CN101941943A - Synthesis method of 2-chlorine-3-cyanopyridine - Google Patents
Synthesis method of 2-chlorine-3-cyanopyridine Download PDFInfo
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- CN101941943A CN101941943A CN 201010273816 CN201010273816A CN101941943A CN 101941943 A CN101941943 A CN 101941943A CN 201010273816 CN201010273816 CN 201010273816 CN 201010273816 A CN201010273816 A CN 201010273816A CN 101941943 A CN101941943 A CN 101941943A
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- cyanopyridine
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- oxygen
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- 238000001308 synthesis method Methods 0.000 title abstract 3
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 claims abstract description 30
- 150000001408 amides Chemical class 0.000 claims abstract description 13
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 239000007787 solid Substances 0.000 claims abstract description 12
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 claims abstract description 11
- 238000003756 stirring Methods 0.000 claims abstract description 6
- 238000005406 washing Methods 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000010025 steaming Methods 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 39
- JAUPUQRPBNDMDT-UHFFFAOYSA-N 2-chloropyridine-3-carbonitrile Chemical compound ClC1=NC=CC=C1C#N JAUPUQRPBNDMDT-UHFFFAOYSA-N 0.000 claims description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 22
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 claims description 21
- 239000000126 substance Substances 0.000 claims description 19
- 238000010189 synthetic method Methods 0.000 claims description 18
- 235000021050 feed intake Nutrition 0.000 claims description 15
- 238000009413 insulation Methods 0.000 claims description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- -1 methane amide Chemical class 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 150000002170 ethers Chemical class 0.000 claims description 8
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 7
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 125000003107 substituted aryl group Chemical group 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 claims description 5
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 3
- 238000010907 mechanical stirring Methods 0.000 claims description 3
- JIKUXBYRTXDNIY-UHFFFAOYSA-N n-methyl-n-phenylformamide Chemical compound O=CN(C)C1=CC=CC=C1 JIKUXBYRTXDNIY-UHFFFAOYSA-N 0.000 claims description 3
- GRZJZRHVJAXMRR-UHFFFAOYSA-N 1-cyclohexyl-2-phenylbenzene Chemical group C1CCCCC1C1=CC=CC=C1C1=CC=CC=C1 GRZJZRHVJAXMRR-UHFFFAOYSA-N 0.000 claims description 2
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 2
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 229940093499 ethyl acetate Drugs 0.000 claims description 2
- 150000002194 fatty esters Chemical class 0.000 claims description 2
- 150000002240 furans Chemical class 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 229940017219 methyl propionate Drugs 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- CBLGQEBXWDKYDI-UHFFFAOYSA-N piperazine-1,4-dicarbaldehyde Chemical compound O=CN1CCN(C=O)CC1 CBLGQEBXWDKYDI-UHFFFAOYSA-N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- WHLUQAYNVOGZST-UHFFFAOYSA-N tifenamil Chemical group C=1C=CC=CC=1C(C(=O)SCCN(CC)CC)C1=CC=CC=C1 WHLUQAYNVOGZST-UHFFFAOYSA-N 0.000 claims description 2
- 239000002904 solvent Substances 0.000 abstract description 15
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 238000005660 chlorination reaction Methods 0.000 abstract description 4
- 239000002699 waste material Substances 0.000 abstract description 3
