CN104926674A - (Z)-3-dimethylamino-2-phenoxy-alpha, beta-unsaturated amide and preparation method thereof - Google Patents
(Z)-3-dimethylamino-2-phenoxy-alpha, beta-unsaturated amide and preparation method thereof Download PDFInfo
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- dimethylamino
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 150000001408 amides Chemical class 0.000 title abstract 4
- -1 aniline compound Chemical class 0.000 claims abstract description 44
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 239000002904 solvent Substances 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- 229940126214 compound 3 Drugs 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 150000001409 amidines Chemical class 0.000 claims description 10
- 238000010025 steaming Methods 0.000 claims description 10
- 238000010898 silica gel chromatography Methods 0.000 claims description 9
- 150000001448 anilines Chemical class 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- REPVNSJSTLRQEQ-UHFFFAOYSA-N n,n-dimethylacetamide;n,n-dimethylformamide Chemical compound CN(C)C=O.CN(C)C(C)=O REPVNSJSTLRQEQ-UHFFFAOYSA-N 0.000 claims 4
- HWWYDZCSSYKIAD-UHFFFAOYSA-N 3,5-dimethylpyridine Chemical compound CC1=CN=CC(C)=C1 HWWYDZCSSYKIAD-UHFFFAOYSA-N 0.000 claims 2
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 claims 1
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 abstract description 13
- 238000000034 method Methods 0.000 abstract description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 abstract 2
- 239000007795 chemical reaction product Substances 0.000 abstract 2
- 229940113088 dimethylacetamide Drugs 0.000 abstract 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 13
- 239000012071 phase Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 10
- IMPPGHMHELILKG-UHFFFAOYSA-N 4-ethoxyaniline Chemical compound CCOC1=CC=C(N)C=C1 IMPPGHMHELILKG-UHFFFAOYSA-N 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 238000003760 magnetic stirring Methods 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 238000004064 recycling Methods 0.000 description 5
- 235000002639 sodium chloride Nutrition 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 2
- KYMRXTOEFJZXOB-AAKIMCHBSA-N ClC1=CC=C(O\C(\C(=O)NC2=CC=C(C=C2)OCC)=C/N(C)C)C=C1.C(C=C)(=O)N Chemical compound ClC1=CC=C(O\C(\C(=O)NC2=CC=C(C=C2)OCC)=C/N(C)C)C=C1.C(C=C)(=O)N KYMRXTOEFJZXOB-AAKIMCHBSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- HZMHLKQFPHEMKQ-UHFFFAOYSA-N [O].C(C)(=O)Cl Chemical compound [O].C(C)(=O)Cl HZMHLKQFPHEMKQ-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 229940059260 amidate Drugs 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 150000003857 carboxamides Chemical class 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
- 239000012434 nucleophilic reagent Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- WINDXPMAARBVOY-UHFFFAOYSA-N 1-butyltellanylbutane Chemical compound CCCC[Te]CCCC WINDXPMAARBVOY-UHFFFAOYSA-N 0.000 description 1
- JUIKUQOUMZUFQT-UHFFFAOYSA-N 2-bromoacetamide Chemical compound NC(=O)CBr JUIKUQOUMZUFQT-UHFFFAOYSA-N 0.000 description 1
- PKUPAJQAJXVUEK-UHFFFAOYSA-N 2-phenoxyacetyl chloride Chemical compound ClC(=O)COC1=CC=CC=C1 PKUPAJQAJXVUEK-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- YKLZQTOZWPEVHV-NYAKATHWSA-N CN(\C=C(\C(=O)NC1=CC=C(C=C1)OCC)/OC1=CC=CC=C1)C.C(C=C)(=O)N Chemical compound CN(\C=C(\C(=O)NC1=CC=C(C=C1)OCC)/OC1=CC=CC=C1)C.C(C=C)(=O)N YKLZQTOZWPEVHV-NYAKATHWSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 230000002082 anti-convulsion Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 238000005447 aza-Wittig reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- YRNNKGFMTBWUGL-UHFFFAOYSA-L copper(ii) perchlorate Chemical compound [Cu+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O YRNNKGFMTBWUGL-UHFFFAOYSA-L 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 235000019633 pungent taste Nutrition 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 229930185107 quinolinone Natural products 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Abstract
The invention discloses a (Z)-3-dimethylamino-2-phenoxy-alpha, beta-unsaturated amide and a preparation method thereof. The preparation method comprises a first reaction step of reacting an aniline compound I with DMF (Dimethyl Formamide)-DMA (Dimethyl Acetamide) (N,N-dimethyl formamide dimethyl acetal) at an appropriate temperature and in a corresponding solvent, wherein after the reaction product is purified, corresponding aromatic amidine 2 is generated; a second reaction step of reacting the generated corresponding aromatic amidine 2 with a compound 3 in existence of appropriate temperature, appropriate solvent and alkali, wherein after the reaction product is purified, a compound 4, i.e. the (Z)-3-dimethylamino-2-phenoxy-alpha, beta-unsaturated amide is generated. The invention provides the method for preparing the (Z)-3-dimethylamino-2-phenoxy-alpha, beta-unsaturated amide by high selective reaction, and the reaction process is simple, the preparation method is low in cost, safe and environment friendly.
