CN103694168B - The preparation method of the chloro-4-trifluoromethyl-nicotinonitrile of a kind of 6- - Google Patents
The preparation method of the chloro-4-trifluoromethyl-nicotinonitrile of a kind of 6- Download PDFInfo
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- CN103694168B CN103694168B CN201310644856.8A CN201310644856A CN103694168B CN 103694168 B CN103694168 B CN 103694168B CN 201310644856 A CN201310644856 A CN 201310644856A CN 103694168 B CN103694168 B CN 103694168B
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- FCYFQKPMNQFMKA-UHFFFAOYSA-N 2-chloro-4-(trifluoromethyl)pyridine-3-carbonitrile Chemical compound FC(F)(F)C1=CC=NC(Cl)=C1C#N FCYFQKPMNQFMKA-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 60
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 32
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 32
- OPVSJJVFZHNNHG-UHFFFAOYSA-N 6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonitrile Chemical compound OC1=CC(=C(C=N1)C#N)C(F)(F)F OPVSJJVFZHNNHG-UHFFFAOYSA-N 0.000 claims abstract description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 72
- 238000001514 detection method Methods 0.000 claims description 24
- 239000012074 organic phase Substances 0.000 claims description 24
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 24
- 239000011734 sodium Substances 0.000 claims description 24
- 238000004809 thin layer chromatography Methods 0.000 claims description 24
- 238000000605 extraction Methods 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 12
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 12
- 239000012153 distilled water Substances 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 12
- 230000001105 regulatory effect Effects 0.000 claims description 11
- WRXXBTBGBXYHSG-UHFFFAOYSA-N 2,6-dichloro-4-(trifluoromethyl)pyridine-3-carbonitrile Chemical compound FC(F)(F)C1=CC(Cl)=NC(Cl)=C1C#N WRXXBTBGBXYHSG-UHFFFAOYSA-N 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 claims description 6
- 229960000583 acetic acid Drugs 0.000 claims description 6
- 239000012362 glacial acetic acid Substances 0.000 claims description 6
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 5
- 230000001276 controlling effect Effects 0.000 claims description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 claims description 2
- 229910003446 platinum oxide Inorganic materials 0.000 claims description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- MXQLUANSPBCUGU-UHFFFAOYSA-N 6-chloro-4-(trifluoromethyl)pyridine-3-carbonitrile Chemical compound FC(F)(F)C1=CC(Cl)=NC=C1C#N MXQLUANSPBCUGU-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 238000004949 mass spectrometry Methods 0.000 description 4
- 239000007806 chemical reaction intermediate Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000010960 commercial process Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses the preparation method of the chloro-4-trifluoromethyl-nicotinonitrile of a kind of 6-, comprise the steps: the synthesis of the chloro-6-methoxyl group of 2--4-trifluoromethyl-nicotinonitrile; The synthesis of 6-methoxyl group-4-trifluoromethyl-nicotinonitrile; The synthesis of 6-hydroxyl-4-trifluoromethyl-nicotinonitrile; The synthesis of the chloro-4-trifluoromethyl-nicotinonitrile of 6-.Productive rate of the present invention is high, and reactions steps is short, simple to operate, efficiently easy.
Description
Technical field
The invention belongs to technical field of chemistry, relate in particular to the preparation method of the chloro-4-trifluoromethyl-nicotinonitrile of a kind of 6-.
Background technology
6-chloro-4-trifluoromethyl-nicotinonitrile is intermediate important in pharmaceutical synthesis, can be applicable to treat prostate cancer pharmaceutical synthesis (see Guo Chuanxing etc. biological organic with pharmaceutical chemistry bulletin, 2012,22(2): 1230-1236); The synthesis of efficient chiral lactam (see Ornelas etc. tetrahedron bulletin, 2011,52(37): 4760-4763); And the pharmaceutical synthesis (see patent PCT Int Appl., 2009152133,2009) for the treatment of immunity and tumour.The synthetic route Patent documents of interest report of current 6-chloro-4-trifluoromethyl-nicotinonitrile is as follows:
PCT Int Appl., 2009152133,2009, Wishart (Wei Shate) etc. report the synthetic route of the chloro-4-trifluoromethyl-nicotinonitrile of 6-, and concrete synthetic route is as follows:
The technique of above-mentioned preparation 6-chloro-4-trifluoromethyl-nicotinonitrile adopts the chloro-4-trifluoromethyl-Niacin Nicitinic Acid of 6-as raw material, and this material finished product is less, need synthesize through other route.
