin. by dibromodifluoromethane.
The present invention utilizes the side product dibromo difluoromethane in fluorine carbon geochemistry industrial process, is also a kind of extinguishing chemical 1202,
Because dibromodifluoromethane is the ozone consuming in atmosphere in itself, environment is caused a devastating effect it is impossible to direct use
Its waste liquid can not be poured into pond, the present invention is easily reacted with nucleopilic reagent (CuCN) using dibromodifluoromethane, can
To prepare difluoro bromoacetonitrile, easily provide raw material for preparing ethyl bromide difluoride, direct hydrolysis and alcoholysis can obtain two
Fluorine bromoacetate.
Wherein, described difluoro bromoacetonitrile is to be reacted with nucleopilic reagent by dichlorodifluoromethane to obtain, and described nucleopilic reagent is
CuCN、Zn(CN)2One of with NaCN, described reaction is to carry out in organic solvent, and described organic solvent is N, N- diformazan
Base Methanamide (DMF), glycol dimethyl ether (DME), one or more of 1- methyl -2 ketopyrrolidine (NMP).Nucleopilic reagent
For reaction equation during CuCN it is：
Further, in the reaction of synthesis difluoro bromoacetonitrile, with dibenzo-18 crown-6 as catalyst, every 100g nucleophilic examination
Add catalyst 1～6g in agent, be then slowly added dropwise the dichlorodifluoromethane solution being dissolved in organic solvent, anti-at 15～30 DEG C
Should.Depending on the time of reaction passes through to monitor conversion ratio.After reaction stops, first can steam, be collected with cold well again and produce at 40-60 DEG C
Thing.
Preferably, every 100g nucleopilic reagent is dissolved in 400～600mL organic solvent, is subsequently adding catalyst.
It is highly preferred that synthesis difluoro bromoacetonitrile reaction in, by dichlorodifluoromethane be dissolved in DMF and
In the mixed solvent of glycol dimethyl ether, the concentration of dissolving is 0.1～1mol/L；N,N-dimethylformamide and glycol dinitrate
The volume ratio of ether is 1：1～3.
In the reaction that difluoro bromoacetonitrile is esterified after hydrolyzing in ethanol water, difluoro bromoacetonitrile is in ethanol water
Concentration is 0.5～20mol/L, and in ethanol water, the mass content of ethanol is 90～99%.
In the reaction that difluoro bromoacetonitrile is esterified after hydrolyzing in ethanol water, difluoro bromoacetonitrile is dissolved in ethanol water
In, add sulfuric acid solution, at 10～35 DEG C of temperature, insulated and stirred 1～15 hour, then heating reflux reaction.
Preferably, every mole of difluoro bromoacetonitrile adds 10～30mL sulfuric acid solution, the quality of sulphuric acid in described sulfuric acid solution
Content is 40～80%.
It is further preferred that the time of heating reflux reaction is 5～10 hours；Separated product after back flow reaction.
The beneficial effects of the present invention is：
Inventors herein have recognized that the difluoro bromoacetonitrile being obtained with industry is as raw material, by one kettle way by difluoro bromine second
Nitrile ethanol water alcoholysis be esterified, directly obtain ethyl bromide difluoride, during do not use poisonous catalyst, it is to avoid with
The bromo- halothane of 1,1- bis- fluoro- 1- is raw material, using the oxidation technologies such as oleum oxidant, made difluoro acetyl bromide halogen
The required route of (acyl fluorides, acyl chlorides and acylbromide etc.) intermediate, eliminates because preparing the above-mentioned described potentially danger of this intermediate,
The extremely strong by-product production of the hydrogen halide corrosions such as fluohydric acid gas especially can be avoided, greatly improve Environmental security, operation
Safety.
Method proposed by the present invention, is raw material it is not necessary to pass through to generate in poisonous difluoro acetyl bromide halogen by difluoro bromoacetonitrile
The process of mesosome, difluoro bromoacetic acid alcoholysis esterification again after direct hydrolysis, it is to avoid or the oxidant of employing is oleum, its behaviour
Make bad environments, pollution is greatly；Utilize oxygen using in peroxide or ozone, or high pressure system, but poor selectivity,
Yield is extremely low.With the presence of the by-product that the hydrogen halide corrosions such as fluohydric acid gas are extremely strong simultaneously during avoiding, to metal and enamel
Material all can have great corrosivity, thus reduces to the requirement producing consersion unit, can be in common enamel reaction dress
Carry out in putting.
Specific embodiment
Following examples are used for the present invention is described, but are not limited to the scope of the present invention.
Raw material used in embodiment, if no special instructions, is commercial.
Embodiment 1：
Difluoro bromoacetonitrile is prepared by difluorodibromomethane
90 grams of Cupricin. powder are added to 500 milliliter 1:1 (volume ratio) N,N-dimethylformamide (DMF)/second two
In diethylene glycol dimethyl ether (DME) mixed solvent, and add 1 gram of catalyst dibenzo-18 crown-6, slowly the difluoro of Deca mole metering
Methylene bromide is dissolved in DMF/DME (volume ratio 1:1) mixed solution in, starts after reaction half an hour under the conditions of 20 DEG C of temperature to supervise
Survey, with GC (chromatographic column：PEG-20M) monitoring is till conversion ratio is 80%.