Description
Technical field
The invention belongs to the synthesis technical field of amides organic compound, be specifically related to one (Z)-3-dimethylamino-2-phenoxy group-α, beta-unsaturated acyl amine and preparation method thereof.
Background technology
α is contained, beta-unsaturated acyl amine in many medicines and agricultural chemicals.Such as anticonvulsion, antidepressant, anti-female hormone, pain relieving and germ resistance etc., α, beta-unsaturated acyl amine is also widely used in the key areas such as agricultural, materials industry.α, beta-unsaturated acyl aminated compounds, with its multi-functional constructional feature, has become the intermediate that in organic synthesis, a class is important, may be used for preparing the multiple heterocycles compounds such as quinoline, quinolinone, furans, piperidone, pyridine, pyridone, pyrroles.In general, α, the reaction of beta-unsaturated acyl aminated compounds mainly contains: with the reaction of electrophilic reagent, with the reaction of nucleophilic reagent, electrocyclic reaction, reduction and oxidizing reaction.From structure, this α, the existing nucleophilicity of beta-unsaturated acyl amine also has Electron Affinities, not only can react with nucleophilic reagent but also can react with electrophilic reagent.
α, the preparation method of beta-unsaturated acyl aminated compounds, patent 1 (United States Patent (USP) the 2nd, 451, No. 436), 2(Japanese Unexamined Patent Publication 4-208258 publication) and 3 (Japanese Unexamined Patent Publication 6-199752 publications) disclose the method for N,N-DMAA using acrylate.But, in this method, not only need vinylformic acid to carry out esterification, but also need the step ester group of gained ester cpds being converted into amide group.Usually, by ester group in the conversion of amide group, need the polyol compounds such as glycerol as solvent, therefore need the step be separated from solvent by resultant after the completion of reaction.Therefore, in yield, expense, there is too high problem.
In prior art, other prepares α, and the method for beta-unsaturated acyl amine is: first unsaturated acid is made acyl chlorides, and then obtains product with secondary amine amidate action.Produce that acyl chlorides generally needs to use that oxalyl chloride, phosphorus trichloride, phosphorus oxychloride or sulfur oxychloride etc. are volatile by unsaturated acid, pungency and corrodibility is strong, toxicity is larger pharmaceutical chemicals, not only environment is produced and pollute, and too increase the difficulty of the abstraction and purification in production process.Saturated amide compound can at α; α is prepared in the dehydration of β position; beta-unsaturated acyl amine compound; such as; patent CN1826314 A(2006) disclose a kind of α; the preparation method of beta-unsaturated acyl amine compound; first blocking group is introduced saturated amide compound; dewater under the existence of dehydrogenation catalyst and applicable oxygenant, react and form double bond; finally remove blocking group and obtain final product; but needed for whole reaction process, chemical reagent is many, long reaction time, complicated condition.
2013 European organic chemistry magazine [(Eur.J.0rg.Chem., 2013 (7): 1218)] report and use cupric perchlorate catalysis phenylformic acid and Carbox amide synthesis acid amide compounds.But this catalyst system to substrate requirements high and reaction needed carry out under the high temperature of 100 ° of C.
2014 Chinese patent CN103232357B have reported one and have prepared α, the method of beta-unsaturated acyl amine, in an inert atmosphere, with cinnamic acid compound and Carbox amide for reactant, with molysite and oxygenant for catalyst system, product α is prepared, beta-unsaturated acyl amine by amidate action.The method not only uses various molysite as catalyzer, but also needs tertbutyl peroxide etc. to be oxygenant.