" tetrahedron bulletin " (2004,60(51), Ke Tete (Cottet)) synthetic route of disclosed 6-chloro-4-trifluoromethyl-nicotinonitrile is as follows:
The processing step of above-mentioned preparation 6-chloro-4-trifluoromethyl-nicotinonitrile is longer, and operation is comparatively complicated, and inserting carbonyl reaction process in this route need react under-78 DEG C of low temperature, and operational condition is comparatively harsh.
Summary of the invention
The object of the invention is to overcome above-mentioned shortcoming and provide a kind of productive rate high, reactions steps is short, simple to operate, the preparation method of the chloro-4-trifluoromethyl-nicotinonitrile of efficiently easy 6-.
The present invention is the preparation method of the chloro-4-trifluoromethyl-nicotinonitrile of a kind of 6-, comprises the steps:
(1) synthesis of the chloro-6-methoxyl group of 2--4-trifluoromethyl-nicotinonitrile
By 2,6-dichlor-4-trifluoromethyl-nicotinonitrile 90 mass parts is dissolved in methyl alcohol 450 ~ 700 mass parts, add the sodium methylate of 2,6-dichlor-4-trifluoromethyl-nicotinonitrile quality 3.1 ~ 4.9 times amount, normal-temperature reaction 180 ~ 240 minutes, complete through thin-layer chromatography detection reaction, be spin-dried for methyl alcohol, add distilled water 400 ~ 550 mass parts, extract twice by ethyl acetate 200 ~ 300 mass parts, get organic phase, use anhydrous Na
2sO
4dry 2 hours, filter, be spin-dried for obtain the chloro-6-methoxyl group of oily matter 2--4-trifluoromethyl-nicotinonitrile;
(2) synthesis of 6-methoxyl group-4-trifluoromethyl-nicotinonitrile
Chloro-for the 2-of gained 6-methoxyl group-4-trifluoromethyl-nicotinonitrile 80 mass parts is dissolved in methyl alcohol 400 ~ 700 mass parts, add catalyzer 8 mass parts, controlling pressure is 1.5MPa ~ 2.0 MPa, replacing hydrogen five times, normal-temperature reaction 20 ~ 24 hours, complete through thin-layer chromatography detection reaction, be spin-dried for methyl alcohol, add 350 ~ 480 mass parts distilled water, with 300 ~ 400 mass parts extraction into ethyl acetate twice, get organic phase, use anhydrous Na
2sO
4dry 2.5 hours, filter, be spin-dried for obtain yellow liquid 6-methoxyl group-4-trifluoromethyl-nicotinonitrile;
(3) synthesis of 6-hydroxyl-4-trifluoromethyl-nicotinonitrile
6-methoxyl group-4-trifluoromethyl-nicotinonitrile 70 mass parts of gained is joined in reaction flask, add mixed solution 350 ~ 700 parts by volume of hydrogen bromide that volume ratio is 3:1 and Glacial acetic acid, be warmed up to 100 DEG C ~ 110 DEG C, react 120 ~ 180 minutes, complete through thin-layer chromatography detection reaction, be cooled to room temperature, PH=7 ~ 9 are regulated with saturated sodium bicarbonate, with 380 ~ 600 mass parts extraction into ethyl acetate twice, merge organic phase, use anhydrous Na
2sO
4dry 3 hours, filter, be spin-dried for obtain light yellow liquid 6-hydroxyl-4-trifluoromethyl-nicotinonitrile;
(4) synthesis of the chloro-4-trifluoromethyl-nicotinonitrile of 6-
6-hydroxyl-4-trifluoromethyl-nicotinonitrile 80 mass parts of gained is joined in reaction flask, add the tetramethyl ammonium chloride of 6-hydroxyl-4-trifluoromethyl-nicotinonitrile quality 0.58 ~ 1.17 times amount, add phosphorus oxychloride 550 ~ 750 mass parts, be warmed up to 70 DEG C ~ 130 DEG C, react 120 minutes ~ 180 minutes, complete through thin-layer chromatography detection reaction, be cooled to room temperature, phosphorus oxychloride is spin-dried for dried Rotary Evaporators, reactant is poured in ice, PH=7 ~ 10 are regulated with saturated sodium bicarbonate, with 400 ~ 650 mass parts extraction into ethyl acetate twice, merge organic phase, use anhydrous Na
2sO
4dry 2 hours, filter, be spin-dried for obtain the chloro-4-trifluoromethyl-nicotinonitrile of white solid 6-.