- 238000005265 energy consumption Methods 0.000 abstract description 2
- 239000012295 chemical reaction liquid Substances 0.000 abstract 1
- 238000001816 cooling Methods 0.000 abstract 1
- 238000001035 drying Methods 0.000 abstract 1
- 150000002148 esters Chemical class 0.000 abstract 1
- 238000001914 filtration Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- LCEDQNDDFOCWGG-UHFFFAOYSA-N morpholine-4-carbaldehyde Chemical compound O=CN1CCOCC1 LCEDQNDDFOCWGG-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 239000012320 chlorinating reagent Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 2
- LYGJENNIWJXYER-BJUDXGSMSA-N nitromethane Chemical group [11CH3][N+]([O-])=O LYGJENNIWJXYER-BJUDXGSMSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical group ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- FNRMMDCDHWCQTH-UHFFFAOYSA-N 2-chloropyridine;3-chloropyridine;4-chloropyridine Chemical compound ClC1=CC=NC=C1.ClC1=CC=CN=C1.ClC1=CC=CC=N1 FNRMMDCDHWCQTH-UHFFFAOYSA-N 0.000 description 1
- PEUIFVLJTVIWDG-ZETCQYMHSA-N C[C@@H](C=[I-])N1CCOCC1 Chemical compound C[C@@H](C=[I-])N1CCOCC1 PEUIFVLJTVIWDG-ZETCQYMHSA-N 0.000 description 1
- 239000005507 Diflufenican Substances 0.000 description 1
- 239000005586 Nicosulfuron Substances 0.000 description 1
- JZFPYUNJRRFVQU-UHFFFAOYSA-N Niflumic acid Chemical compound OC(=O)C1=CC=CN=C1NC1=CC=CC(C(F)(F)F)=C1 JZFPYUNJRRFVQU-UHFFFAOYSA-N 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- MVPPADPHJFYWMZ-IDEBNGHGSA-N chlorobenzene Chemical group Cl[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 MVPPADPHJFYWMZ-IDEBNGHGSA-N 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- WYEHFWKAOXOVJD-UHFFFAOYSA-N diflufenican Chemical compound FC1=CC(F)=CC=C1NC(=O)C1=CC=CN=C1OC1=CC=CC(C(F)(F)F)=C1 WYEHFWKAOXOVJD-UHFFFAOYSA-N 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- RONZAEMNMFQXRA-UHFFFAOYSA-N mirtazapine Chemical compound C1C2=CC=CN=C2N2CCN(C)CC2C2=CC=CC=C21 RONZAEMNMFQXRA-UHFFFAOYSA-N 0.000 description 1
- 229960001785 mirtazapine Drugs 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- RTCOGUMHFFWOJV-UHFFFAOYSA-N nicosulfuron Chemical compound COC1=CC(OC)=NC(NC(=O)NS(=O)(=O)C=2C(=CC=CN=2)C(=O)N(C)C)=N1 RTCOGUMHFFWOJV-UHFFFAOYSA-N 0.000 description 1
- 229960000916 niflumic acid Drugs 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000011218 segmentation Effects 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 230000001519 thymoleptic effect Effects 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
Abstract
The invention discloses a synthesis method of 2-chlorine-3-cyanopyridine shown in a formula (I), which comprises the steps of: adding di(trichloromethyl) carbonic ester shown in a formula (III) and substituted amide shown in a formula (IV) to an organic solvent to react and prepare a Vilsmeier reagent; then adding N-oxygen-3-cyanopyridine shown in a formula (II); controlling the temperature between 60 to 160 DEG C and fully reacting; steaming the reaction liquid to eliminate the solvent; then adding water while hot; stirring and cooling to room temperature; separating out a great quantity of solid; filtering; washing the solid; and drying to prepare the 2-chlorine-3-cyanopyridine. In the invention, the novel friendly-environment Vilsmeier reagent is firstly prepared; a chlorination reaction is carried out to synthesize target products by utilizing the Vilsmeier reagent as a chlorination reagent, therefore, the synthesis method has the advantages of safety, less three wastes, less energy consumption, high yield of the products, high purity, low cost, and the like and is suitable for industrial production.
Description
(1) technical field
The invention discloses a kind of synthetic method of 2-chloro-3-cyanopyridine.