Huang Zhizhen, Wu Luling are at Chin. J. Org. Chem., and 1996,16 (4): 340-343 report (E)-α, the Stereo-selective synthesis of beta-unsaturated acyl amine.This method is that under Jin Shu Palladium and dibutyl tellurid effect, bromo acetamide and aldehyde generate target compound by azaWittig reaction.
Summary of the invention
The object of the present invention is to provide one (Z)-3-dimethylamino-2-phenoxy group-α, beta-unsaturated acyl amine and preparation method thereof, to solve the problems of the technologies described above.
For achieving the above object, the technical solution used in the present invention is:
A kind of (Z)-3-dimethylamino-2-phenoxy group-α, beta-unsaturated acyl amine is compound 4 in following general formula:
Wherein: in amino benzenes compounds 1, R
1for independently-H ,-F ,-Cl ,-Br ,-I ,-CN ,-NO
2,-OH ,-CO
2me ,-CO
2et ,-CONHMe ,-CONHEt, C
1-C
6alkyl; R
2for independently-H ,-F ,-OH ,-CN; R
3for independently-H ,-CN ,-NO
2;
In compound 3: R
4for-H ,-Cl.
A kind of (Z)-3-dimethylamino-2-phenoxy group-α, the preparation method of beta-unsaturated acyl amine, comprise the following steps: the reaction the first step, in proper temperature and coordinative solvent, with amino benzenes compounds 1 and DMF-DMA(N, dinethylformamide dimethylacetal) react and the corresponding fragrant amidine 2 of purified rear generation; Reaction second step, reacts the corresponding fragrant amidine 2 of generation with compound 3 in proper temperature, appropriate solvent and under the existence of alkali and purified rear generation compound 4, i.e. (Z)-3-dimethylamino-2-phenoxy group-α, beta-unsaturated acyl amine.
As the further scheme of the present invention: the proper temperature in the described reaction the first step refers to 20 – 80 DEG C, coordinative solvent refers to any one of methylene dichloride, 1,2-ethylene dichloride, tetracol phenixin, chloroform, tetrahydrofuran (THF).
As the further scheme of the present invention: the proper temperature in described reaction second step is room temperature--to 68
oc; Appropriate solvent be methylene dichloride, 1,2-ethylene dichloride, tetracol phenixin, chloroform, tetrahydrofuran (THF) any one.
As the further scheme of the present invention: the alkali in described reaction second step refers to sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, sodium hydroxide, potassium hydroxide, sodium phosphate, sodium hydride, potassium tert.-butoxide, triethylamine, diisopropylethylamine, pyridine, 3, any one of 5-lutidine, 4-N, N-lutidine, DBU.
As the further scheme of the present invention: described fragrant amidine 2 is 1:1 3 with the mol ratio of compound 3.
As the further scheme of the present invention: amino benzenes compounds 1 and DMF-DMA(N, dinethylformamide dimethylacetal) mol ratio be 1: 1 ~ 30.
As the further scheme of the present invention: in the described reaction the first step fragrant amidine 2 purification process for revolve steam removing DMF-DMA(N, dinethylformamide dimethylacetal) solvent, recrystallization, silica gel column chromatography.
As the further scheme of the present invention: compound 4 in described reaction second step, i.e. (Z)-3-dimethylamino-2-phenoxy group-α, beta-unsaturated acyl amine purification process is for steaming solvent, recrystallization, silica gel column chromatography, underpressure distillation.
As the further scheme of the present invention: the reaction the first step, amino benzenes compounds 1 and DMF-DMA reaction times are 2-24 hour; Corresponding for generation fragrant amidine 2 and compound 3 reaction times are 6-36 hour by reaction second step.
Beneficial effect of the present invention is: a kind of highly selective reaction preparation one class (Z)-3-dimethylamino-2-phenoxy group-α provided by the invention, and method, the reaction process of beta-unsaturated acyl amine are simple, and expense is low, and safety, environmental protection.
Embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated.