Wherein: the catalyzer in step (2) is palladium carbon or platinum oxide (PtO
2).
The present invention compared with prior art, has obvious beneficial effect, as can be known from the above technical solutions: the present invention is that raw material obtains the chloro-4-trifluoromethyl-nicotinonitrile of product 6-with 2,6-dichlor-4-trifluoromethyl-nicotinonitrile, and chemical equation is as follows:
Ⅲ Ⅱ
Ⅰ
There is substitution reaction preparation by 6-hydroxyl-4-trifluoromethyl-nicotinonitrile (II) and obtain in the chloro-4-trifluoromethyl-nicotinonitrile (I) of 6-, temperature of reaction is 70 DEG C ~ 130 DEG C, and this reaction side reaction is few, and productive rate is high;
Reaction intermediate 6-hydroxyl-4-trifluoromethyl-nicotinonitrile (II) by 6-methoxyl group-4-trifluoromethyl-nicotinonitrile (III), hydrolysis reaction preparation occurs and obtains, and temperature of reaction is 100 DEG C ~ 110 DEG C;
Reaction intermediate 6-methoxyl group-4-trifluoromethyl-nicotinonitrile (III) be by the chloro-6-methoxyl group of 2--4-trifluoromethyl-nicotinonitrile (
) under the effect of catalyzer, pass into the preparation of hydrogen generation reduction reaction and obtain, reaction conditions is 1.5MPa ~ 2.0 MPa, and temperature of reaction is normal temperature;
The chloro-6-methoxyl group of reaction intermediate 2--4-trifluoromethyl-nicotinonitrile (
) be prepared by raw material 2,6-dichlor-4-trifluoromethyls-nicotinonitrile and sodium methylate generation substitution reaction and obtained, reaction conditions is normal temperature and pressure, simple to operate;
As from the foregoing, reactions steps of the present invention is short, does not relate to low-temp reaction and easy and simple to handle, and reaction cost is low, can be widely used in commercial process.
The specific embodiment of the present invention is provided in detail by following examples.
Embodiment
Describe the present invention below in conjunction with example, explain and illustrate technical scheme feature of the present invention further.
embodiment 1
A preparation method for the chloro-4-trifluoromethyl-nicotinonitrile of 6-, comprises the steps:
(1) the chloro-6-methoxyl group of 2--4-trifluoromethyl-nicotinonitrile (
) synthesis
2,6-dichlor-4-trifluoromethyl-nicotinonitrile 90g is dissolved in methyl alcohol 450g, adds 279g sodium methylate, normal-temperature reaction 220 minutes, complete through thin-layer chromatography detection reaction, be spin-dried for methyl alcohol, add distilled water 400g, extract twice by 200g ethyl acetate, get organic phase, use anhydrous Na
2sO
4dry 2 hours, filter, be spin-dried for obtain the chloro-6-methoxyl group of oily matter 2--4-trifluoromethyl-nicotinonitrile (78.3g), productive rate was 88.6%.
(2) synthesis of 6-methoxyl group-4-trifluoromethyl-nicotinonitrile (III)
Chloro-for the 2-of gained 6-methoxyl group-4-trifluoromethyl-nicotinonitrile 80g is dissolved in methyl alcohol 400g, add palladium carbon 8g, control pressure is 1.5MPa, replacing hydrogen five times, normal-temperature reaction 20 hours, complete through thin-layer chromatography detection reaction, be spin-dried for methyl alcohol, add 350g distilled water, with 300g extraction into ethyl acetate twice, get organic phase, use anhydrous Na
2sO
4dry 2.5 hours, filter, be spin-dried for obtain yellow liquid 6-methoxyl group-4-trifluoromethyl-nicotinonitrile (60.76g), productive rate was 88.9%.