(2) background technology
2-chloro-3-cyanopyridine is the key intermediate of 2-chlorine apellagrin, the 2-chlorine apellagrin is as important fine-chemical intermediate, be used for synthetic many medical pain killers or anti-inflammatory agent, medical microbiotic, cardiovascular agent and disinfectant use in agriculture, sterilant and weedicide etc., (US 6 for example to be used for synthetic non-steroidal anti-inflammatory analgesics niflumic acid, 228,810 B1), thymoleptic mirtazapine (US6,495,685 B1), inverase nevirapine (US 20040002603 A1), (US 4 for herbicide nicosulfuron (US 4,786,734) and diflufenican, 618,366) etc.
At present, the synthetic method of the 2-chlorine apellagrin of report is a lot of both at home and abroad, a wherein important synthetic route is that the 3-cyanopyridine generates N-oxygen-3-cyanopyridine or N-oxygen-3-formamido group pyridine through hydrogen peroxide oxidation, chlorination obtains 2-chloro-3-cyanopyridine again, at last through obtaining the 2-chlorine apellagrin after basic hydrolysis and the acid treatment, because this method raw material is easy to get, and is simple to operate, is the technology of a suitable suitability for industrialized production.
In this technology, its committed step is that N-oxygen-3-cyanopyridine or N-oxygen-3-formamido group chloropyridine prepare 2-chloro-3-cyanopyridine, before the present invention provides, in the prior art in this reaction in step used chlorinating agent and catalyzer mainly contain two kinds:
(1) adopting two (trichloromethyl) carbonic ethers is chlorinating agent, and organic amine such as triethylamine, pyridine are acid binding agent, and Synthetic 2-chloro-3-cyanopyridine (JP8-217753, CN101659637), yield is lower, and environmental issue is bigger; (2) adopt POCl
3Be chlorinating agent, triethylamine is an acid binding agent, adopts the segmentation thermal-insulating method to react, and obtains 2-chloro-3-cyanopyridine, and yield is 85% (CN101117332A).Though this class methods yield is high, but use traditionally to reagent such as the unfriendly reagent of environment such as phosphorus trichloride, phosphorus pentachloride, phosphorous oxychloride, triethylamines, its acidity is very strong, big to equipment corrosion, this technology also produces a large amount of phosphorated waste water simultaneously, difficult treatment, and pollution problem is serious.
(3) summary of the invention
The technical problem to be solved in the present invention provides that a kind of technology is simple, production safety is reliable and stable, reaction yield is high, the synthetic method of good product quality, cost is low, the three wastes are few 2-chloro-3-cyanopyridine.
For solving the problems of the technologies described above, the technical solution used in the present invention is as follows:
A kind of synthetic method suc as formula the 2-chloro-3-cyanopyridine shown in (I), described synthetic method comprises: the substituted amide shown in two (trichloromethyl) carbonic ethers shown in the formula (III) and the formula (IV) is reacted in organic solvent make Vilsmeier reagent; Add the N-oxygen-3-cyanopyridine shown in the formula (II) then, controlled temperature is 60～160 ℃ of fully reactions, after the gained reaction solution steams and desolventizes, add water while hot, stir and be cooled to room temperature, have a large amount of solids to separate out, filter, the solid washing promptly gets described 2-chloro-3-cyanopyridine after the oven dry; Described raw material N-oxygen-3-cyanopyridine: two (trichloromethyl) carbonic ether: the amount of substance ratio that feeds intake of substituted amide is 1.0: 0.32～1.0: 0.2～3.6;
In the formula (IV), R
1, R
2Independently be selected from separately alkyl, the C3～C6 of C1～C4 cycloalkyl, aryl, substituted aryl, contain 1～2 and be selected from N, O or heteroatomic heterocyclic radical of S or substituted heterocyclic radical, described substituted aryl or substituted heterocyclic radical are replaced by following any 1～3 substituting group: the alkyl of C1～C4, alkoxyl group, halogen, trifluoromethyl, nitro; Perhaps R
1, R
2Formation contains 1～2 and is selected from N, O or heteroatomic 3～6 yuan saturated heterocyclic or the unsaturated heterocycle of S, does not contain other substituting group on described 3～6 yuan saturated heterocyclic or the ring of unsaturated heterocycle or is replaced by following any 1～3 substituting group: the alkyl of C1～C4, alkoxyl group, halogen, trifluoromethyl, nitro.
