CN111056997A - Synthetic method of benzamide compound - Google Patents
Synthetic method of benzamide compound Download PDFInfo
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- CN111056997A CN111056997A CN201911247761.6A CN201911247761A CN111056997A CN 111056997 A CN111056997 A CN 111056997A CN 201911247761 A CN201911247761 A CN 201911247761A CN 111056997 A CN111056997 A CN 111056997A
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- CN
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- Prior art keywords
- trifluoromethyl
- reaction
- chloro
- pyridine
- ethyl
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- -1 benzamide compound Chemical class 0.000 title claims description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 title claims description 3
- 238000010189 synthetic method Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 142
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 51
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 50
- 239000003054 catalyst Substances 0.000 claims abstract description 36
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 32
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 claims abstract description 17
- ABNQGNFVSFKJGI-UHFFFAOYSA-N 2,3-dichloro-5-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CN=C(Cl)C(Cl)=C1 ABNQGNFVSFKJGI-UHFFFAOYSA-N 0.000 claims abstract description 15
- MXIUWSYTQJLIKE-UHFFFAOYSA-N 2-(trifluoromethyl)benzoyl chloride Chemical compound FC(F)(F)C1=CC=CC=C1C(Cl)=O MXIUWSYTQJLIKE-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 10
- 239000012452 mother liquor Substances 0.000 claims abstract description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 9
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 63
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 48
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 46
- 239000002904 solvent Substances 0.000 claims description 43
- 238000010438 heat treatment Methods 0.000 claims description 36
- 238000003756 stirring Methods 0.000 claims description 36
- 239000012074 organic phase Substances 0.000 claims description 34
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 34
- 239000012071 phase Substances 0.000 claims description 33
- 239000007787 solid Substances 0.000 claims description 31
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- MKBUJCYCRMOWFB-UHFFFAOYSA-N 3-chloro-n-ethyl-5-(trifluoromethyl)pyridin-2-amine Chemical compound CCNC1=NC=C(C(F)(F)F)C=C1Cl MKBUJCYCRMOWFB-UHFFFAOYSA-N 0.000 claims description 26
- 239000000047 product Substances 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- KVDJTXBXMWJJEF-UHFFFAOYSA-N fluopyram Chemical compound ClC1=CC(C(F)(F)F)=CN=C1CCNC(=O)C1=CC=CC=C1C(F)(F)F KVDJTXBXMWJJEF-UHFFFAOYSA-N 0.000 claims description 24
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 24
- 238000001914 filtration Methods 0.000 claims description 23
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 18
- 238000010992 reflux Methods 0.000 claims description 18
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 17
- 238000005984 hydrogenation reaction Methods 0.000 claims description 14
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 13
- 230000015572 biosynthetic process Effects 0.000 claims description 13
- 238000003786 synthesis reaction Methods 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 12
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 12
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 10
- 239000007868 Raney catalyst Substances 0.000 claims description 10
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 10
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 238000004821 distillation Methods 0.000 claims description 9
- 239000012065 filter cake Substances 0.000 claims description 9
- 230000007935 neutral effect Effects 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- 230000001502 supplementing effect Effects 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 8
- 238000000746 purification Methods 0.000 claims description 8
- DDFYFBUWEBINLX-UHFFFAOYSA-M tetramethylammonium bromide Chemical compound [Br-].C[N+](C)(C)C DDFYFBUWEBINLX-UHFFFAOYSA-M 0.000 claims description 8
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 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 7
- BBGKDYHZQOSNMU-UHFFFAOYSA-N dicyclohexano-18-crown-6 Chemical compound O1CCOCCOC2CCCCC2OCCOCCOC2CCCCC21 BBGKDYHZQOSNMU-UHFFFAOYSA-N 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 238000007670 refining Methods 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims 1
- 238000001308 synthesis method Methods 0.000 abstract description 8
- 238000009903 catalytic hydrogenation reaction Methods 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 abstract 1
- 230000001276 controlling effect Effects 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 5
- 239000005783 Fluopyram Substances 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 230000000855 fungicidal effect Effects 0.000 description 2
- 239000000417 fungicide Substances 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- FBRJYBGLCHWYOE-UHFFFAOYSA-N 2-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(F)(F)F FBRJYBGLCHWYOE-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000000911 decarboxylating effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000007031 hydroxymethylation reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000001105 regulatory effect Effects 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
- C07D213/61—Halogen atoms or nitro radicals
Abstract
The invention discloses a method for synthesizing N- [2- [ 3-chloro-5- (trifluoromethyl) pyridine-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide, which comprises the following steps: ethyl cyanoacetate and 2, 3-dichloro-5- (trifluoromethyl) pyridine are used as raw materials, firstly, reaction mother liquor under the action of a catalyst and alkali is refluxed by adding N, N-dimethylformamide with the pH value of 2-5 to obtain 3-chloro-5- (trifluoromethyl) -2-acetonitrile pyridine, then, the 3-chloro-5- (trifluoromethyl) -2-ethylamine pyridine is obtained through catalytic hydrogenation reduction, and finally, the 3-chloro-5- (trifluoromethyl) -2-ethylamine pyridine and 2- (trifluoromethyl) benzoyl chloride are condensed in the presence of a water phase to obtain a target compound N- [2- [ 3-chloro-5- (trifluoromethyl) pyridine-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide. The synthesis method adopted by the invention reduces the reaction steps, has simple operation, mild conditions, less three wastes and high yield, and is a synthesis method of N- [2- [ 3-chloro-5- (trifluoromethyl) pyridine-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide.