Embodiment 1
4-phenetidine 27.4 grams (0.2 mole) and DMF dimethylacetal 35.7 grams (0.3 mole) is added in 100 milliliters of single necked round bottom flask.Add methylene dichloride (30 milliliters) as solvent and a magneton, reaction mixture at room temperature stirs 5 hours.TLC analyzes and shows that 4-phenetidine disappears and has new dot generation.Revolve and steam removing methylene dichloride, methyl alcohol and excessive N, after dinethylformamide dimethylacetal (recyclable and be used further in preparation feedback) a sticky oil thing be (E)-N '-(4-phenelyl)-N, N-dimethylamino carbonamidine, 37.6 grams, productive rate 98%.
1H NMR (CDCl
3), 300 MHz (
δppm ): 7.93 (1H, s), 7.47 (2H, d), 7.01(2H, d), 3.76 (2H, q), 2.95 (3H, s), 2.98 (3H, s), 1.37(3H, t); MS: m/z（M+1） 193.01。
By (E)-N '-(4-phenelyl)-N, N-dimethylamino carbonamidine (3.84 grams, 0.02 mole), methylene dichloride (20 milliliters), triethylamine (4.17 milliliters, 3.03 gram, 0.03 mole) and a magneton join in the single necked round bottom flask of 50 milliliters, start magnetic stirring apparatus, then slowly drip 2-phenoxyacetyl chloride (5.12 grams with syringe, 0.03 mole), whole dropping process lasts about 15 minutes.After dripping, reaction mixture is at room temperature stirred and spends the night.Revolve and steam except desolventizing.Then in reaction flask, add ethyl acetate (20 milliliters) and water (20 milliliters) and stir 10 minutes, being transferred in a separating funnel, separate lower floor's inorganic phase.Inorganic phase ethyl acetate (10 milliliters) extracts.Merge organic phase and wash with saturated aqueous common salt (20 milliliters) and water (20 milliliters).Organic phase anhydrous sodium sulfate drying.Revolve after steaming recycling design, residue over silica gel column chromatography (ethyl acetate/normal hexane: 1:5) obtains product (Z)-3-(dimethylamino)-N-(4-phenelyl)-2-phenoxy group acrylamide [(Z)-3-(dimethylamino)-N-(4-ethoxyphenyl)-2-phenoxyacrylamide] 3.07 grams, productive rate 47%.
1H NMR (CDCl
3), 300 MHz (
δppm ): 9.89 (1H, s), 7.49 (2H, m), 7.29(2H, m), 7.04(1H, m), 6.96(2H, m), 6.82 (2H, m), 6.49 (1H, s), 3.75 (2H, q), 2.99 (3H, s), 3.02 (3H, s), 1.36 (3H, t); MS: m/z（M+1） 327.10。
Embodiment 2
4-phenetidine 54.8 grams (0.4 mole) and DMF dimethylacetal 86 grams (0.5 mole) is added in 250 milliliters of single necked round bottom flask.Add tetrahydrofuran (THF) (100 milliliters) as solvent and a magneton, reaction mixture at room temperature stirs and spends the night.TLC analyzes and shows that 4-phenetidine disappears and has new dot generation.Revolve and to steam after removing tetrahydrofuran (THF), methyl alcohol and excessive DMF dimethylacetal (recyclable and be used further in preparation feedback) to obtain a sticky oil thing.Ethyl acetate (80 milliliters) and water (50 milliliters) to be joined in above-mentioned reaction flask and to transfer to after being stirred 10 minutes in a separating funnel.Release lower floor's inorganic phase.Organic phase anhydrous sodium sulfate drying.Product (E)-N '-(4-phenelyl)-N, N-dimethylamino carbonamidine is obtained, 71.3 grams, productive rate 92% after revolving steaming.
By (E)-N '-(4-phenelyl)-N, N-dimethylamino carbonamidine (38.4 grams, 0.2 mole), chloroform (250 milliliters), triethylamine (41.7 milliliters, 30.3 grams 0.3 mole) and a magneton join in the single necked round bottom flask of 500 milliliters, start magnetic stirring apparatus, then 2-phenol oxygen Acetyl Chloride 98Min. (51.2 grams, 0.3 mole) is slowly dripped, whole dropping process lasts about 25 minutes with syringe.After dripping, reaction mixture is at room temperature stirred and spends the night.Revolve and steam except desolventizing.Then in reaction flask, add ethyl acetate (100 milliliters) and water (60 milliliters) and stir 10 minutes, being transferred in a separating funnel, separate lower floor's inorganic phase.Inorganic phase ethyl acetate (80 milliliters) extracts.Merge organic phase and wash with saturated aqueous common salt (80 milliliters) and water (80 milliliters).Organic phase anhydrous sodium sulfate drying.Revolve after steaming recycling design, residue over silica gel column chromatography (ethyl acetate/normal hexane: 1:5) obtains product (Z)-3-(dimethylamino)-N-(4-phenelyl)-2-phenoxy group acrylamide 27.2 grams, productive rate 42%.