Further, the aromatic nucleus of aryl of the present invention or substituted aryl is phenyl ring, cyclohexyl biphenyl or condensed ring etc.
It is further, of the present invention that to contain 1～2 heterocycle that is selected from N, O or heteroatomic heterocyclic radical of S or substituted heterocyclic radical be furan nucleus, thiphene ring, quinoline ring or indole ring.
Further; one of substituted amide shown in the formula of the present invention (IV) is preferred following: N; dinethylformamide, N; N-dibutyl formamide, N-methyl-N-phenyl formamide, N; N-encircles penta own methane amide, N-N-formyl morpholine N-, N-methyl-N-(2-thienyl) methane amide, N; N-diphenylformamide, N, N-two (1-naphthyl) methane amide, 1,4-diformyl piperazine.
Further, organic solvent of the present invention is selected from the mixture of one of following or any several arbitrary proportions: the halogenated alkane of C1～C5, the fatty ester of C1～C8, benzene,toluene,xylene, chlorobenzene, oil of mirbane, hexanaphthene, dithiocarbonic anhydride, Nitromethane 99Min..
Further, the mixture of preferred one of the following or any several arbitrary proportions of organic solvent of the present invention: methylene dichloride, trichloromethane, ethyl acetate, methyl propionate, ethyl propionate, butanone, pimelinketone, tetrahydrofuran (THF), 2-methyltetrahydrofuran or benzene,toluene,xylene, oil of mirbane, hexanaphthene, Nitromethane 99Min..
The volume of organic solvent consumption is counted 1～20mL/g with the quality of N-oxygen-3-cyanopyridine among the present invention, is preferably 2～10mL/g.
Further, the preferred N-oxygen of the present invention-3-cyanopyridine is 1.0: 0.32～0.6: 1.0～2.2 with the amount of substance ratio that feeds intake of two (trichloromethyl) carbonic ethers, substituted amide.
Further, the preferred controlled temperature of the present invention is at-10～10 ℃ of preparation Vilsmeier reagent, and more preferably controlled temperature is about 0 ℃.
Further, after the present invention added N-oxygen-3-cyanopyridine, preferred control reaction temperature was 80-130 ℃.
The present invention follows the tracks of reaction process by TLC, and the reaction times is generally at 4-12 hour.
The concrete synthetic method of described 2-chloro-3-cyanopyridine of recommending of the present invention is carried out according to following steps: by amount of substance than N-oxygen-3-cyanopyridine: two (trichloromethyl) carbonic ether: substituted amide is 1.0: 0.32～0.6: 1.0～2.2 to feed intake, at first substituted amide and organic solvent are added in the reaction flask, open mechanical stirring, ice bath is cooled to 0 ℃, drips the organic solvent that is dissolved with two (trichloromethyl) carbonic ethers and prepares Vilsmeier reagent.After dropwising, after adding raw material N-oxygen-3-cyanopyridine, adjust 80～130 ℃ of temperature, insulation reaction 4～12h, TLC follows the tracks of, the back steaming that reacts completely desolventizes, and adds water while hot, stirs and is cooled to room temperature, there are a large amount of solids to separate out, filter, the solid washing promptly gets described 2-chloro-3-cyanopyridine after the oven dry.
The present invention compared with prior art, its beneficial effect is embodied in: this technology makes eco-friendly novel Vilsmeier reagent earlier, be chlorination reagent with Vilsmeier reagent then, have safety, the three wastes are few, energy consumption is little, product yield is high, purity is good, low cost and other advantages is suitable for suitability for industrialized production.