Description
Technical Field
The invention belongs to the field of pesticide synthesis, and particularly relates to a synthesis method of N- [2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide.
Background
N- [2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide is an important agricultural fungicide known under the generic name fluopyram (EP1674455A1 and Liuanchang et al, synthesis of the novel fungicide fluopyram, pesticide 2015,54 (7): 485-. The synthesis method of N- [2- [ 3-chloro-5- (trifluoromethyl) pyridine-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide has less reports, and the market is monopolized by Bayer. The literature reports that the synthetic route of N- [2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide has two main routes: route one: taking o-trifluoromethylbenzoic acid as a raw material, carrying out acylation, amidation and hydroxymethylation to obtain N-hydroxymethyl-2-trifluoromethyl benzamide, and then esterifying the N-hydroxymethyl-2-trifluoromethyl benzamide with acetyl chloride or acetic anhydride to obtain N-acetoxymethyl-2-trifluoromethyl benzamide; condensing N-acetoxymethyl-2-trifluoromethyl benzamide and 3-chloro-5-trifluoromethyl-2-pyridine diethyl malonate, and hydrolyzing and decarboxylating to obtain the target product fluopyram. And a second route: the method uses 2, 3-dichloro-5-trifluoromethylpyridine as a raw material, and the raw material is condensed with ethyl cyanoacetate, hydrolyzed and decarboxylated to obtain 2-acetonitrile-3-chloro-5-trifluoromethylpyridine, and then the target product fluopyram is obtained through hydrogenation and amidation reactions. The analysis of the synthetic route reported in the literature shows that: the first route is longer in synthetic route, and the intermediate product is not easy to purify, so that the reaction product is extremely dark in color, more in byproducts, unfavorable for subsequent reaction and poor in atom economy. While the second route is relatively suitable for industrial production, the synthesis route is more complex, the conditions are not mild, the operation is complex, and the yield is not higher than 44%. The synthetic route of route two is as follows:
disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a method for synthesizing N- [2- [ 3-chloro-5- (trifluoromethyl) pyridine-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide, which has the advantages of few reaction steps, mild conditions, simple operation, few three wastes and high yield.
In order to solve the technical problems, the invention provides a continuous synthesis method of N- [2- [ 3-chloro-5- (trifluoromethyl) pyridine-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide, and the synthetic technical route is as follows:
in the formula:
the solvent 1 is one or a mixture of two or more of N, N-dimethylformamide, N-dimethylacetamide, methanol, ethanol, tert-butyl alcohol, benzene, toluene, ethyl acetate and methyl acetate.
The alkali is one or a mixture of two or more of potassium carbonate, sodium bicarbonate, sodium hydride, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide and sodium tert-butoxide.
The catalyst 1 is one or a mixture of two or more of tetramethyl ammonium bromide, tetramethyl ammonium chloride, tetrabutyl ammonium chloride, triethyl benzyl ammonium chloride, potassium iodide, 18-crown-6 and dicyclohexyl 18-crown-6.
The acid is one or a mixture of two or more of citric acid, p-toluenesulfonic acid, phosphoric acid, 10% hydrochloric acid and 5% sulfuric acid.
The solvent 2 is one or a mixture of two or more of methanol, ethanol, benzene, toluene, ethyl acetate, acetic acid and acetic anhydride.
The catalyst 2 is one or the mixture of two or more of 5 percent of palladium carbon, 10 percent of palladium carbon and Raney nickel.
The solvent 3 is n-hexane, petroleum ether, dichloromethane, chloroform, dichloroethane, benzene, toluene or ethyl acetate.
The catalyst 3 is one or a mixture of two or more of tetramethyl ammonium bromide, tetramethyl ammonium chloride, tetrabutyl ammonium chloride, triethyl benzyl ammonium chloride, potassium iodide, 18-crown-6 and dicyclohexyl 18-crown-6.
The acid-binding agent is one or a mixture of two or more of potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and triethylamine.
The specific operation is as follows:
step (1): adding ethyl cyanoacetate, a solvent 1 and a catalyst into a reaction bottle, adding alkali in batches under uniform stirring, then slowly dropwise adding 2, 3-dichloro-5- (trifluoromethyl) pyridine after stirring for 0.5h at the temperature of 25 ℃, heating to 70 ℃ for reaction for 1h after dropwise adding, stopping the reaction, filtering insoluble substances, supplementing N, N-dimethylformamide, adjusting the pH value of the reaction mother liquor to be 2-5 by using acid, separating out solids, heating to reflux reaction for 3h, stopping the reaction, carrying out reduced pressure distillation, collecting and recovering the solvent under the conditions of 50-110 ℃/133-266 Pa, and obtaining a reddish brown residue, namely 3-chloro-5- (trifluoromethyl) -2-acetonitrile pyridine, wherein the reddish brown residue is not required to be purified and is directly used for the next reaction;
step (2): adding the 3-chloro-5- (trifluoromethyl) -2-acetonitrile pyridine prepared in the step (1), a solvent 2 and a hydrogenation catalyst into a hydrogenation kettle, introducing hydrogen under the condition of ammonia water or no ammonia water, heating to 15-80 ℃ under the pressure of less than 0.3Mpa, stirring for reaction for 3-4 h, stopping reaction, filtering out a catalyst, distilling under reduced pressure, collecting the solvent at the temperature of 40-130 ℃/133-266 Pa, adding the remainder into a reaction kettle, refluxing and reacting N, N-dimethyl under the condition of concentrated hydrochloric acid for 1h, stopping the reaction, extracting the reaction solution by using a solvent 3, collecting a water phase, adjusting the water phase to be neutral, extracting the water phase by using the solvent 3, combining organic phases, the organic phase of the 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine is obtained, and the product is directly used for the next reaction without refining.
