CN104230753A - Method for synthesizing fluoroacetonitrile - Google Patents
Method for synthesizing fluoroacetonitrile Download PDFInfo
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- CN104230753A CN104230753A CN201410426436.7A CN201410426436A CN104230753A CN 104230753 A CN104230753 A CN 104230753A CN 201410426436 A CN201410426436 A CN 201410426436A CN 104230753 A CN104230753 A CN 104230753A
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- acetonitrile
- fluoride
- reaction
- distillation
- fluoroacetonitrile
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Abstract
The invention belongs to the field of organic synthesis, and in particular relates to a method for synthesizing fluoroacetonitrile. The method comprises the following steps: performing substitution reaction on an acetonitrile derivative and inorganic fluoride salt in a polar solvent, and distilling and purifying for multiple times, thereby obtaining a high-purity product fluoroacetonitrile, wherein the formula of the substation reaction is YF+XCH2CN->FCH2CN+YX. According to the method, the acetonitrile derivative and the inorganic fluoride salt are adopted to react to obtain a target product at one time, virulent raw materials are avoided, the process route is shortened, and the yield is high; as the polar organic solvent which is low in price, easy to obtain and environment-friendly is adopted, environment pollution is avoided; the method is conductive to achieving industrialization production of fluoroacetonitrile, is gentle in reaction condition, low in production cost, high in yield and environment-friendly.
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 synthesis of agricultural chemicals and pharmaceutical prod, has huge market potential value.Such as: in fluoride acetonitrile and tertiary butyl acetic acid, react the generation tertiary butyl-3-amino-4-2-fluoro-2-butene acid esters, this material carries out Borch reduction in acid condition and generates 3-amino-4-fluorine butyric acid, and 3-amino-4-fluorine butyric acid can be used for treating neural system excitement and suppressing the disease caused of lacking of proper care; Its benzindole derivative can as 5HT3 receptor antagonist; Utilize fluoride acetonitrile to synthesize containing flucytosine and derivative thereof, be widely used in anti-cancer composition; In addition, fluoride acetonitrile is also the important intermediate of synthesis α-fluoridize aldehyde derivatives, and α-fluoridize aldehyde derivatives can be used for anti-inflammatory and disappears quick.Along with the market demands of these fluorochemicalss above-mentioned are more and more high with application, the market requirement of this medicinal intermediate of fluoride acetonitrile will be increasing.
The traditional synthetic method of fluoride acetonitrile is the hydroxyacetonitrile being obtained by reacting p-toluenesulfonyl protection by hydroxyacetonitrile and Tosyl chloride; target product is obtained by reacting again with Potassium monofluoride; the reactions steps of this route is longer; the production loss in every portion all can be larger; and with contaminative, its trash discharge will cause environmental pollution.Second method uses on flowing afterglow (flowing afterglow) device, and S occurs for chloromethyl cyanide and gaseous fluorine ion
n2 reactions, route productive rate is low, does not have practicality; The third method, use fluoro ethanamide, dewater under Vanadium Pentoxide in FLAKES condition, need to prepare fluoro ethanamide in advance in addition, hydroxyacetonitrile is the highly toxic product belonging to control class, adopts it to be that raw material has certain restriction in suitability for industrialized production.Therefore, a kind of environmental pollution is little, and the invention being more conducive to the operational path of the suitability for industrialized production realizing fluoride acetonitrile has very important realistic meaning and marketable value.
Summary of the invention
The object of this invention is to provide a kind of conditioned response gentle, 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 acetonitrile derivative and inorganic fluoriding salt, in polar solvent, substitution reaction occurs, after repeatedly distillation purifying, obtain product fluoride acetonitrile;
Reaction expression is:
YF+XCH
2CN→FCH
2CN+YX；
Wherein, in inorganic fluoriding salt YF, Y is Li, Na, K, Mg, Ca, Fe or silicate; Acetonitrile derivative XCH
2in 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 conditions, acetonitrile derivative and inorganic fluoriding salt are added in reactor according to the ratio that molar weight is 0.74 ~ 1.5:1, open whipping appts, be warming up to 50-120 DEG C, reaction times 1-6h;
B). after step a) reaction terminates, reaction product is cooled to less than 70 DEG C, enters water distilling apparatus, after being warming up to 80-120 DEG C, distillation, receiving liquid the dry ice bath cools, until absence of liquid flows out, obtains crude product;
C). crude product step b) obtained is placed in single port flask, air distillation, and 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, MgF
2, CaF
2, FeF
3or the one in silicofluoride, acetonitrile derivative XCH
2cN is ClCH
2cN, BrCH
2cN, ICH
2cN, MsOCH
2cN or TsOCH
2one in CN.