(4) embodiment:
Below with specific embodiment technical scheme of the present invention is described, but protection scope of the present invention is not limited thereto:
Embodiment one
Press amount of substance than N-oxygen-3-cyanopyridine: two (trichloromethyl) carbonic ether: N, dinethylformamide is to feed intake at 1.0: 0.32: 115, wherein N-oxygen-3-cyanopyridine is 10.8g, two (trichloromethyl) carbonic ether is 9.5g, N-formyl morpholine N-is 11.9g, solvent is toluene 22mL, counts 2mL/g with the quality of N-oxygen-3-cyanopyridine.
At first with N, dinethylformamide and toluene 10mL add in the reaction flask, open mechanical stirring, and ice bath is cooled to 0 ℃, drip the toluene 12mL solvent that is dissolved with two (trichloromethyl) carbonic ethers and obtain white solid Vilsmeier salt.After dropwising, add raw material N-oxygen-3-cyanopyridine, elevated temperature to 70 ℃, insulation reaction.TLC follows the tracks of, and the 12h afterreaction is complete.Steaming desolventizes, and adds water while hot, stirs and is cooled to room temperature, has a large amount of whites to separate out admittedly, filters, and the solid washing promptly gets described 2-chloro-3-cyanopyridine 8.7g after the oven dry, and yield is 70%, and purity is 98.2%.
Embodiment two
Press amount of substance than N-oxygen-3-cyanopyridine: two (trichloromethyl) carbonic ether: N, the N-dibutyl formamide is to feed intake at 1.0: 0.33: 1.2, wherein N-oxygen-3-cyanopyridine is 10.8g, solvent is 1,2-ethylene dichloride 22mL, quality with N-oxygen-3-cyanopyridine is counted 2mL/g, and temperature of reaction is for refluxing insulation reaction 10h.
React described 2-chloro-3-cyanopyridine 9.3g, yield is 75%, purity is 97.3%.
Embodiment three
By amount of substance than N-oxygen-3-cyanopyridine: two (trichloromethyl) carbonic ether: N-methyl-N-phenyl formamide is to feed intake at 1.0: 0.40: 1.4, wherein N-oxygen-3-cyanopyridine is 10.8g, solvent is oil of mirbane 43mL, quality with N-oxygen-3-cyanopyridine is counted 4mL/g, temperature of reaction is 140 ℃, insulation reaction 10h.
React described 2-chloro-3-cyanopyridine 9.6g, yield is 78%, purity is 98.9%.
Embodiment four
Press amount of substance than N-oxygen-3-cyanopyridine: two (trichloromethyl) carbonic ether: N, N-di-n-butyl methane amide is to feed intake at 1.0: 0.45: 1.4, wherein N-oxygen-3-cyanopyridine is 10.8g, two (trichloromethyl) carbonic ether is 11.9g, solvent is Nitromethane 99Min. 43mL, quality with N-oxygen-3-cyanopyridine is counted 4mL/g, and temperature of reaction is 60 ℃, insulation reaction 12h.
React described 2-chloro-3-cyanopyridine 9.9g, yield is 80%, purity is 98.2%.
Embodiment five
Press amount of substance than N-oxygen-3-cyanopyridine: two (trichloromethyl) carbonic ether: N, it is to feed intake at 1.0: 0.5: 1.8 that N-encircles penta own methane amide, wherein N-oxygen-3-cyanopyridine is 10.8g, two (trichloromethyl) carbonic ether is 14.9g, solvent is Nitromethane 99Min. 55mL, quality with N-oxygen-3-cyanopyridine is counted 5mL/g, and temperature of reaction is 60 ℃, insulation reaction 15h.
React described 2-chloro-3-cyanopyridine 10.1g, yield is 82%, purity is 99.4%.
Embodiment six
By amount of substance than N-oxygen-3-cyanopyridine: two (trichloromethyl) carbonic ether: N-formyl morpholine N-is to feed intake at 1.0: 0.5: 1.8, wherein N-oxygen-3-cyanopyridine is 10.8g, solvent is 2-methyltetrahydrofuran 55mL, quality with N-oxygen-3-cyanopyridine is counted 5mL/g, temperature of reaction is a reflux temperature, insulation reaction 12h.