And (3): adding the organic phase of the 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine prepared in the step (2), a catalyst and water into a reaction kettle, controlling the temperature at 0 ℃, adding an acid-binding agent in batches, heating to 5 ℃, stirring slowly and dropwise adding 2- (trifluoromethyl) benzoyl chloride, keeping the temperature at 25 ℃ for 1h after finishing dripping, stopping reaction, standing, layering, separating a water phase, collecting the organic phase, removing the organic phase to obtain a white solid, washing with water, performing suction filtration, and collecting a filter cake to obtain a white solid, namely the target product N- [2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide.
The synthesis method comprises the following steps of (1):
the mol ratio of the ethyl cyanoacetate to the alkali to the 2, 3-dichloro-5- (trifluoromethyl) pyridine is as follows: 1-1.2: 1-1.5: 1.
The solvent 1 is one or a mixture of two or more of N, N-dimethylformamide, N-dimethylacetamide, methanol, ethanol, tert-butyl alcohol, benzene, toluene, ethyl acetate and methyl acetate.
The amount of the solvent 1 is 300ml to 800ml per mol of ethyl cyanoacetate.
The alkali is one or a mixture of two or more of potassium carbonate, sodium bicarbonate, sodium hydride, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide and sodium tert-butoxide.
The catalyst 1 is one or a mixture of two or more of tetramethyl ammonium bromide, tetramethyl ammonium chloride, tetrabutyl ammonium chloride, triethyl benzyl ammonium chloride, potassium iodide, 18-crown-6 and dicyclohexyl 18-crown-6.
The amount of the catalyst 1 is 1-5%.
The dosage of the N, N-dimethylformamide is 100ml to 600ml of solvent required by each mole of 2, 3-dichloro-5- (trifluoromethyl) pyridine.
The regulating acid is one or a mixture of two or more of citric acid, phosphoric acid, 10% hydrochloric acid and 5% sulfuric acid, and the step (2) in the synthesis method is as follows:
the solvent 2 is one or a mixture of two or more of methanol, ethanol, benzene, toluene, ethyl acetate, acetic acid and acetic anhydride.
The amount of the solvent 2 is 300ml to 500ml for each mol of 3-chloro-5- (trifluoromethyl) -2-acetonitrile pyridine. The catalyst 2 is one or the mixture of two or more of 5 percent of palladium carbon, 10 percent of palladium carbon and Raney nickel.
The amount of the catalyst 2 is 0.4-2%.
The condition of the concentrated hydrochloric acid is that 100ml to 150ml of concentrated hydrochloric acid is needed for each mole of 3-chloro-5- (trifluoromethyl) -2-acetonitrile pyridine.
The solvent 3 is n-hexane, petroleum ether, dichloromethane, chloroform, dichloroethane, benzene, toluene or ethyl acetate.
The amount of the solvent 3 used is 300ml to 500ml per mole of 3-chloro-5- (trifluoromethyl) -2-ethylamino-pyridine.
Step (3) of the above synthesis method:
the mol ratio of the 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine to the alkali to the 2- (trifluoromethyl) benzoyl chloride is as follows: 1-1.05: 1-1.5: 1.
The catalyst 3 is one or a mixture of two or more of tetramethyl ammonium bromide, tetramethyl ammonium chloride, tetrabutyl ammonium chloride, triethyl benzyl ammonium chloride, potassium iodide, 18-crown-6 and dicyclohexyl 18-crown-6.
The amount of the catalyst 3 is 1-5%.
The acid-binding agent is one or a mixture of two or more of potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and triethylamine.
The water amount is 100ml to 300ml for each mol of 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine.
The preferred method of the invention is as follows:
step (1): adding ethyl cyanoacetate, N-dimethylformamide and triethylbenzylammonium chloride into a reaction bottle, adding potassium carbonate in batches under uniform stirring, then controlling the temperature to be 25 ℃, stirring for 0.5h, slowly dropwise adding 2, 3-dichloro-5- (trifluoromethyl) pyridine, heating to 70 ℃ for reaction for 1h after dropwise adding, stopping the reaction, filtering out insoluble substances, supplementing N, N-dimethylformamide, adjusting the pH value of the reaction mother liquor to be 2 by using 10% hydrochloric acid, separating out solids, heating to reflux reaction for 3h, stopping the reaction, carrying out reduced pressure distillation, collecting and recovering a solvent under the conditions of 110 ℃/133-266 Pa to obtain a reddish brown residue, namely 3-chloro-5- (trifluoromethyl) -2-acetonitrile, which is directly used for the next reaction without purification, wherein the raw materials of ethyl cyanoacetate, potassium carbonate and 2, the mol ratio of the 3-dichloro-5- (trifluoromethyl) pyridine is as follows: 1-1.2: 1-1.5: 1.