Embodiment 3
4-phenetidine 27.4 grams (0.2 mole) and DMF dimethylacetal 35.7 grams (0.3 mole) is added in 100 milliliters of single necked round bottom flask.Add methylene dichloride (30 milliliters) as solvent and a magneton, reaction mixture at room temperature stirs 5 hours.TLC analyzes and shows that 4-phenetidine disappears and has new dot generation.Revolve and steam removing methylene dichloride, methyl alcohol and excessive N, after dinethylformamide dimethylacetal (recyclable and be used further in preparation feedback) a sticky oil thing be (E)-N '-(4-phenelyl)-N, N-dimethylamino carbonamidine, 37.6 grams, productive rate 98%.
1H NMR (CDCl
3), 300 MHz (
δppm ): 7.93 (1H, s), 7.47 (2H, d), 7.01(2H, d), 3.76 (2H, q), 2.95 (3H, s), 2.98 (3H, s), 1.37(3H, t); MS: m/z（M+1） 193.01。
By (E)-N '-(4-phenelyl)-N, N-dimethylamino carbonamidine (38.4 grams, 0.2 mole), chloroform (250 milliliters), triethylamine (41.7 milliliters, 30.3 grams 0.3 mole) and a magneton join in the single necked round bottom flask of 500 milliliters, at 40 DEG C, start magnetic stirring apparatus, then slowly drip 2-phenol oxygen Acetyl Chloride 98Min. (51.2 grams with syringe, 0.3 mole), whole dropping process lasts about 30 minutes.After dripping, reaction mixture is at room temperature stirred and spends the night.Revolve and steam except desolventizing.Then in reaction flask, add ethyl acetate (100 milliliters) and water (60 milliliters) and stir 10 minutes, being transferred in a separating funnel, separate lower floor's inorganic phase.Inorganic phase ethyl acetate (80 milliliters) extracts.Merge organic phase and wash with saturated aqueous common salt (80 milliliters) and water (80 milliliters).Organic phase anhydrous sodium sulfate drying.Revolve after steaming recycling design, residue over silica gel column chromatography (ethyl acetate/normal hexane: 1:5) obtains product (Z)-3-(dimethylamino)-N-(4-phenelyl)-2-phenoxy group acrylamide 29.8 grams, productive rate 45.7%.
Embodiment 4
4-phenetidine 54.8 grams (0.4 mole) and DMF dimethylacetal 86 grams (0.5 mole) is added in 250 milliliters of single necked round bottom flask.Add tetrahydrofuran (THF) (100 milliliters) as solvent and a magneton, reaction mixture at room temperature stirs and spends the night.TLC analyzes and shows that 4-phenetidine disappears and has new dot generation.Revolve and to steam after removing tetrahydrofuran (THF), methyl alcohol and excessive DMF dimethylacetal (recyclable and be used further in preparation feedback) to obtain a sticky oil thing.Ethyl acetate (80 milliliters) and water (50 milliliters) to be joined in above-mentioned reaction flask and to transfer to after being stirred 10 minutes in a separating funnel.Release lower floor's inorganic phase.Organic phase anhydrous sodium sulfate drying.Product (E)-N '-(4-phenelyl)-N, N-dimethylamino carbonamidine is obtained, 71.3 grams, productive rate 92% after revolving steaming.