(3) synthesis of 6-hydroxyl-4-trifluoromethyl-nicotinonitrile (II)
6-methoxyl group-4-trifluoromethyl-nicotinonitrile the 70g of gained is joined in reaction flask, add the mixed solution that hydrogen bromide volume is 262.5ml and Glacial acetic acid 87.5ml, be warmed up to 100 DEG C, react 180 minutes, complete through thin-layer chromatography detection reaction, be cooled to room temperature, PH=7 is regulated with saturated sodium bicarbonate, with 380g extraction into ethyl acetate twice, merge organic phase, use anhydrous Na
2sO
4dry 3 hours, filter, be spin-dried for underpressure distillation and obtain light yellow liquid 6-hydroxyl-4-trifluoromethyl-nicotinonitrile (56.81g), productive rate was 87.2%.
(4) synthesis of the chloro-4-trifluoromethyl-nicotinonitrile (I) of 6-
6-hydroxyl-4-trifluoromethyl-nicotinonitrile the 80g of gained is joined in reaction flask, add 46.4g tetramethyl ammonium chloride, add phosphorus oxychloride 550g, be warmed up to 70 DEG C, react 180 minutes, complete through thin-layer chromatography detection reaction, be cooled to room temperature, be spin-dried for phosphorus oxychloride with dried Rotary Evaporators, reactant is poured in ice, PH=7 is regulated with saturated sodium bicarbonate, with 400g extraction into ethyl acetate twice, merge organic phase, use anhydrous Na
2sO
4dry 2 hours, filter, be spin-dried for obtain the chloro-4-trifluoromethyl-nicotinonitrile (77.56g) of white solid 6-, productive rate was 88.3%.
1HNMR(400MHz,DMSO-d6)δ7.496(s,1H),8.914(s,1H);
Mass spec 207(M+).
embodiment 2
A preparation method for the chloro-4-trifluoromethyl-nicotinonitrile of 6-, comprises the steps:
(1) the chloro-6-methoxyl group of 2--4-trifluoromethyl-nicotinonitrile (
) synthesis
2,6-dichlor-4-trifluoromethyl-nicotinonitrile 90g is dissolved in methyl alcohol 500g, adds 360g sodium methylate, normal-temperature reaction 200 minutes, complete through thin-layer chromatography detection reaction, be spin-dried for methyl alcohol, add distilled water 450g, extract twice with ethyl acetate 250g, get organic phase, use anhydrous Na
2sO
4dry 2 hours, filter, be spin-dried for obtain the chloro-6-methoxyl group of oily matter 2--4-trifluoromethyl-nicotinonitrile (78.9g), productive rate was 89.3%.
(2) synthesis of 6-methoxyl group-4-trifluoromethyl-nicotinonitrile (III)
Chloro-for the 2-of gained 6-methoxyl group-4-trifluoromethyl-nicotinonitrile 80g is dissolved in methyl alcohol 620g, add platinum oxide 8g, control pressure is 1.8MPa, replacing hydrogen five times, normal-temperature reaction 22 hours, complete through thin-layer chromatography detection reaction, be spin-dried for methyl alcohol, add 450g distilled water, with 350g extraction into ethyl acetate twice, get organic phase, use anhydrous Na
2sO
4dry 2.5 hours, filter, be spin-dried for obtain yellow liquid 6-methoxyl group-4-trifluoromethyl-nicotinonitrile (62.47g), productive rate was 91.4%.