It is slowly ramped to 50 DEG C, so that difluoro bromoacetonitrile is steamed, then by less than 0 DEG C of cold well, cryogenic collector difluoro bromoacetonitrile.
Carbon-13 nmr spectra：13CNMR：σC115.5ppm, σC98.6ppm.
Embodiment 2：
90 grams of Cupricin. powder are added to 500 milliliter 1:2 (volume ratio) N,N-dimethylformamide (DMF)/second two
In diethylene glycol dimethyl ether (DME) mixed solvent, and add 2 grams of catalyst dibenzo-18 crown-6, slowly the difluoro dibromo of Deca metering
Methane is dissolved in DMF/DME (volume ratio 1:2) mixed solution, after reaction half an hour under the conditions of 20 DEG C, with GC (chromatographic column：
PEG-20M) detection conversion ratio is stopped reaction when 85%.Slowly heat up 50 DEG C, so that difluoro bromoacetonitrile is steamed, then by less than 0
DEG C cold well, cryogenic collector difluoro bromoacetonitrile.
Carbon-13 nmr spectra：13CNMR：σC115.5ppm, σC98.4ppm.
Embodiment 3：
90 grams of Cupricin. powder are added to 500 milliliter 1:3 (volume ratio) N,N-dimethylformamide (DMF)/second two
In diethylene glycol dimethyl ether (DME) mixed solvent, and add 3 grams of catalyst dibenzo-18 crown-6, slowly the difluoro dibromo of Deca metering
Methane DMF/DME mixed solution, under the conditions of 20 DEG C below reaction half an hour after, with GC (chromatographic column：PEG-20M) measure conversion
Rate be 90% when till.Slowly heat up 50 DEG C, so that difluoro bromoacetonitrile is steamed, then by less than 0 DEG C of cold well cryogenic collector difluoro bromine
Acetonitrile.
Carbon-13 nmr spectra：13CNMR：σC115.4ppm,σC98.6ppm.
Embodiment 4
90 grams of (1mol) Cupricin. powder are added to 500 milliliter 1:4 (volume ratio) N,N-dimethylformamide
(DMF) in/glycol dimethyl ether (DME) mixed solvent, and 1～5 gram of catalyst dibenzo-18 crown-6, slowly Deca meter are added
The difluorodibromomethane of amount is dissolved in DMF/DME (volume ratio 1:4) mixed solution, after reaction half an hour under the conditions of 20 DEG C, uses
GC (chromatographic column：PEG-20M) monitoring to conversion ratio is 91%.Slowly heat up 50 DEG C, so that difluoro bromoacetonitrile is steamed, then by being less than
0 DEG C of cold well cryogenic collector difluoro bromoacetonitrile,
Carbon-13 nmr spectra：13CNMR：σC115.6ppm,σC98.5ppm.
Embodiment 5
Ethyl bromide difluoride is prepared by difluoro bromoacetonitrile
78 grams of (0.5mol) difluoro bromoacetonitriles are dissolved in 400 milliliter of 95% (mass fraction, similarly hereinafter) ethanol solution, plus
Enter 10 milliliter of 50% (mass fraction, similarly hereinafter) sulfuric acid solution, be heated to 30 DEG C, insulated and stirred 10 hours, slowly it is heated to reflux 5 little
When, by rectification, with GC (capillary chromatograph：PEG-20M), suitable ingredients are collected in detection, obtain 60.5 grams of difluoro bromoacetic acid second
Ester, the purity of product is 99.0%.
Proton nmr spectra1HNMR：σH4.46ppm(2H),σH1.51ppm(3H).
Embodiment 6
78.0 grams of (0.5mol) difluoro bromoacetonitriles are dissolved in 400 milliliter of 95% ethanol solution, add 10 milliliter 50%
Sulfuric acid solution, is heated to 20 DEG C, and insulated and stirred 15 hours is slowly heated to reflux 5 hours, by rectification, with GC (capillary chromatography
Post：PEG-20M), suitable ingredients are collected in detection, obtain 72.5 grams of ethyl bromide difluorides, the purity of product is 99.1%.
Proton nmr spectra1HNMR：σH4.46ppm(2H),σH1.50ppm(3H).
Embodiment 7
78 grams of (0.5mol) difluoro bromoacetonitriles are dissolved in 400 milliliter of 95% ethanol solution, add 10 milliliter of 50% sulfur
Acid solution, is heated to 20 DEG C, and insulated and stirred 15 hours is slowly heated to reflux 7 hours, by rectification, with GC (capillary chromatograph：
PEG-20M), suitable ingredients are collected in detection, obtain 80.5 grams of ethyl bromide difluorides, the purity of product is 99.2%.
