CN104230753B - A kind of synthetic method of fluoride acetonitrile - Google Patents
A kind of synthetic method of fluoride acetonitrile Download PDFInfo
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- CN104230753B CN104230753B CN201410426436.7A CN201410426436A CN104230753B CN 104230753 B CN104230753 B CN 104230753B CN 201410426436 A CN201410426436 A CN 201410426436A CN 104230753 B CN104230753 B CN 104230753B
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Abstract
The invention belongs to organic synthesis field, be specifically related to a kind of synthetic method of fluoride acetonitrile, comprise that substitution reaction occurs in polar solvent for acetonitrile derivative and inorganic fluoride salt, through repeatedly obtaining high-purity product fluoride acetonitrile after distillation purifying; Described substitution reaction equation general formula is YF+XCH2CN→FCH2CN+YX. This method has been used acetonitrile derivative and inorganic fluoride salt to obtain target product through single step reaction, has avoided using hypertoxic raw material, shortens process route, and yield is high; And the green polar organic solvent that adopts market to be cheaply easy to get, removes environmental pollution, and the method is more conducive to realize the suitability for industrialized production of fluoride acetonitrile, is also a kind of conditioned response gentleness, and production cost is low, and productive rate is high, the synthetic method of environment amenable fluoride acetonitrile.
Description
Technical field
The invention belongs to organic synthesis field, be specifically related to a kind of synthetic method of fluoride acetonitrile.
Background technology
Fluoride acetonitrile is a kind of pharmaceutical intermediate, is widely used in the synthetic of agricultural chemicals and medical product, has huge market potential value. For example: in fluoride acetonitrile and tert-butyl group acetic acid, reaction generates the tert-butyl group-3-amino-4-2-fluoro-2-butene acid esters, this material carries out Borch reduction and generates 3-amino-4-fluorine butyric acid under acid condition, and 3-amino-4-fluorine butyric acid can be used for treating the disease that nervous system is excited and inhibition imbalance causes; Its benzindole derivative can be used as 5HT3 receptor antagonist; Utilize fluoride acetonitrile synthetic containing Flucytosine and derivative thereof, be widely used in anti-cancer composition; In addition, fluoride acetonitrile is also synthetic α-fluoridize the important intermediate of aldehyde derivatives, and α-fluoridize aldehyde derivatives can be used for anti-inflammatory and disappears quick. Along with market demands and the application of above-mentioned these fluorochemicals are more and more high, the market demand of this medicinal intermediate of fluoride acetonitrile will be increasing.
The traditional synthetic method of fluoride acetonitrile is the hydroxyacetonitrile that obtains p-toluenesulfonyl protection by hydroxyacetonitrile and paratoluensulfonyl chloride reaction; react and obtain target product with potassium fluoride again; the reactions steps of this route is longer; the production loss of every portion all can be larger; and with contaminative, its trash discharge will cause environmental pollution. Second method is to use on flowing afterglow (flowingafterglow) device, and S occurs for chloroacetonitrile and gaseous fluorine ionN2 reactions, route productive rate is low, does not have practicality; The third method, is used fluoro acetamide, under phosphorus pentoxide condition, dewaters, and need to prepare in advance fluoro acetamide in addition, and hydroxyacetonitrile is the toxic articles that belong to control class, and adopting it is that raw material has certain restriction in suitability for industrialized production. Therefore, a kind of environmental pollution is little, and the invention that is more conducive to the process route of the suitability for industrialized production that realizes fluoride acetonitrile has very important realistic meaning and market value.
Summary of the invention
The object of this invention is to provide a kind of conditioned response gentleness, production cost is low, and productive rate is high, the synthetic method of environment amenable fluoride acetonitrile.
Technical scheme of the present invention is as follows:
A synthetic method for fluoride acetonitrile, is characterized in that, comprises that substitution reaction occurs in polar solvent for acetonitrile derivative and inorganic fluoride salt, through repeatedly obtaining product fluoride acetonitrile after distillation purifying;
Reaction expression is:
YF+XCH2CN→FCH2CN+YX；
Wherein, in inorganic fluoride salt YF, Y is Li, Na, K, Mg, Ca, Fe or silicate; Acetonitrile derivative XCH2In CN, X is chlorine, bromine, iodine, mesyloxy or tolysulfonyl oxygen base.
Further, the synthetic method of described a kind of fluoride acetonitrile, concrete bag following steps alive:
A). under polar solvent condition, the ratio that is 0.74～1.5:1 according to mole by acetonitrile derivative and inorganic fluoride salt adds in reactor, opens agitating device, is warming up to 50-120 DEG C, reaction time 1-6h;
B). after step a) reaction finishes, product is cooled to below 70 DEG C, enters distilling apparatus, be warming up to after 80-120 DEG C, distillation, receiving liquid is cooling with the dry ice bath, until no liquid flows out, obtains crude product;
C). the crude product that step b) is obtained is placed in single port flask, air-distillation, temperature is 100-120 DEG C, collects the cut of 75-85 DEG C.