(3) synthesis of 6-hydroxyl-4-trifluoromethyl-nicotinonitrile (II)
6-methoxyl group-4-trifluoromethyl-nicotinonitrile the 70g of gained is joined in reaction flask, add the mixed solution that hydrogen bromide volume is 375ml and Glacial acetic acid 125ml, be warmed up to 105 DEG C, react 150 minutes, complete through thin-layer chromatography detection reaction, be cooled to room temperature, PH=8 is regulated with saturated sodium bicarbonate, with 500g extraction into ethyl acetate twice, merge organic phase, use anhydrous Na
2sO
4dry 3 hours, filter, be spin-dried for obtain light yellow liquid 6-hydroxyl-4-trifluoromethyl-nicotinonitrile (59.09g), productive rate was 90.7%.
(4) synthesis of the chloro-4-trifluoromethyl-nicotinonitrile (I) of 6-
6-hydroxyl-4-trifluoromethyl-nicotinonitrile the 80g of gained is joined in reaction flask, add 72.8g tetramethyl ammonium chloride, add phosphorus oxychloride 600g, be warmed up to 110 DEG C, react 150 minutes, complete through thin-layer chromatography detection reaction, be cooled to room temperature, be spin-dried for phosphorus oxychloride with dried Rotary Evaporators, reactant poured in ice, regulate PH=8 with saturated sodium bicarbonate, with 600g extraction into ethyl acetate twice, merge organic phase anhydrous Na
2sO
4dry 2 hours, filter, be spin-dried for obtain the chloro-4-trifluoromethyl-nicotinonitrile (79.41g) of white solid 6-, productive rate was 90.4%.
1HNMR(400MHz,DMSO-d6)δ7.496(s,1H),8.914(s,1H);
Mass spec 207(M+).
embodiment 3
A preparation method for the chloro-4-trifluoromethyl-nicotinonitrile of 6-, comprises the steps:
(1) the chloro-6-methoxyl group of 2--4-trifluoromethyl-nicotinonitrile (
) synthesis
2,6-dichlor-4-trifluoromethyl-nicotinonitrile 90g is dissolved in methyl alcohol 600g, adds 405g sodium methylate, normal-temperature reaction 240 minutes, complete through thin-layer chromatography detection reaction, be spin-dried for methyl alcohol, add distilled water 500g, extract twice with ethyl acetate 250g, get organic phase, use anhydrous Na
2sO
4dry 2 hours, filter, be spin-dried for obtain the chloro-6-methoxyl group of oily matter 2--4-trifluoromethyl-nicotinonitrile (80.57g), productive rate was 91.2%.
(2) synthesis of 6-methoxyl group-4-trifluoromethyl-nicotinonitrile (III)
Chloro-for the 2-of gained 6-methoxyl group-4-trifluoromethyl-nicotinonitrile 80g is dissolved in methyl alcohol 620g, add palladium carbon 8g, control pressure is 1.8MPa, replacing hydrogen five times, normal-temperature reaction 22 hours, complete through thin-layer chromatography detection reaction, be spin-dried for methyl alcohol, add 450g distilled water, with 350g extraction into ethyl acetate twice, get organic phase, use anhydrous Na
2sO
4dry 2.5 hours, filter, be spin-dried for obtain yellow liquid 6-methoxyl group-4-trifluoromethyl-nicotinonitrile (64.11g), productive rate was 93.8%.
(3) synthesis of 6-hydroxyl-4-trifluoromethyl-nicotinonitrile (II)
6-methoxyl group-4-trifluoromethyl-nicotinonitrile the 70g of gained is joined in reaction flask, add the mixed solution that hydrogen bromide volume is 450ml and Glacial acetic acid 150ml, be warmed up to 105 DEG C, react 150 minutes, complete through thin-layer chromatography detection reaction, be cooled to room temperature, PH=8 is regulated with saturated sodium bicarbonate, with 500g extraction into ethyl acetate twice, merge organic phase, use anhydrous Na
2sO
4dry 3 hours, filter, be spin-dried for obtain light yellow liquid 6-hydroxyl-4-trifluoromethyl-nicotinonitrile (59.61g), productive rate was 91.5%.