Compared with prior art, beneficial effect of the present invention is:
Present method employs acetonitrile derivative and inorganic fluoriding salt obtains target product through single step reaction, avoids the raw material using severe toxicity, and shorten operational path, yield is high; And the green polar organic solvent adopting market to be cheaply easy to get, removing environmental pollution; The method is more conducive to the suitability for industrialized production realizing fluoride acetonitrile, and be also that a kind of conditioned response is gentle, 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, join in the reaction flask of 3L, add 600ml glycerine by the bromoacetonitrile of 1.2Kg and the anhydrous potassium fluoride of 500g, open electric mixer, and start heating, temperature rises to 74 DEG C, reaction 5.5h.
2. after above-mentioned reaction terminates, be cooled to 58 DEG C, load onto water distilling apparatus, be warming up to 100 DEG C, distillation, connects liquid bottle dry ice and cools, until absence of liquid flows out; This step product yield is 95.2%, and purity reaches 95.8%.
3. above-mentioned product is placed in 500ml single port bottle, normal pressure 110 DEG C distillation, collects the cut of 78-80 DEG C, connects liquid bottle acetone and cools, obtain the fluoride acetonitrile that purity is 99.5%.
Embodiment 2
1. at ambient temperature, joined in the reaction flask of 3 liters by the anhydrous Sodium Fluoride of the bromoacetonitrile of 1Kg and 480g, 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 terminates, be cooled to 50 DEG C, load onto water distilling apparatus, be warming up to 120 DEG C, distillation, connects liquid bottle dry ice and cools, until absence of liquid flows out.This step product yield is 96%, and purity reaches 96.3%.
3. above-mentioned product is placed in 500ml single port bottle, normal pressure 110 DEG C distillation, collects the cut of 78-80 DEG C, connects liquid bottle acetone bath and cools, obtain the fluoride acetonitrile that purity is 99.8%.
Embodiment 3
1. at ambient temperature, joined in the reaction flask of 3 liters by the anhydrous lithium fluoride of the chloromethyl cyanide of 1.3Kg and 580g, 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 terminates, be cooled to 52 DEG C, load onto water distilling apparatus, be warming up to 110 DEG C, distillation, connects liquid bottle dry ice and cools, until absence of liquid flows out.This step product yield is 95.4%, and purity reaches 96.1%.
3. above-mentioned product is placed in 500ml single port bottle, normal pressure 120 DEG C distillation, collects the cut of 78-80 DEG C, connects liquid bottle acetone bath and cools, obtain the fluoride acetonitrile that purity is 99.8%.
Embodiment 4
1. at ambient temperature, join in the reaction flask of 3 liters by the anhydrous magnesium fluoride of the bromoacetonitrile of 600ml and 550g, open electric mixer, and start heating, temperature rises to 120 DEG C, reaction 1h.
2. after above-mentioned reaction terminates, be cooled to 50 DEG C, load onto water distilling apparatus, be warming up to 80 DEG C, underpressure distillation, connect liquid bottle dry ice and cool, until absence of liquid flows out.This step product yield is 97.0%, and purity reaches 96.6%.
3. above-mentioned product is placed in 500ml single port bottle, normal pressure 120 DEG C distillation, collects the cut of 78-80 DEG C, connects liquid bottle acetone bath and cools, obtain the fluoride acetonitrile that purity is 99.9%.
Embodiment 5
1. at ambient temperature, joined in the reaction flask of 3 liters by the anhydrous Calcium Fluoride (Fluorspan) of the iodomethyl cyanide of 0.95Kg and 500g, 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 terminates, be cooled to 52 DEG C, load onto water distilling apparatus, be warming up to 110 DEG C, distillation, connects liquid bottle dry ice and cools, until absence of liquid flows out.This step product yield is 95.7%, and purity reaches 96.6%.
3. above-mentioned product is placed in 500ml single port bottle, normal pressure 120 DEG C distillation, collects the cut of 78-80 DEG C, connects liquid bottle acetone bath and cools, obtain the fluoride acetonitrile that purity is 99.8%.
Embodiment 6
1. at ambient temperature, the tosyloxy acetonitrile of 0.52Kg and the silicofluoride of 600g are joined in the reaction flask 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 terminates, be cooled to 52 DEG C, load onto water distilling apparatus, be warming up to 110 DEG C, distillation, connects liquid bottle dry ice and cools, until absence of liquid flows out.This step product yield is 97.1%, and purity reaches 97.5%.
3. above-mentioned product is placed in 500ml single port bottle, normal pressure 120 DEG C distillation, collects the cut of 78-80 DEG C, connects liquid bottle acetone bath and cools, obtain the fluoride acetonitrile that purity is 99.9%.