Further, described polar solvent is bromoacetonitrile, propione, dimethyl fumarate, ethylene glycol, the one in two glycerine or glycerine.
As preferably, inorganic fluoride YF is LiF, NaF, KF, MgF2，CaF2、FeF3Or one in fluosilicate, acetonitrile derivative XCH2CN is ClCH2CN、BrCH2CN、ICH2CN、MsOCH2CN or TsOCH2One in CN.
Compared with prior art, beneficial effect of the present invention is:
This method has been used acetonitrile derivative and inorganic fluoride salt to obtain target product through single step reaction, has avoided using hypertoxic raw material, shortens process route, and yield is high; And the green polar organic solvent that adopts market to be cheaply easy to get, removes environmental pollution; The method is more conducive to realize the suitability for industrialized production of fluoride acetonitrile, is also a kind of conditioned response gentleness, and production cost is low, and productive rate is high, the synthetic method of environment amenable fluoride acetonitrile.
Specific embodiment
Below by specific embodiment, technical scheme of the present invention is further described, to increase the understanding of those skilled in the art to content of the present invention.
Embodiment 1
1. at ambient temperature, the anhydrous potassium fluoride of the bromoacetonitrile of 1.2Kg and 500g is joined in the reaction bulb of 3L, add 600ml glycerine, open electric mixer, and start heating, temperature rises to 74 DEG C, reaction 5.5h.
2. after above-mentioned reaction finishes, be cooled to 58 DEG C, load onto distilling apparatus, be warming up to 100 DEG C, distillation, connects liquid bottle dry ice cooling, until no liquid flows out; This step product yield is 95.2%, and purity has reached 95.8%.
3. above-mentioned product is placed in 500ml single port bottle, and the cut of 78-80 DEG C is collected in 110 DEG C of distillations of normal pressure, connects liquid bottle acetone cooling, obtains purity and be 99.5% fluoride acetonitrile.
Embodiment 2
1. at ambient temperature, the anhydrous sodium fluoride of the bromoacetonitrile of 1Kg and 480g is joined in the reaction bulb of 3 liters, add the dimethyl fumarate of 600ml, open electric mixer, and start heating, temperature rises to 83 DEG C, reaction 3.5h.
2. after above-mentioned reaction finishes, be cooled to 50 DEG C, load onto distilling apparatus, be warming up to 120 DEG C, distillation, connects liquid bottle dry ice cooling, until no liquid flows out. This step product yield is 96%, and purity has reached 96.3%.
3. above-mentioned product is placed in 500ml single port bottle, and the cut of 78-80 DEG C is collected in 110 DEG C of distillations of normal pressure, connects liquid bottle acetone bath cooling, obtains purity and be 99.8% fluoride acetonitrile.
Embodiment 3
1. at ambient temperature, the anhydrous lithium fluoride of the chloroacetonitrile of 1.3Kg and 580g is joined in the reaction bulb of 3 liters, add the ethylene glycol of 600ml, open electric mixer, and start heating, temperature rises to 100 DEG C, reaction 6h.
2. after above-mentioned reaction finishes, be cooled to 52 DEG C, load onto distilling apparatus, be warming up to 110 DEG C, distillation, connects liquid bottle dry ice cooling, until no liquid flows out. This step product yield is 95.4%, and purity has reached 96.1%.
3. above-mentioned product is placed in 500ml single port bottle, and the cut of 78-80 DEG C is collected in 120 DEG C of distillations of normal pressure, connects liquid bottle acetone bath cooling, obtains purity and be 99.8% fluoride acetonitrile.
Embodiment 4
1. at ambient temperature, the anhydrous magnesium fluoride of the bromoacetonitrile of 600ml and 550g is joined in the reaction bulb of 3 liters, open electric mixer, and start heating, temperature rises to 120 DEG C, reaction 1h.
2. after above-mentioned reaction finishes, be cooled to 50 DEG C, load onto distilling apparatus, be warming up to 80 DEG C, decompression distillation, connects liquid bottle dry ice cooling, until no liquid flows out. This step product yield is 97.0%, and purity has reached 96.6%.
3. above-mentioned product is placed in 500ml single port bottle, and the cut of 78-80 DEG C is collected in 120 DEG C of distillations of normal pressure, connects liquid bottle acetone bath cooling, obtains purity and be 99.9% fluoride acetonitrile.
Embodiment 5
1. at ambient temperature, the anhydrous calcirm-fluoride of the iodoacetonitrile of 0.95Kg and 500g is joined in the reaction bulb of 3 liters, add the propione of 600ml, open electric mixer, and start heating, temperature rises to 100 DEG C, reaction 2.5h.
2. after above-mentioned reaction finishes, be cooled to 52 DEG C, load onto distilling apparatus, be warming up to 110 DEG C, distillation, connects liquid bottle dry ice cooling, until no liquid flows out. This step product yield is 95.7%, and purity has reached 96.6%.