Step (2): adding the 3-chloro-5- (trifluoromethyl) -2-acetonitrile pyridine prepared in the step (1), ethanol, 5 percent palladium-carbon and Raney nickel mixed catalyst 2 into a hydrogenation kettle, introducing hydrogen gas, heating to 80 deg.C under 0.2Mpa, stirring for reaction for 4 hr, stopping reaction, filtering to remove catalyst, distilling under reduced pressure, collecting the solvent at 70 ℃/133-266 Pa, adding the remainder into a reaction kettle, refluxing and reacting N, N-dimethyl under the condition of concentrated hydrochloric acid for 1h, stopping the reaction, extracting the reaction solution by using dichloromethane to remove an organic phase, collecting a water phase, adjusting the water phase to be neutral, extracting the water phase by using dichloromethane, combining the organic phases, the organic phase of the 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine is obtained, and the product is directly used for the next reaction without refining. The amount of hydrogenation catalyst was 1% palladium on carbon 5% and 1% Raney nickel 1% in combination.
And (3): adding the dichloromethane solution of 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine prepared in the step (2), triethylbenzyl ammonium chloride and water into a reaction kettle, controlling the temperature to be 0 ℃, adding potassium carbonate in batches, heating to 5 ℃, slowly dropwise adding 2- (trifluoromethyl) benzoyl chloride under vigorous stirring, keeping the temperature at 25 ℃ for 1h, stopping reaction, standing, layering, separating a water phase, collecting a dichloromethane organic phase, removing dichloromethane to obtain a solid, washing with water, performing suction filtration, and collecting a filter cake to obtain a white solid, namely the target product N- [2- [ 3-chloro-5- (trifluoromethyl) pyridine-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide, the raw materials 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine, the raw materials, The molar ratio of base to 2- (trifluoromethyl) benzoyl chloride is: 1-1.05: 1-1.5: 1.
Compared with the prior art, the invention has the beneficial effects that: (1) the total yield of the scheme is improved to 62 percent, while the total yield of the prior art is only 44 percent; (2) the reaction condition is mild, and the hydrogenation reduction pressure is reduced to below 0.3MPa from 30MPa reported in the literature; (3) the synthetic route is shorter, and the operation steps and the discharge of three wastes are reduced.
Detailed Description
The following examples are intended to further illustrate the synthesis of N- [2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide in the present invention, but the present invention is by no means limited to the following examples.
Example 1
Step (1): adding 11.8g of ethyl cyanoacetate, 30ml of N, N-dimethylformamide and 5% of triethylbenzylammonium chloride into a 100ml reaction bottle, adding 5.6g of potassium carbonate in batches under uniform stirring, then stirring for 0.5h at the temperature of 25 ℃, slowly dropwise adding 21.5g of 2, 3-dichloro-5- (trifluoromethyl) pyridine, heating to 70 ℃ for reaction for 1h after dropwise adding, stopping the reaction, filtering out insoluble substances, supplementing 10ml of N, N-dimethylformamide, adjusting the pH value of a reaction mother liquor to be 2 by using 10% of hydrochloric acid, separating out a solid, heating to reflux reaction for 3h, stopping the reaction, carrying out reduced pressure distillation, collecting and recovering a solvent under the conditions of 110 ℃/133-Pa 266, obtaining 19g of a reddish brown residue with the content of 98% and the yield of 85%, namely 3-chloro-5- (trifluoromethyl) -2-acetonitrile-based pyridine, the product is used in the next reaction without purification.
1HNMR(500MHz,DMSO-d6):δ4.52(s,2H, 2CH),8.56(s,2H, 2CH) 8.97(s, 1H); the melting point is 34-35 DEG C
Step (2): adding 19g of 3-chloro-5- (trifluoromethyl) -2-acetonitrile pyridine prepared in the step (1), 30ml of ethanol, 1% of two mixed catalysts 2 of 5% palladium carbon and raney nickel into a hydrogenation kettle, introducing hydrogen, heating to 80 ℃ under the pressure of 0.2Mpa, stirring for reaction for 4h, stopping the reaction, filtering out the catalyst, carrying out reduced pressure distillation, collecting the solvent under the conditions of 70 ℃/133-266 Pa, adding the remainder into a 50ml reaction bottle, adding 15ml of concentrated hydrochloric acid, carrying out reflux reaction for 1h, stopping the reaction, removing an organic phase from a reaction solution extracted by 10ml of dichloromethane, collecting the water phase, adjusting the water phase to be neutral, extracting the water phase by 20ml of dichloromethane, combining the organic phases to obtain a dichloromethane solution of 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine, containing 16.1g of a product, the content is 98 percent, the yield is 83 percent, and the product is directly used for the next reaction without refining.
1HNMR(500MHz,D2O):δδ3.40～3.43(m,2H, 2CH),3.50～3.54(m,2H, 2CH),8.27(s,1H),8.83(s,1H)；
And (3): adding 20ml of dichloromethane solution of 16.1g of 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine prepared in the step (2), 5% of triethylbenzyl ammonium chloride and 10ml of water into a reaction kettle, controlling the temperature to be 0 ℃, adding 9.7g of potassium carbonate in batches, heating to 5 ℃, slowly dropwise adding 14.6g of 2- (trifluoromethyl) benzoyl chloride under vigorous stirring, keeping the temperature at 25 ℃ for 1h, stopping the reaction, layering after standing, separating a water phase, collecting a dichloromethane organic phase, removing dichloromethane to obtain a solid, washing and filtering with water, collecting a filter cake, drying to obtain a white solid, namely the target product N- [2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide, weighing 24.6g, the yield thereof was found to be 88%.