Embodiment 7
1. at ambient temperature, by joining in the reaction flask 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 terminates, be cooled to 50 DEG C, load onto water distilling apparatus, be warming up to 110 DEG C, distillation, connects liquid bottle dry ice and cools, until absence of liquid flows out.This step product yield is 94.9%, and purity reaches 97.1%.
3. above-mentioned product is placed in 500ml single port bottle, normal pressure 120 DEG C distillation, collects the cut of 78-80 DEG C, connects liquid bottle acetone bath and cools, obtain the fluoride acetonitrile that purity is 99.8%.
The above; be the specific embodiment of the present invention, but protection scope of the present invention is not limited in this, is anyly familiar with those skilled in the art in the technical scope that the present invention discloses; change can be expected easily or replace, all should be encompassed within 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 (4)
1. a synthetic method for fluoride acetonitrile, is characterized in that, comprises acetonitrile derivative and inorganic fluoriding salt, in polar solvent, substitution reaction occurs, after repeatedly distillation purifying, obtain product fluoride acetonitrile;
Reaction expression is:
YF+XCH
2CN→FCH
2CN+YX；
Wherein, in inorganic fluoriding salt YF, Y is Li, Na, K, Mg, Ca, Fe or silicate; Acetonitrile derivative XCH
2in CN, X is chlorine, bromine, iodine, mesyloxy or tolysulfonyl oxygen base.
2. the synthetic method of a kind of fluoride acetonitrile according to claim 1, is characterized in that, concrete bag following steps alive:
A). under polar solvent conditions, acetonitrile derivative and inorganic fluoriding salt are added in reactor according to the ratio that molar weight is 0.74 ~ 1.5:1, open whipping appts, be warming up to 50-120 DEG C, reaction times 1-6h;
B). after step a) reaction terminates, reaction product is cooled to less than 70 DEG C, enters water distilling apparatus, after being warming up to 80-120 DEG C, distillation, receiving liquid the dry ice bath cools, until absence of liquid flows out, obtains crude product;
C). crude product step b) obtained is placed in single port flask, then air distillation, and temperature is 100-120 DEG C, collects the cut of 75-85 DEG C, and the cooling of receiving liquid acetone bath obtains pure products.
3. the synthetic method of a kind of fluoride acetonitrile according to claim 1 and 2, is characterized in that, described polar solvent is bromoacetonitrile, propione, dimethyl fumarate, ethylene glycol, the one in two glycerine or glycerine.
4. according to claim 1, inorganic fluoride YF is LiF, NaF, KF, MgF
2, CaF
2, FeF
3or the one in silicofluoride, acetonitrile derivative XCH
2cN is ClCH
2cN, BrCH
2cN, ICH
2cN, MsOCH
2cN or TsOCH
2one in CN.
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| CN201410426436.7A CN104230753B (en) | 2014-08-27 | 2014-08-27 | A kind of synthetic method of fluoride acetonitrile |
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| CN201410426436.7A CN104230753B (en) | 2014-08-27 | 2014-08-27 | A kind of synthetic method of fluoride acetonitrile |
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| CN104230753B CN104230753B (en) | 2016-05-18 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114751842A (en) * | 2022-04-25 | 2022-07-15 | 扬州市普林斯医药科技有限公司 | Preparation method of bromoacetonitrile |
| CN117430492A (en) * | 2023-12-20 | 2024-01-23 | 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 |
-
2014
- 2014-08-27 CN CN201410426436.7A patent/CN104230753B/en active Active
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 |
|---|
| GITEL,P.O. 等: "α-Cyanoalkylation. II. Preparation and properties of α-fluorinated nitriles", 《ZHURNAL OBSHCHEI KHIMII》, vol. 36, no. 5, 31 December 1966 (1966-12-31) * |
| MOELLENDAL, HARALD 等: "Microwave Spectrum and Conformational Composition of 3-Fluoropropionitrile (FCH2CH2CN)", 《JOURNAL OF PHYSICAL CHEMISTRY A》, vol. 116, no. 3, 15 December 2011 (2011-12-15), pages 1015 - 1022 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114751842A (en) * | 2022-04-25 | 2022-07-15 | 扬州市普林斯医药科技有限公司 | Preparation method of bromoacetonitrile |
| CN117430492A (en) * | 2023-12-20 | 2024-01-23 | 山东国邦药业有限公司 | Preparation method of difluoro acetic acid |
| CN117430492B (en) * | 2023-12-20 | 2024-03-22 | 山东国邦药业有限公司 | Preparation method of difluoro acetic acid |
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