3. above-mentioned product is placed in 500ml single port bottle, and the cut of 78-80 DEG C is collected in 120 DEG C of distillations of normal pressure, connects liquid bottle acetone bath cooling, obtains purity and be 99.8% fluoride acetonitrile.
Embodiment 6
1. at ambient temperature, the fluosilicate of the tosyloxy acetonitrile of 0.52Kg and 600g is joined in the reaction bulb of 3 liters, add the ethylene glycol of 600ml, open electric mixer, and start heating, temperature rises to 78 DEG C, reaction 4h.
2. after above-mentioned reaction finishes, be cooled to 52 DEG C, load onto distilling apparatus, be warming up to 110 DEG C, distillation, connects liquid bottle dry ice cooling, until no liquid flows out. This step product yield is 97.1%, and purity has reached 97.5%.
3. above-mentioned product is placed in 500ml single port bottle, and the cut of 78-80 DEG C is collected in 120 DEG C of distillations of normal pressure, connects liquid bottle acetone bath cooling, obtains purity and be 99.9% fluoride acetonitrile.
Embodiment 7
1. at ambient temperature, by joining in the reaction bulb of 3 liters without water ferric fluoride of the mesyloxy acetonitrile of 0.54Kg and 620g, add two glycerine of 600ml, open electric mixer, and start heating, temperature rises to 55 DEG C, reaction 6h.
2. after above-mentioned reaction finishes, be cooled to 50 DEG C, load onto distilling apparatus, be warming up to 110 DEG C, distillation, connects liquid bottle dry ice cooling, until no liquid flows out. This step product yield is 94.9%, and purity has reached 97.1%.
3. above-mentioned product is placed in 500ml single port bottle, and the cut of 78-80 DEG C is collected in 120 DEG C of distillations of normal pressure, connects liquid bottle acetone bath cooling, obtains purity and be 99.8% fluoride acetonitrile.
The above; be the specific embodiment of the present invention, but protection scope of the present invention is not limited in this, any be familiar with those skilled in the art the present invention disclose technical scope in; can expect easily changing or replacing, within all should being encompassed in protection scope of the present invention. Therefore, protection scope of the present invention should described be as the criterion with the protection domain of claim.
Claims (2)
1. a synthetic method for fluoride acetonitrile, is characterized in that, comprises that acetonitrile derivative and inorganic fluoride salt get in polar solventGeneration reaction, through repeatedly obtaining product fluoride acetonitrile after distillation purifying;
Reaction expression is:
YF+XCH2CN→FCH2CN+YX
Wherein, in inorganic fluoride salt YF, Y is Li, Na, K, Mg, Ca, Fe or silicate; Acetonitrile derivative XCH2CNIn, X is chlorine, bromine, iodine, mesyloxy or tolysulfonyl oxygen base;
The synthetic method of above-mentioned a kind of fluoride acetonitrile, concrete bag following steps alive:
A). under polar solvent condition, the ratio that is 0.74～1.5:1 according to mole by acetonitrile derivative and inorganic fluoride salt addsIn reactor, open agitating device, be warming up to 50-120 DEG C, reaction time 1-6h;
B). step a) react and finish after, product is cooled to below 70 DEG C, enters distilling apparatus, be warming up to after 80-120 DEG C,Distillation, receiving liquid is cooling with the dry ice bath, until no liquid flows out, obtains crude product;
C). the crude product that step b) is obtained is placed in single port flask, then air-distillation, and temperature is 100-120 DEG C, collects 75-85 DEG CCut, the cooling pure products that obtains of acetone bath for receiving liquid.
2. the synthetic method of a kind of fluoride acetonitrile according to claim 1, is characterized in that, described polar solvent is bromoacetonitrile,Propione, dimethyl fumarate, ethylene glycol, the one in two glycerine or glycerine.
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| CN117430492B (en) * | 2023-12-20 | 2024-03-22 | 山东国邦药业有限公司 | Preparation method of difluoro acetic acid |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2442290A (en) * | 1946-03-23 | 1948-05-25 | Harshaw Chem Corp | Production of fluoroacetonitrile |
| US4342780A (en) * | 1977-07-11 | 1982-08-03 | Merrell-Toraude Et Cie | Method of depleting endogenous monoamines |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2442290A (en) * | 1946-03-23 | 1948-05-25 | Harshaw Chem Corp | Production of fluoroacetonitrile |
| US4342780A (en) * | 1977-07-11 | 1982-08-03 | Merrell-Toraude Et Cie | Method of depleting endogenous monoamines |
Non-Patent Citations (2)
| Title |
|---|
| Microwave Spectrum and Conformational Composition of 3-Fluoropropionitrile (FCH2CH2CN);Moellendal, Harald 等;《Journal of Physical Chemistry A》;20111215;第116卷(第3期);第1015-1022页 * |
| α-Cyanoalkylation. II. Preparation and properties of α-fluorinated nitriles;Gitel,P.O. 等;《Zhurnal Obshchei Khimii》;19661231;第36卷(第5期);第873页倒数第1-5行、第874页第1-4行和第872页表以及STN中的摘要 * |
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