(4) synthesis of the chloro-4-trifluoromethyl-nicotinonitrile (I) of 6-
6-hydroxyl-4-trifluoromethyl-nicotinonitrile the 80g of gained is joined in reaction flask, add 84g tetramethyl ammonium chloride, add phosphorus oxychloride 600g, be warmed up to 110 DEG C, react 150 minutes, complete through thin-layer chromatography detection reaction, be cooled to room temperature, be spin-dried for phosphorus oxychloride with dried Rotary Evaporators, reactant is poured in ice, PH=8 is regulated with saturated sodium bicarbonate, with 600g extraction into ethyl acetate twice, merge organic phase, use anhydrous Na
2sO
4dry 2 hours, filter, be spin-dried for obtain the chloro-4-trifluoromethyl-nicotinonitrile (82.22g) of white solid 6-, productive rate was 93.6%.
1HNMR(400MHz,DMSO-d6)δ7.496(s,1H),8.914(s,1H);
Mass spec 207(M+).
embodiment 4
A preparation method for the chloro-4-trifluoromethyl-nicotinonitrile of 6-, comprises the steps:
(1) the chloro-6-methoxyl group of 2--4-trifluoromethyl-nicotinonitrile (
) synthesis
2,6-dichlor-4-trifluoromethyl-nicotinonitrile 90g is dissolved in methyl alcohol 700g, adds 441g sodium methylate, normal-temperature reaction 180 minutes, complete through thin-layer chromatography detection reaction, be spin-dried for methyl alcohol, add distilled water 550g, extract twice with ethyl acetate 300g, get organic phase, use anhydrous Na
2sO
4dry 2 hours, filter, be spin-dried for obtain the chloro-6-methoxyl group of oily matter 2--4-trifluoromethyl-nicotinonitrile (83.31g), productive rate was 94.3%.
(2) synthesis of 6-methoxyl group-4-trifluoromethyl-nicotinonitrile (III)
Chloro-for the 2-of gained 6-methoxyl group-4-trifluoromethyl-nicotinonitrile 80g is dissolved in methyl alcohol 700g, add palladium carbon 8g, control pressure is 2.0MPa, replacing hydrogen five times, normal-temperature reaction 24 hours, complete through thin-layer chromatography detection reaction, be spin-dried for methyl alcohol, add 480g distilled water, with 400g extraction into ethyl acetate twice, get organic phase, use anhydrous Na
2sO
4dry 2.5 hours, filter, be spin-dried for obtain yellow liquid 6-methoxyl group-4-trifluoromethyl-nicotinonitrile (64.32g), productive rate was 94.1%.
(3) synthesis of 6-hydroxyl-4-trifluoromethyl-nicotinonitrile (II)
6-methoxyl group-4-trifluoromethyl-nicotinonitrile the 70g of gained is joined in reaction flask, add the mixed solution that hydrogen bromide volume is 525ml and Glacial acetic acid 175ml, be warmed up to 110 DEG C, react 120 minutes, complete through thin-layer chromatography detection reaction, be cooled to room temperature, PH=9 is regulated with saturated sodium bicarbonate, with 600g extraction into ethyl acetate twice, merge organic phase, use anhydrous Na
2sO
4dry 3 hours, filter, be spin-dried for obtain light yellow liquid 6-hydroxyl-4-trifluoromethyl-nicotinonitrile (60.45g), productive rate was 92.8%.
(4) synthesis of the chloro-4-trifluoromethyl-nicotinonitrile (I) of 6-
6-hydroxyl-4-trifluoromethyl-nicotinonitrile the 80g of gained is joined in reaction flask, add 93.6g tetramethyl ammonium chloride, add phosphorus oxychloride 750g, be warmed up to 130 DEG C, react 120 minutes, complete through thin-layer chromatography detection reaction, be cooled to room temperature, be spin-dried for phosphorus oxychloride with dried Rotary Evaporators, reactant is poured in frozen water, PH=10 is regulated with saturated sodium bicarbonate, with 650g extraction into ethyl acetate twice, merge organic phase, use anhydrous Na
2sO
4dry 2 hours, filter, be spin-dried for obtain the chloro-4-trifluoromethyl-nicotinonitrile (83.54g) of white solid 6-, productive rate was 95.1%.
1HNMR(400MHz,DMSO-d6)δ7.496(s,1H),8.914(s,1H);
Mass spec 207(M+).