1HNMR(500MHz,DMSO-d6):δ3.22～3.25(t,2H),3.67～3.72(m,2H),7.48～7.51(m,1H),7.62(t,1H),7.69～7.76(m,2H),8.43(s,1H),8.58(s,1H),8.90(s,1H)；13CNMR(125MHz,DMSO-d6):167.5,160.5,143.5,136.0,133.5,133.0,132.0,131.6,129.5,128.4,125.8,36.5,33.4；
The final product, N- [2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide, was demonstrated by the above characterization data.
Example 2
Step (1): adding 11.3g of ethyl cyanoacetate, 30ml of methanol and 5% of potassium iodide into a 100ml reaction bottle, adding 5.6g of sodium methoxide in batches under uniform stirring, then stirring for 0.5h at the temperature of 25 ℃, slowly dropwise adding 21.5g of 2, 3-dichloro-5- (trifluoromethyl) pyridine, heating to 70 ℃ for reaction for 1h after dropwise adding, stopping the reaction, filtering out insoluble substances, supplementing 40ml of N, N-dimethylformamide, adjusting the pH value of reaction mother liquor to 2 by using 10% of hydrochloric acid to precipitate solids, heating to reflux reaction for 3h, stopping the reaction, distilling under reduced pressure, collecting and recovering a solvent under the conditions of 110 ℃/133-266 Pa to obtain 19g of a reddish brown residue with the content of 98% and the yield of 85%, namely 3-chloro-5- (trifluoromethyl) -2-acetonitrile-based pyridine, wherein the residue is directly used for the next reaction without purification,
step (2): adding 19g of 3-chloro-5- (trifluoromethyl) -2-acetonitrile pyridine prepared in the step (1), 30ml of methanol and 2% of 5% palladium carbon into a hydrogenation kettle, adding 1ml of ammonia water, introducing hydrogen, heating to 80 ℃ under the pressure of 0.2Mpa, stirring for reaction for 4h, stopping the reaction, filtering out a catalyst, distilling under reduced pressure, collecting a solvent under the conditions of 60 ℃/133-266 Pa, adding the remainder into a 50ml reaction bottle, adding 15ml of concentrated hydrochloric acid, refluxing for reaction for 1h, stopping the reaction, extracting the reaction liquid by 10ml of cyclohexane, removing an organic phase, collecting the water phase, adjusting the water phase to be neutral, extracting the water phase by 20ml of cyclohexane, combining the organic phases to obtain a dichloromethane solution of the 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine, wherein the dichloromethane solution contains 16.3g of the product and the content of 98%, the yield is 84%, and the product is directly used for the next reaction without refining.
And (3): adding 20ml of cyclohexane solution of 16.3g of 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine prepared in the step (2), 5 percent of tetramethylammonium chloride and 10ml of water into a reaction kettle, controlling the temperature to be 0 ℃, adding 8.7g of triethylamine in batches, heating to 5 ℃, slowly dropwise adding 14.6g of 2- (trifluoromethyl) benzoyl chloride under vigorous stirring, keeping the temperature at 25 ℃ for 1h after dropwise adding, stopping the reaction, standing, layering, separating a water phase, collecting a cyclohexane organic phase, removing cyclohexane to obtain a solid, washing and filtering the solid, collecting a filter cake, and drying to obtain a white solid, namely the target product N- [2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide, weighing 24.9g and obtaining the yield of 88%.
Example 3
Step (1): adding 13.6g of ethyl cyanoacetate, 30ml of ethyl acetate and 5% of 18-crown-6 into a 100ml reaction bottle, adding 20.7g of potassium carbonate in batches under uniform stirring, then stirring for 0.5h at the temperature of 25 ℃, slowly dropwise adding 21.5g of 2, 3-dichloro-5- (trifluoromethyl) pyridine, heating to 70 ℃ for reaction for 1h after dropwise adding, stopping the reaction, filtering out insoluble substances, supplementing 30ml of N, N-dimethylformamide, adjusting the pH value of the reaction mother liquor to 2 with 10% of hydrochloric acid to precipitate solid, heating to reflux reaction for 3h, stopping the reaction, carrying out reduced pressure distillation, collecting and recovering a solvent at 70 ℃/133-266 Pa to obtain 19.3g of brown red residue with the content of 98%, wherein the yield is 86%, namely the 3-chloro-5- (trifluoromethyl) -2-acetonitrile-based pyridine, without purification, is directly used for the next reaction step,
step (2): adding 19.3g of 3-chloro-5- (trifluoromethyl) -2-acetonitrile pyridine prepared in the step (1), 30ml of acetic acid and 1% of 5% palladium carbon into a hydrogenation kettle, introducing hydrogen, heating to 80 ℃ under the pressure of 0.2Mpa, stirring for reaction for 4h, stopping the reaction, filtering out a catalyst, distilling under reduced pressure, collecting a solvent under the conditions of 60 ℃/133-266 Pa, adding the remainder into a 50ml reaction bottle, adding 15ml of concentrated hydrochloric acid, refluxing for reaction for 1h, stopping the reaction, removing an organic phase by using 10ml of toluene extraction reaction liquid, collecting the water phase to be neutral, extracting the water phase by using 20ml of toluene, and combining the organic phases to obtain a toluene solution of the 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine, wherein the toluene solution contains 16.2g of a product, has the content of 98%, the yield of 84%, and the product is not required to be refined, directly used for the next reaction.