By (E)-N '-(4-phenelyl)-N, N-dimethylamino carbonamidine (3.84 grams, 0.02 mole), methylene dichloride (20 milliliters), triethylamine (4.17 milliliters, 0.03 mole) and a magneton join in the single necked round bottom flask of 50 milliliters, start magnetic stirring apparatus, then 2-(4 '-chlorobenzene oxygen) Acetyl Chloride 98Min. (6.15,0.03 mole) is slowly dripped, whole dropping process lasts about 15 minutes with syringe.After dripping, reaction mixture is at room temperature stirred and spends the night.Revolve and steam except desolventizing.Then in reaction flask, add ethyl acetate (20 milliliters) and water (20 milliliters) and stir 10 minutes, being transferred in a separating funnel, separate lower floor's inorganic phase.Inorganic phase ethyl acetate (10 milliliters) extracts.Merge organic phase and wash with saturated aqueous common salt (20 milliliters) and water (20 milliliters).Organic phase anhydrous sodium sulfate drying.Revolve after steaming recycling design, residue over silica gel column chromatography (ethyl acetate/normal hexane: 1:5) product (Z)-2-(4 '-chlorophenoxy)-3-dimethylamino)-N-(4 '-phenelyl) acrylamide [(Z)-2-(4-chlorophenoxy)-3-(dimethylamino)-N-(4-ethoxyphenyl) acrylamide] 3.17 grams, productive rate 44%.
1H NMR (CDCl
3), 300 MHz (
δppm ): 9.91 (1H, s), 7.58 (2H, m), 7.49 (2H, m), 6.96 (2H, m), 6.82 (2H, m), 6.49 (1H, s), 3.75 (2H, q), 2.99 (3H, s), 3.02 (3H, s), 1.36 (3H, t);MS: m/z（M+1） 361.10。
Embodiment 5
4-phenetidine 54.8 grams (0.4 mole) and DMF dimethylacetal 86 grams (0.5 mole) is added in 250 milliliters of single necked round bottom flask.Add tetrahydrofuran (THF) (100 milliliters) as solvent and a magneton, reaction mixture at room temperature stirs and spends the night.TLC analyzes and shows that 4-phenetidine disappears and has new dot generation.Revolve and to steam after removing tetrahydrofuran (THF), methyl alcohol and excessive DMF dimethylacetal (recyclable and be used further in preparation feedback) to obtain a sticky oil thing.Ethyl acetate (80 milliliters) and water (50 milliliters) to be joined in above-mentioned reaction flask and to transfer to after being stirred 10 minutes in a separating funnel.Release lower floor's inorganic phase.Organic phase anhydrous sodium sulfate drying.Product (E)-N '-(4-phenelyl)-N, N-dimethylamino carbonamidine is obtained, 71.3 grams, productive rate 92% after revolving steaming.
By (E)-N '-(4-phenelyl)-N, N-dimethylamino carbonamidine (3.84 grams, 0.02 mole), methylene dichloride (20 milliliters), triethylamine (4.17 milliliters, 0.03 mole) and a magneton join in the single necked round bottom flask of 50 milliliters, start magnetic stirring apparatus, less than 35 DEG C, slowly drip 2-(4 '-chlorobenzene oxygen) Acetyl Chloride 98Min. (6.15 with syringe, 0.03 mole), whole dropping process lasts about 30 minutes.Reaction mixture is at room temperature stirred and spends the night.Revolve and steam except desolventizing.Then in reaction flask, add ethyl acetate (20 milliliters) and water (20 milliliters) and stir 10 minutes, being transferred in a separating funnel, separate lower floor's inorganic phase.Inorganic phase ethyl acetate (10 milliliters) extracts.Merge organic phase and wash with saturated aqueous common salt (20 milliliters) and water (20 milliliters).Organic phase anhydrous sodium sulfate drying.Revolve after steaming recycling design, residue over silica gel column chromatography (ethyl acetate/normal hexane: 1:5) obtains product (Z)-2-(-4 '-chlorobenzene oxygen)-3-(dimethylamino)-phenelyl) acrylamide [(Z)-2-(4-chlorophenoxy)-3-(dimethylamino)-N-(4-ethoxyphenyl) acrylamide] 4.97 grams, productive rate 69%.
Obviously, embodiment described above is only the present invention's part embodiment, instead of whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art, not making the every other embodiment obtained under creative work prerequisite, belong to the scope of protection of the invention.
Claims (10)
1. (Z)-3-dimethylamino-2-phenoxy group-α, beta-unsaturated acyl amine, is characterized in that, is compound 4 in following general formula:
Wherein: in amino benzenes compounds 1, R
1for independently-H ,-F ,-Cl ,-Br ,-I ,-CN ,-NO
2,-OH ,-CO
2me ,-CO
2et ,-CONHMe ,-CONHEt, C
1-C
6alkyl; R
2for independently-H ,-F ,-OH ,-CN; R
3for independently-H ,-CN ,-NO
2;
In compound 3: R
4for-H ,-Cl.