The above, it is only preferred embodiment of the present invention, not any pro forma restriction is done to the present invention, anyly do not depart from technical solution of the present invention content, the any simple modification done above embodiment according to technical spirit of the present invention, equivalent variations and modification, all still belong in the scope of technical solution of the present invention.
Claims (1)
1. a preparation method for the chloro-4-trifluoromethyl-nicotinonitrile of 6-, comprises the steps:
(1) synthesis of the chloro-6-methoxyl group of 2--4-trifluoromethyl-nicotinonitrile
By 2,6-dichlor-4-trifluoromethyl-nicotinonitrile 90 mass parts is dissolved in methyl alcohol 450 ~ 700 mass parts, add the sodium methylate of 2,6-dichlor-4-trifluoromethyl-nicotinonitrile quality 3.1 ~ 4.9 times amount, normal-temperature reaction 180 ~ 240 minutes, complete through thin-layer chromatography detection reaction, be spin-dried for methyl alcohol, add distilled water 400 ~ 550 mass parts, extract twice by ethyl acetate 200 ~ 300 mass parts, get organic phase, use anhydrous Na
2sO
4dry 2 hours, filter, be spin-dried for obtain the chloro-6-methoxyl group of oily matter 2--4-trifluoromethyl-nicotinonitrile;
(2) synthesis of 6-methoxyl group-4-trifluoromethyl-nicotinonitrile
Chloro-for the 2-of gained 6-methoxyl group-4-trifluoromethyl-nicotinonitrile 80 mass parts is dissolved in methyl alcohol 400 ~ 700 mass parts, add catalyzer 8 mass parts, controlling pressure is 1.5MPa ~ 2.0 MPa, replacing hydrogen five times, normal-temperature reaction 20 ~ 24 hours, complete through thin-layer chromatography detection reaction, be spin-dried for methyl alcohol, add 350 ~ 480 mass parts distilled water, with 300 ~ 400 mass parts extraction into ethyl acetate twice, get organic phase, use anhydrous Na
2sO
4dry 2.5 hours, filter, be spin-dried for obtain yellow liquid 6-methoxyl group-4-trifluoromethyl-nicotinonitrile;
(3) synthesis of 6-hydroxyl-4-trifluoromethyl-nicotinonitrile
6-methoxyl group-4-trifluoromethyl-nicotinonitrile 70 mass parts of gained is joined in reaction flask, add mixed solution 350 ~ 700 parts by volume of hydrogen bromide that volume ratio is 3:1 and Glacial acetic acid, be warmed up to 100 DEG C ~ 110 DEG C, react 120 ~ 180 minutes, complete through thin-layer chromatography detection reaction, be cooled to room temperature, PH=7 ~ 9 are regulated with saturated sodium bicarbonate, with 380 ~ 600 mass parts extraction into ethyl acetate twice, merge organic phase, use anhydrous Na
2sO
4dry 3 hours, filter, be spin-dried for obtain light yellow liquid 6-hydroxyl-4-trifluoromethyl-nicotinonitrile;
(4) synthesis of the chloro-4-trifluoromethyl-nicotinonitrile of 6-
6-hydroxyl-4-trifluoromethyl-nicotinonitrile 80 mass parts of gained is joined in reaction flask, add the tetramethyl ammonium chloride of 6-hydroxyl-4-trifluoromethyl-nicotinonitrile quality 0.58 ~ 1.17 times amount, add phosphorus oxychloride 550 ~ 750 mass parts, be warmed up to 70 DEG C ~ 130 DEG C, react 120 minutes ~ 180 minutes, complete through thin-layer chromatography detection reaction, be cooled to room temperature, phosphorus oxychloride is spin-dried for dried Rotary Evaporators, reactant is poured in ice, PH=7 ~ 10 are regulated with saturated sodium bicarbonate, with 400 ~ 650 mass parts extraction into ethyl acetate twice, merge organic phase, use anhydrous Na
2sO
4dry 2 hours, filter, be spin-dried for obtain the chloro-4-trifluoromethyl-nicotinonitrile of white solid 6-, wherein: the catalyzer in step (2) is palladium carbon or platinum oxide.
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