And (3): adding 16.2g of 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine prepared in the step (2) in 20ml of toluene solution, 5% of triethylbenzylammonium chloride and 10ml of water into a reaction kettle, controlling the temperature to be 0 ℃, adding 6.1g of potassium hydroxide in batches, heating to 5 ℃, slowly dropwise adding 14.6g of 2- (trifluoromethyl) benzoyl chloride under vigorous stirring, keeping the temperature at 25 ℃ for 1h after dropwise adding, stopping the reaction, standing, layering, separating a water phase, collecting a toluene organic phase, removing toluene to obtain a solid, washing and filtering the solid, collecting a filter cake, drying to obtain a white solid, namely the target product N- [2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide, weighing 25.5g, and obtaining the yield of 89%.
Example 4
Step (1): adding 13.6g of ethyl cyanoacetate, 80ml of benzene and 5% of tetramethylammonium bromide into a 500ml reaction bottle, adding 20.7g of potassium carbonate in batches under uniform stirring, then stirring for 0.5h at the temperature of 25 ℃, slowly dropwise adding 21.5g of 2, 3-dichloro-5- (trifluoromethyl) pyridine, heating to 70 ℃ for reaction for 1h after dropwise adding, stopping the reaction, filtering out insoluble substances, supplementing 60ml of N, N-dimethylformamide, adjusting the pH value of reaction mother liquor to 2 by using 10% of hydrochloric acid to precipitate solids, heating to reflux reaction for 3h, stopping the reaction, distilling under reduced pressure, collecting and recovering a solvent under the conditions of 70 ℃/133-266 Pa to obtain 19.2g of a reddish brown residue with the content of 98% and the yield of 85.5%, namely the 3-chloro-5- (trifluoromethyl) -2-acetonitrile-based pyridine, directly using for next step reaction without purification,
step (2): adding 19.2g of 3-chloro-5- (trifluoromethyl) -2-acetonitrile pyridine prepared in the step (1), 50ml of acetic anhydride and 2% of raney nickel into a hydrogenation kettle, introducing hydrogen, heating to 80 ℃ under normal pressure, stirring for reaction for 4h, stopping the reaction, filtering out a catalyst, distilling under reduced pressure, collecting a solvent under the conditions of 130 ℃/133-266 Pa, adding the remainder into a 50ml reaction bottle, adding 15ml of concentrated hydrochloric acid for reflux reaction for 1h, stopping the reaction, extracting a reaction solution by using 20ml of dichloroethane, removing an organic phase, collecting the water phase to be neutral, extracting the water phase by using 30ml of dichloroethane, combining the organic phases to obtain a dichloroethane solution of the 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine, wherein the dichloroethane solution contains 16.5g of a product, the content is 98%, and the yield is 84.5%, the product is not required to be refined and is directly used for the next reaction.
And (3): adding 30ml of dichloroethane solution of 16.5g of 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine prepared in the step (2), 5% of dicyclohexyl 18-crown-6 and 30ml of water into a reaction kettle, controlling the temperature and adding 7.9g of sodium bicarbonate in batches at 0 ℃, heating to 5 ℃, slowly dropwise adding 14.6g of 2- (trifluoromethyl) benzoyl chloride under vigorous stirring, keeping the temperature at 25 ℃ for reaction for 1h, stopping the reaction, standing, layering, separating out a water phase, collecting a dichloroethane organic phase, removing dichloroethane to obtain a solid, washing and suction-filtering the solid, collecting a filter cake, drying to obtain a white solid, namely the target product N- [2- [ 3-chloro-5- (trifluoromethyl) pyridine-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide, weigh 25.2g, 88% yield.
Example 5
Step (1): adding 13.6g of ethyl cyanoacetate, 50ml of N, N-dimethylacetamide and 5% of tetramethylammonium bromide into a 500ml reaction bottle, adding 20.7g of potassium carbonate in batches under uniform stirring, then stirring for 0.5h at the temperature of 25 ℃, slowly dropwise adding 21.5g of 2, 3-dichloro-5- (trifluoromethyl) pyridine, heating to 70 ℃ for reaction for 1h after dropwise adding, stopping the reaction, filtering out insoluble substances, supplementing 60ml of N, N-dimethylformamide, adjusting the pH value of reaction mother liquor to 2 with 10% of hydrochloric acid to precipitate a solid, heating to reflux reaction for 3h, stopping the reaction, carrying out reduced pressure distillation, collecting and recovering a solvent under the conditions of 70 ℃/133-Pa 266 to obtain 19.2g of a reddish brown residue with the content of 98%, and obtaining the yield of 85.5%, namely 3-chloro-5- (trifluoromethyl) -2-acetonitrile-based pyridine, the product is directly used for the next reaction without purification,
step (2): adding 19.2g of 3-chloro-5- (trifluoromethyl) -2-acetonitrile pyridine prepared in the step (1), 50ml of ethanol and 2% raney nickel into a hydrogenation kettle, adding 1ml of ammonia water, introducing hydrogen, heating to 70 ℃ under the condition of 0.1Mpa, stirring and reacting for 3.5h, stopping the reaction, filtering out a catalyst, carrying out reduced pressure distillation, collecting a solvent under the conditions of 70 ℃/133-266 Pa, adding the remainder into a 50ml reaction bottle, adding 10ml of concentrated hydrochloric acid, refluxing and reacting for 1h, stopping the reaction, removing an organic phase from a reaction liquid extracted by 20ml of ethyl acetate, collecting the water phase, adjusting the water phase to be neutral, extracting the water phase by 30ml of ethyl acetate, combining the organic phases to obtain an ethyl acetate solution of the 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine, wherein the content of the ethyl acetate solution is 16.5g and 98%, the yield is 84.5%, and the product is directly used for the next reaction without refining.