React described 2-chloro-3-cyanopyridine 10.2g, yield is 82%, purity is 99.4%.
Embodiment seven
By amount of substance than N-oxygen-3-cyanopyridine: two (trichloromethyl) carbonic ether: N-formyl morpholine N-is to feed intake at 1.0: 0.8: 2.9, wherein N-oxygen-3-cyanopyridine is 10.8g, solvent is toluene 86mL, quality with N-oxygen-3-cyanopyridine is counted 8mL/g, temperature of reaction is 90 ℃, insulation reaction 10h.
React described 2-chloro-3-cyanopyridine 10.5g, yield is 84%, purity is 98.4%.
Embodiment eight
By amount of substance than N-oxygen-3-cyanopyridine: two (trichloromethyl) carbonic ether: N-formyl morpholine N-is to feed intake at 1.0: 1.0: 3.6, wherein N-oxygen-3-cyanopyridine is 10.8g, two (trichloromethyl) carbonic ether is 14.9g, N-formyl morpholine N-is 46.4g, solvent is oil of mirbane 108mL, quality with N-oxygen-3-cyanopyridine is counted 10mL/g, and temperature of reaction is a reflux temperature, insulation reaction 8h.
React described 2-chloro-3-cyanopyridine 8.47g, yield is 68%, purity is 99.0%.
Embodiment nine
By amount of substance than N-oxygen-3-cyanopyridine: two (trichloromethyl) carbonic ether: N-methyl-N-(2-thienyl) methane amide is to feed intake at 1.0: 0.5: 1.8, wherein N-oxygen-3-cyanopyridine is 10.8g, solvent is chlorobenzene 55mL, quality with N-oxygen-3-cyanopyridine is counted 5mL/g, temperature of reaction is 110 ℃, insulation reaction 10h.
React described 2-chloro-3-cyanopyridine 10.5g, yield is 85%, purity is 98.9%.
Embodiment ten
By amount of substance than N-oxygen-3-cyanopyridine: two (trichloromethyl) carbonic ether: N-formyl morpholine N-is to feed intake at 1.0: 0.5: 0.2, wherein N-oxygen-3-cyanopyridine is 10.8g, solvent is oil of mirbane 55mL, quality with N-oxygen-3-cyanopyridine is counted 5mL/g, temperature of reaction is a reflux temperature, insulation reaction 4h.。
React described 2-chloro-3-cyanopyridine 5.36g, yield is 43%, purity is 99.5%.
Embodiment 11
Press amount of substance than N-oxygen-3-cyanopyridine: two (trichloromethyl) carbonic ether: N, the N-diphenylformamide is to feed intake at 1.0: 0.5: 1.5, wherein N-oxygen-3-cyanopyridine is 10.8g, solvent is pimelinketone 55mL, quality with N-oxygen-3-cyanopyridine is counted 5mL/g, temperature of reaction is a reflux temperature, insulation reaction 12h.。
React described 2-chloro-3-cyanopyridine 10.3g, yield is 83%, purity is 99.0%.
Embodiment 12
Press amount of substance than N-oxygen-3-cyanopyridine: two (trichloromethyl) carbonic ether: 1; 4-diformyl piperazine is to feed intake at 1.0: 0.5: 0.75; wherein N-oxygen-3-cyanopyridine is 10.8g; solvent is 2-methyltetrahydrofuran 55mL; quality with N-oxygen-3-cyanopyridine is counted 5mL/g; temperature of reaction is a reflux temperature, insulation reaction 12h.。
React described 2-chloro-3-cyanopyridine 10.3g, yield is 83%, purity is 99.0%.
Embodiment 13
Press amount of substance than N-oxygen-3-cyanopyridine: two (trichloromethyl) carbonic ether: N, N-two (1-naphthyl) methane amide is to feed intake at 1.0: 0.5: 1.5, wherein N-oxygen-3-cyanopyridine is 10.8g, solvent is 2-methyltetrahydrofuran 55mL, quality with N-oxygen-3-cyanopyridine is counted 5mL/g, temperature of reaction is a reflux temperature, insulation reaction 12h.。
React described 2-chloro-3-cyanopyridine 10.3g, yield is 83%, purity is 99.0%.