Proton nmr spectra1HNMR：σH4.47ppm(2H),σH1.52ppm(3H).
Embodiment 8
78 grams of (0.5mol) difluoro bromoacetonitriles are dissolved in 400 milliliter of 95% ethanol solution, adds 20 milliliter of 50% sulphuric acid
Solution, is heated to 10 DEG C, and insulated and stirred 15 hours is slowly heated to reflux 7 hours, by rectification, with GC (capillary chromatograph：
PEG-20M), suitable ingredients are collected in detection, and the purity obtaining 92.5 grams of ethyl bromide difluoride products is 99.3%.
Proton nmr spectra1HNMR：σH4.45ppm(2H),σH1.51ppm(3H).
Although present disclosure has been made to be discussed in detail by above preferred embodiment, but it should be appreciated that above-mentioned
Description is not considered as limitation of the present invention.It will be understood by those skilled in the art that it is straight from this patent disclosure and general knowledge
Connect equivalence changes or the modification of some deformation derived or associate, or the replacement of prior art, and feature, can be realized this
The function of patent description and effect, all belong to this patent protection domain.
Claims (9)
1. a kind of preparation method of ethyl bromide difluoride is it is characterised in that with difluoro bromoacetonitrile as raw material, by one kettle way system
Standby, the alcoholysis esterification in ethanol water of difluoro bromoacetonitrile, obtain ethyl bromide difluoride.
2. the preparation method of ethyl bromide difluoride according to claim 1 is it is characterised in that described difluoro bromoacetonitrile is
Reacted with nucleopilic reagent by dichlorodifluoromethane and obtain, described nucleopilic reagent is CuCN, Zn (CN)2One of with NaCN, institute
Stating reaction is to carry out in organic solvent, and described organic solvent is DMF, glycol dimethyl ether, 1- methyl -2
One or more of ketopyrrolidine.
3. the preparation method of ethyl bromide difluoride according to claim 2 is it is characterised in that synthesize difluoro bromoacetonitrile
In reaction, with dibenzo-18 crown-6 as catalyst, add catalyst 1～6g in every 100g nucleopilic reagent, be then slowly added dropwise
It is dissolved in the dichlorodifluoromethane solution of organic solvent, react at 15～30 DEG C.
4. the preparation method of ethyl bromide difluoride according to claim 3 is it is characterised in that every 100g nucleopilic reagent is molten
In 400～600mL organic solvent, it is subsequently adding catalyst.
5. the preparation method of ethyl bromide difluoride according to claim 3 is it is characterised in that synthesize difluoro bromoacetonitrile
In reaction, dichlorodifluoromethane is dissolved in DMF and the mixed solvent of glycol dimethyl ether, dissolving dense
Spend for 0.1～1mol/L；The volume ratio of N,N-dimethylformamide and glycol dimethyl ether is 1：1～3.
6. the preparation method of the ethyl bromide difluoride according to any one of Claims 1 to 5 is it is characterised in that difluoro bromine
Concentration in ethanol water for the acetonitrile is 0.5～20mol/L, and in ethanol water, the mass content of ethanol is 90～99%.
7. the preparation method of the ethyl bromide difluoride according to any one of Claims 1 to 5 is it is characterised in that difluoro bromine
Acetonitrile is dissolved in ethanol water, adds sulfuric acid solution, at 10～35 DEG C of temperature, insulated and stirred 1～15 hour, then heat back
Stream reaction.
8. the preparation method of ethyl bromide difluoride according to claim 7 is it is characterised in that every mole of difluoro bromoacetonitrile
Add 10～30mL sulfuric acid solution, in described sulfuric acid solution, the mass content of sulphuric acid is 40～80%.
9. ethyl bromide difluoride according to claim 7 preparation method it is characterised in that heating reflux reaction when
Between be 1～10 hour；Separated product after back flow reaction.
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| CN109180479A (en) * | 2018-09-30 | 2019-01-11 | 禾信天成科技（天津）有限公司 | A kind of preparation method of difluoro bromacetate |
| CN113214080A (en) * | 2021-05-17 | 2021-08-06 | 安徽康尔辉药业有限公司 | Preparation process of ethyl difluorobromoacetate |
| CN114014781A (en) * | 2021-11-25 | 2022-02-08 | 南通宝凯药业有限公司 | Synthesis process of 2-bromo-2, 2-difluoroacetonitrile |
| CN116621686A (en) * | 2023-07-21 | 2023-08-22 | 山东国邦药业有限公司 | Preparation method of difluoro acetic acid |
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| CN109180479A (en) * | 2018-09-30 | 2019-01-11 | 禾信天成科技（天津）有限公司 | A kind of preparation method of difluoro bromacetate |
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| CN114014781A (en) * | 2021-11-25 | 2022-02-08 | 南通宝凯药业有限公司 | Synthesis process of 2-bromo-2, 2-difluoroacetonitrile |
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| CN116621686B (en) * | 2023-07-21 | 2023-10-27 | 山东国邦药业有限公司 | Preparation method of difluoro acetic acid |
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