2. (Z)-3-dimethylamino-2-phenoxy group-α as claimed in claim 1, the preparation method of beta-unsaturated acyl amine, it is characterized in that, comprise the following steps: the reaction the first step, in proper temperature and coordinative solvent, to react to DMF-DMA with amino benzenes compounds 1 and the corresponding fragrant amidine 2 of purified rear generation; Reaction second step, reacts the corresponding fragrant amidine 2 of generation with compound 3 in proper temperature, appropriate solvent and under the existence of alkali and purified rear generation compound 4, i.e. (Z)-3-dimethylamino-2-phenoxy group-α, beta-unsaturated acyl amine.
3. one according to claim 2 (Z)-3-dimethylamino-2-phenoxy group-α, the preparation method of beta-unsaturated acyl amine, it is characterized in that: the proper temperature in the described reaction the first step refers to 20 – 80 DEG C, coordinative solvent refers to any one of methylene dichloride, 1,2-ethylene dichloride, tetracol phenixin, chloroform, tetrahydrofuran (THF).
4. one according to claim 2 (Z)-3-dimethylamino-2-phenoxy group-α, the preparation method of beta-unsaturated acyl amine, is characterized in that: the proper temperature in described reaction second step is room temperature--to 68
oc; Appropriate solvent be methylene dichloride, 1,2-ethylene dichloride, tetracol phenixin, chloroform, tetrahydrofuran (THF) any one.
5. one according to claim 2 (Z)-3-dimethylamino-2-phenoxy group-α, the preparation method of beta-unsaturated acyl amine, it is characterized in that, alkali in described reaction second step refers to sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, sodium hydroxide, potassium hydroxide, sodium phosphate, sodium hydride, potassium tert.-butoxide, triethylamine, diisopropylethylamine, pyridine, 3,5-lutidine, 4-N, N-lutidine, DBU any one.
6. one according to claim 2 (Z)-3-dimethylamino-2-phenoxy group-α, the preparation method of beta-unsaturated acyl amine, is characterized in that, described fragrant amidine 2 is 1:1 3 with the mol ratio of compound 3.
7. one according to claim 2 (Z)-3-dimethylamino-2-phenoxy group-α, the preparation method of beta-unsaturated acyl amine, is characterized in that, amino benzenes compounds 1 is 1: 1 ~ 30 with the mol ratio of DMF-DMA.
8. one according to claim 2 (Z)-3-dimethylamino-2-phenoxy group-α, the preparation method of beta-unsaturated acyl amine, it is characterized in that, in the described reaction the first step, the purification process of fragrant amidine 2 steams removing DMF-DMA solvent, recrystallization, silica gel column chromatography for revolving.
9. one according to claim 2 (Z)-3-dimethylamino-2-phenoxy group-α, the preparation method of beta-unsaturated acyl amine, it is characterized in that, compound 4 in described reaction second step, i.e. (Z)-3-dimethylamino-2-phenoxy group-α, beta-unsaturated acyl amine purification process is for steaming solvent, recrystallization, silica gel column chromatography, underpressure distillation.
10. one according to claim 2 (Z)-3-dimethylamino-2-phenoxy group-α, the preparation method of beta-unsaturated acyl amine, is characterized in that, the reaction the first step, and amino benzenes compounds 1 and DMF-DMA reaction times are 2-24 hour; Corresponding for generation fragrant amidine 2 and compound 3 reaction times are 6-36 hour by reaction second step.
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| CN105503644A (en) * | 2015-12-21 | 2016-04-20 | 刘雪静 | (Z)-3-benzylamino-2-phenoxy-alpha,beta-unsaturated acrylic arylamine and preparing method thereof |
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| CN105503643A (en) * | 2015-12-21 | 2016-04-20 | 刘雪静 | (Z)-3-benzyl alkyl ammonia-2-phenoxy-alpha,beta-unsaturated acrylic arylamine and preparing method thereof |
| CN105503644A (en) * | 2015-12-21 | 2016-04-20 | 刘雪静 | (Z)-3-benzylamino-2-phenoxy-alpha,beta-unsaturated acrylic arylamine and preparing method thereof |
| CN105503644B (en) * | 2015-12-21 | 2017-06-20 | 枣庄学院 | It is a kind of（Z）3 benzyl amino 2 phenoxy group α, β unsaturation acryloyl arylamine and preparation method thereof |
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