Claims (9)
1. synthetic method suc as formula the 2-chloro-3-cyanopyridine shown in (I), described synthetic method comprises: the substituted amide shown in two (trichloromethyl) carbonic ethers shown in the formula (III) and the formula (IV) is reacted in organic solvent make Vilsmeier reagent; Add the N-oxygen-3-cyanopyridine shown in the formula (II) then, controlled temperature is 60～160 ℃ of fully reactions, after the gained reaction solution steams and desolventizes, add water while hot, stir and be cooled to room temperature, have a large amount of solids to separate out, filter, the solid washing promptly gets described 2-chloro-3-cyanopyridine after the oven dry; Described raw material N-oxygen-3-cyanopyridine: two (trichloromethyl) carbonic ether: the amount of substance ratio that feeds intake of substituted amide is 1.0: 0.32～1.0: 0.2～3.6;
In the formula (IV), R
1, R
2Independently be selected from separately alkyl, the C3～C6 of C1～C4 cycloalkyl, aryl, substituted aryl, contain 1～2 and be selected from N, O or heteroatomic heterocyclic radical of S or substituted heterocyclic radical, described substituted aryl or substituted heterocyclic radical are replaced by following any 1～3 substituting group: the alkyl of C1～C4, alkoxyl group, halogen, trifluoromethyl, nitro; Perhaps R
1, R
2Formation contains 1～2 and is selected from N, O or heteroatomic 3～6 yuan saturated heterocyclic or the unsaturated heterocycle of S, does not have other substituting group on described 3～6 yuan saturated heterocyclic or the ring of unsaturated heterocycle or is also replaced by following any 1～3 substituting group: the alkyl of C1～C4, alkoxyl group, halogen, trifluoromethyl, nitro.
2. the synthetic method of 2-chloro-3-cyanopyridine as claimed in claim 1, the aromatic nucleus that it is characterized in that described aryl or substituted aryl is phenyl ring, cyclohexyl biphenyl or condensed ring; It is described that to contain 1～2 heterocycle that is selected from N, O or heteroatomic heterocyclic radical of S or substituted heterocyclic radical be furan nucleus, thiphene ring, quinoline ring or indole ring.
3. the synthetic method of 2-chloro-3-cyanopyridine as claimed in claim 1; it is one of following to it is characterized in that the substituted amide shown in the formula (IV) is selected from: N; dinethylformamide, N; N-dibutyl formamide, N-methyl-N-phenyl formamide, N; N-encircles penta own methane amide, N-N-formyl morpholine N-, N-methyl-N-(2-thienyl) methane amide, N; N-diphenylformamide, N, N-two (1-naphthyl) methane amide, 1,4-diformyl piperazine.
4. in the synthetic method as the described 2-chloro-of one of claim 1～4 3-cyanopyridine, it is characterized in that described organic solvent is selected from the mixture of one of following or any several arbitrary proportions: the halogenated alkane of C1～C5, the fatty ester of C1～C8, benzene,toluene,xylene, chlorobenzene, oil of mirbane, hexanaphthene, dithiocarbonic anhydride, Nitromethane 99Min..
5. in the synthetic method of 2-chloro-3-cyanopyridine as claimed in claim 4, it is characterized in that described organic solvent is selected from the mixture of one of following or any several arbitrary proportions: methylene dichloride, trichloromethane, ethyl acetate, methyl propionate, ethyl propionate, butanone, pimelinketone, tetrahydrofuran (THF), 2-methyltetrahydrofuran or benzene,toluene,xylene, oil of mirbane, hexanaphthene, Nitromethane 99Min..