And (3): adding 16.5g of 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine prepared in the step (2) in 30ml of ethyl acetate solution, 5% of potassium iodide and 30ml of water into a reaction kettle, controlling the temperature to be 0 ℃, adding 7.9g of sodium bicarbonate in batches, heating to 5 ℃, slowly dropwise adding 14.6g of 2- (trifluoromethyl) benzoyl chloride under vigorous stirring, keeping the temperature at 25 ℃ for 1h, stopping the reaction, standing, layering, separating a water phase, collecting an ethyl acetate organic phase, removing the ethyl acetate to obtain a solid, washing and filtering the solid with water, collecting a filter cake, drying to obtain a white solid, namely the target product N- [2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide, weighing 25.2g, the yield thereof was found to be 88%.
Claims (10)
1. A method for synthesizing benzamide compound is characterized by comprising the following steps:
step (1): adding ethyl cyanoacetate, a solvent 1 and a catalyst 1 into a reaction bottle, adding alkali in batches under uniform stirring, then slowly dropwise adding 2, 3-dichloro-5- (trifluoromethyl) pyridine after stirring for 0.5h at the temperature of 25 ℃, heating to 70 ℃ for reaction for 1h after dropwise adding, stopping the reaction, filtering insoluble substances, supplementing N, N-dimethylformamide, adjusting the pH value of the reaction mother liquor to 2-5 by using acid to separate out solids, heating to reflux reaction for 3h, stopping the reaction, carrying out reduced pressure distillation, collecting and recovering the solvent under the conditions of 50-110 ℃/133-266 Pa to obtain a reddish brown residue, namely 3-chloro-5- (trifluoromethyl) -2-acetonitrile-based pyridine, and directly using the reddish brown residue for the next reaction without purification;
the solvent 1 is one or a mixture of two or more of N, N-dimethylformamide, N-dimethylacetamide, methanol, ethanol, tert-butyl alcohol, benzene, toluene, ethyl acetate and methyl acetate, and the amount of the solvent 1 is 300ml to 800ml per mol of ethyl cyanoacetate; the catalyst 1 is one or a mixture of two or more of tetramethyl ammonium bromide, tetramethyl ammonium chloride, tetrabutyl ammonium chloride, triethyl benzyl ammonium chloride, potassium iodide, 18-crown-6 and dicyclohexyl 18-crown-6, and the amount of the catalyst 1 is 1-5%;
step (2): adding 3-chloro-5- (trifluoromethyl) -2-acetonitrile pyridine, a solvent 2 and a catalyst 2 into a hydrogenation kettle, introducing hydrogen under the condition of ammonia water or no ammonia water, heating to 15-80 ℃ under the condition that the pressure is less than 0.3Mpa, stirring for reaction for 3-4 h, stopping the reaction, filtering out the catalyst, distilling under reduced pressure, collecting the solvent under the condition of 40-130 ℃/133-266 Pa, adding the remainder into the reaction kettle, refluxing for reaction for 1h under the condition of concentrated hydrochloric acid, stopping the reaction, extracting a reaction solution with the solvent 3 to remove an organic phase, collecting the water phase to be neutral, extracting the water phase with the solvent 3, and combining the organic phases to obtain the organic phase of the 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine, wherein the product is directly used for the next reaction without being refined;
the solvent 2 is one or a mixture of two or more of methanol, ethanol, benzene, toluene, ethyl acetate, acetic acid and acetic anhydride; the amount of the solvent 2 is 300ml to 500ml for each mol of 3-chloro-5- (trifluoromethyl) -2-acetonitrile pyridine; the catalyst 2 is one or a mixture of two or more of 5% palladium carbon, 10% palladium carbon and Raney nickel, and the amount of the catalyst 2 is 0.4-2%; the solvent 3 is one or a mixture of two or more of n-hexane, petroleum ether, dichloromethane, trichloromethane, dichloroethane, benzene, toluene and ethyl acetate, and the amount of the solvent 3 is 300ml to 500ml per mol of 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine;
and (3): adding the organic phase of the 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine prepared in the step (2), a catalyst 3 and water into a reaction kettle, controlling the temperature to be 0 ℃, adding an acid binding agent in batches, heating to 5 ℃, slowly dropwise adding 2- (trifluoromethyl) benzoyl chloride under vigorous stirring, keeping the temperature at 25 ℃ for 1h after dropwise adding, stopping reaction, standing, layering, separating a water phase, collecting the organic phase, removing the organic phase to obtain a white solid, washing with water, performing suction filtration, and collecting a filter cake to obtain a white solid, namely the target product N- [2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide;
the catalyst 3 is one or a mixture of two or more of tetramethyl ammonium bromide, tetramethyl ammonium chloride, tetrabutyl ammonium chloride, triethyl benzyl ammonium chloride, potassium iodide, 18-crown-6 and dicyclohexyl 18-crown-6, and the amount of the catalyst 3 is 1-5%.
2. The process for the synthesis of N- [2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide according to claim 1 characterized in that: in the step (1), the molar ratio of the ethyl cyanoacetate to the alkali to the 2, 3-dichloro-5- (trifluoromethyl) pyridine is as follows: 1-1.2: 1-1.5: 1.
3. The process for the synthesis of N- [2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide according to claim 1 characterized in that: the alkali in the step (1) is one or a mixture of two or more of potassium carbonate, sodium bicarbonate, sodium hydride, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide and sodium tert-butoxide.
4. The process for the synthesis of N- [2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide according to claim 1 characterized in that: the dosage of N, N-dimethylformamide is 100ml to 600ml of solvent for each mole of 2, 3-dichloro-5- (trifluoromethyl) pyridine.
5. The process for the synthesis of N- [2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide according to claim 1 characterized in that: the acid in the step (1) is one or a mixture of two or more of citric acid, p-toluenesulfonic acid, phosphoric acid, 10% hydrochloric acid and 5% sulfuric acid.
6. The process for the synthesis of N- [2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide according to claim 1 characterized in that: the condition of the concentrated hydrochloric acid in the step (2) is that 100ml to 150ml of concentrated hydrochloric acid is needed for each mole of 3-chloro-5- (trifluoromethyl) -2-acetonitrile pyridine.
7. The process for the synthesis of N- [2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide according to claim 1 characterized in that: the molar ratio of the raw materials 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine, alkali and 2- (trifluoromethyl) benzoyl chloride in the step (3) is as follows: 1-1.05: 1-1.5: 1.
8. The process for the synthesis of N- [2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide according to claim 1 characterized in that: the water used in the step (3) is 100ml to 300ml for each mol of 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine.
9. The process for the synthesis of N- [2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide according to claim 1 characterized in that: the acid-binding agent in the step (3) is one or a mixture of two or more of potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and triethylamine.
10. A process for the synthesis of N- [2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide according to claim 1 comprising the steps of:
step (1): adding ethyl cyanoacetate, N-dimethylformamide and triethylbenzylammonium chloride into a reaction bottle, adding potassium carbonate in batches under uniform stirring, then controlling the temperature to be 25 ℃, stirring for 0.5h, slowly dropwise adding 2, 3-dichloro-5- (trifluoromethyl) pyridine, heating to 70 ℃ for reaction for 1h after dropwise adding, stopping the reaction, filtering out insoluble substances, supplementing N, N-dimethylformamide, adjusting the pH value of the reaction mother liquor to be 2 by using 10% hydrochloric acid, separating out solids, heating to reflux reaction for 3h, stopping the reaction, carrying out reduced pressure distillation, collecting and recovering a solvent under the conditions of 110 ℃/133-266 Pa to obtain a reddish brown residue, namely 3-chloro-5- (trifluoromethyl) -2-acetonitrile, which is directly used for the next reaction without purification, wherein the raw materials of ethyl cyanoacetate, potassium carbonate and 2, the mol ratio of the 3-dichloro-5- (trifluoromethyl) pyridine is as follows: 1-1.2: 1-1.5: 1;
step (2): adding the 3-chloro-5- (trifluoromethyl) -2-acetonitrile pyridine prepared in the step (1), ethanol, 5 percent palladium-carbon and Raney nickel mixed catalyst 2 into a hydrogenation kettle, introducing hydrogen gas, heating to 80 deg.C under 0.2Mpa, stirring for reaction for 4 hr, stopping reaction, filtering to remove catalyst, distilling under reduced pressure, collecting the solvent at 70 ℃/133-266 Pa, adding the remainder into a reaction kettle, refluxing and reacting N, N-dimethyl under the condition of concentrated hydrochloric acid for 1h, stopping the reaction, extracting the reaction solution by using dichloromethane to remove an organic phase, collecting a water phase, adjusting the water phase to be neutral, extracting the water phase by using dichloromethane, combining the organic phases, the organic phase of the 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine is obtained, and the product is directly used for the next reaction without refining. The amount of the hydrogenation catalyst is 1 percent of 5 percent palladium carbon and 1 percent of Raney nickel;
and (3): adding the dichloromethane solution of 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine prepared in the step (2), triethylbenzyl ammonium chloride and water into a reaction kettle, controlling the temperature to be 0 ℃, adding potassium carbonate in batches, heating to 5 ℃, slowly dropwise adding 2- (trifluoromethyl) benzoyl chloride under vigorous stirring, keeping the temperature at 25 ℃ for 1h, stopping reaction, standing, layering, separating a water phase, collecting a dichloromethane organic phase, removing dichloromethane to obtain a solid, washing with water, performing suction filtration, and collecting a filter cake to obtain a white solid, namely the target product N- [2- [ 3-chloro-5- (trifluoromethyl) pyridine-2-yl ] ethyl ] -2- (trifluoromethyl) benzamide, the raw materials 3-chloro-5- (trifluoromethyl) -2-ethylamino pyridine, the raw materials, The molar ratio of base to 2- (trifluoromethyl) benzoyl chloride is: 1-1.05: 1-1.5: 1.
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| CN1674784A (en) * | 2002-08-12 | 2005-09-28 | 拜尔农科股份有限公司 | Novel 2-pyridylethylbenzamide derivative |
| CN109293565A (en) * | 2018-10-26 | 2019-02-01 | 江苏七洲绿色化工股份有限公司 | A kind of preparation method of fluopyram |
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| CN115636764A (en) * | 2022-11-08 | 2023-01-24 | 广东省科学院化工研究所 | Synthetic method of benzamide compound |
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