6. in the synthetic method as the described 2-chloro-of one of claim 1～4 3-cyanopyridine, it is characterized in that controlled temperature is at-10～10 ℃ of preparation Vilsmeier reagent.
7. in the synthetic method as the described 2-chloro-of one of claim 1～4 3-cyanopyridine, it is characterized in that adding N-oxygen-3-cyanopyridine after, control reaction temperature is 80-130 ℃.
8. in the synthetic method as the described 2-chloro-of one of claim 1～4 3-cyanopyridine, it is characterized in that the described N-oxygen-3-cyanopyridine and the amount of substance ratio that feeds intake of two (trichloromethyl) carbonic ethers, substituted amide are 1.0: 0.32～0.6: 1.0～2.2.
9. in the synthetic method of 2-chloro-3-cyanopyridine as claimed in claim 1, the synthetic method that it is characterized in that described 2-chloro-3-cyanopyridine is carried out according to following steps: by amount of substance than N-oxygen-3-cyanopyridine: two (trichloromethyl) carbonic ether: substituted amide is 1.0: 0.32～0.6: 1.0～2.2 to feed intake, at first substituted amide and organic solvent are added in the reaction flask, open mechanical stirring, ice bath is cooled to about 0 ℃, drips the organic solvent that is dissolved with two (trichloromethyl) carbonic ethers and prepares Vilsmeier reagent; After dropwising, after adding raw material N-oxygen-3-cyanopyridine, adjust 80～130 ℃ of temperature, insulation reaction 4～12h, TLC follows the tracks of, the back steaming that reacts completely desolventizes, and adds water while hot, stirs and is cooled to room temperature, there are a large amount of solids to separate out, filter, the solid washing promptly gets described 2-chloro-3-cyanopyridine after the oven dry.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109232413A (en) * | 2018-10-25 | 2019-01-18 | 老河口市天和科技有限公司 | The preparation method of the chloro- nicotinonitrile of 2- |
| CN109232412A (en) * | 2018-10-25 | 2019-01-18 | 老河口市天和科技有限公司 | The preparation method of the chloro- nicotinonitrile of 2- |
| CN109369519A (en) * | 2018-10-23 | 2019-02-22 | 浙江大学 | A kind of environment-friendly preparation method thereof of the chloro- nicotinonitrile of 2- |
| CN111393361A (en) * | 2019-12-30 | 2020-07-10 | 浙江日出药业有限公司 | Safe and environment-friendly 2-chloronicotinic acid synthesis method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08217753A (en) * | 1995-02-16 | 1996-08-27 | Koei Chem Co Ltd | Production of 2-chloro-3-cyanopyridine |
| CN101659637A (en) * | 2009-09-08 | 2010-03-03 | 浙江工业大学 | Preparation method of 2-chloro-3-cyanopyridine |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPH08217753A (en) * | 1995-02-16 | 1996-08-27 | Koei Chem Co Ltd | Production of 2-chloro-3-cyanopyridine |
| CN101659637A (en) * | 2009-09-08 | 2010-03-03 | 浙江工业大学 | Preparation method of 2-chloro-3-cyanopyridine |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109369519A (en) * | 2018-10-23 | 2019-02-22 | 浙江大学 | A kind of environment-friendly preparation method thereof of the chloro- nicotinonitrile of 2- |
| CN109369519B (en) * | 2018-10-23 | 2021-05-04 | 浙江大学 | Green preparation method of 2-chloro-3-cyanopyridine |
| CN109232413A (en) * | 2018-10-25 | 2019-01-18 | 老河口市天和科技有限公司 | The preparation method of the chloro- nicotinonitrile of 2- |
| CN109232412A (en) * | 2018-10-25 | 2019-01-18 | 老河口市天和科技有限公司 | The preparation method of the chloro- nicotinonitrile of 2- |
| CN111393361A (en) * | 2019-12-30 | 2020-07-10 | 浙江日出药业有限公司 | Safe and environment-friendly 2-chloronicotinic acid synthesis method |
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