CN110003093A - The method that bis cyclopentadienyl zirconium dichloride cooperates with benzoic acids ligand catalysis synthesis 1,4- dihydrogen pyridine derivative - Google Patents
The method that bis cyclopentadienyl zirconium dichloride cooperates with benzoic acids ligand catalysis synthesis 1,4- dihydrogen pyridine derivative Download PDFInfo
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- benzoic acids
- zirconium dichloride
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- cyclopentadienyl zirconium
- bis cyclopentadienyl
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- 239000003446 ligand Substances 0.000 title claims abstract description 25
- 235000010233 benzoic acid Nutrition 0.000 title claims abstract description 23
- 150000001559 benzoic acids Chemical class 0.000 title claims abstract description 23
- QMBQEXOLIRBNPN-UHFFFAOYSA-L zirconocene dichloride Chemical compound [Cl-].[Cl-].[Zr+4].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 QMBQEXOLIRBNPN-UHFFFAOYSA-L 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title claims abstract description 18
- 238000006555 catalytic reaction Methods 0.000 title claims abstract description 14
- 230000015572 biosynthetic process Effects 0.000 title abstract description 9
- 238000003786 synthesis reaction Methods 0.000 title abstract description 9
- -1 enamine ester Chemical class 0.000 claims abstract description 44
- XVMIKRZPDSXBTP-UHFFFAOYSA-N 1,3-dibromobutan-2-one Chemical compound CC(Br)C(=O)CBr XVMIKRZPDSXBTP-UHFFFAOYSA-N 0.000 claims abstract description 12
- IZZIWIAOVZOBLF-UHFFFAOYSA-N 5-methoxysalicylic acid Chemical compound COC1=CC=C(O)C(C(O)=O)=C1 IZZIWIAOVZOBLF-UHFFFAOYSA-N 0.000 claims abstract description 8
- LWFUFLREGJMOIZ-UHFFFAOYSA-N 3,5-dinitrosalicylic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1O LWFUFLREGJMOIZ-UHFFFAOYSA-N 0.000 claims abstract description 5
- AAUQLHHARJUJEH-UHFFFAOYSA-N 2-hydroxy-5-methoxybenzoic acid Natural products COC1=CC=CC(O)=C1C(O)=O AAUQLHHARJUJEH-UHFFFAOYSA-N 0.000 claims abstract description 4
- KFIRODWJCYBBHY-UHFFFAOYSA-N 3-nitrophthalic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1C(O)=O KFIRODWJCYBBHY-UHFFFAOYSA-N 0.000 claims abstract description 4
- SLBQXWXKPNIVSQ-UHFFFAOYSA-N 4-nitrophthalic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1C(O)=O SLBQXWXKPNIVSQ-UHFFFAOYSA-N 0.000 claims abstract description 4
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 claims description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical group ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 235000019441 ethanol Nutrition 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 7
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims 2
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 claims 1
- 125000003963 dichloro group Chemical group Cl* 0.000 claims 1
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims 1
- 150000003222 pyridines Chemical class 0.000 claims 1
- 229960004889 salicylic acid Drugs 0.000 claims 1
- 229910052726 zirconium Inorganic materials 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 13
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 abstract description 9
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 abstract description 9
- 229930016911 cinnamic acid Natural products 0.000 abstract description 9
- 235000013985 cinnamic acid Nutrition 0.000 abstract description 9
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 abstract description 9
- 239000003054 catalyst Substances 0.000 abstract description 6
- 239000000047 product Substances 0.000 abstract description 4
- 239000007795 chemical reaction product Substances 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 3
- 238000000926 separation method Methods 0.000 abstract description 3
- 238000004440 column chromatography Methods 0.000 abstract description 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 60
- 125000004494 ethyl ester group Chemical group 0.000 description 28
- 239000002253 acid Substances 0.000 description 25
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 16
- 238000002360 preparation method Methods 0.000 description 16
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- 238000010189 synthetic method Methods 0.000 description 9
- 150000004702 methyl esters Chemical class 0.000 description 5
- UJHSIDUUJPTLDY-UHFFFAOYSA-N (2-nitrophenyl)-phenylmethanone Chemical compound [O-][N+](=O)C1=CC=CC=C1C(=O)C1=CC=CC=C1 UJHSIDUUJPTLDY-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- ZYMCBJWUWHHVRX-UHFFFAOYSA-N (4-nitrophenyl)-phenylmethanone Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(=O)C1=CC=CC=C1 ZYMCBJWUWHHVRX-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- XYRAWLRFGKLUMW-OWOJBTEDSA-N (e)-3-(4-bromophenyl)prop-2-enal Chemical compound BrC1=CC=C(\C=C\C=O)C=C1 XYRAWLRFGKLUMW-OWOJBTEDSA-N 0.000 description 2
- ALGQVMMYDWQDEC-OWOJBTEDSA-N (e)-3-(4-nitrophenyl)prop-2-enal Chemical compound [O-][N+](=O)C1=CC=C(\C=C\C=O)C=C1 ALGQVMMYDWQDEC-OWOJBTEDSA-N 0.000 description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 239000007848 Bronsted acid Substances 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000004799 bromophenyl group Chemical group 0.000 description 2
- IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- IAQRGUVFOMOMEM-ONEGZZNKSA-N trans-but-2-ene Chemical compound C\C=C\C IAQRGUVFOMOMEM-ONEGZZNKSA-N 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 2
- HONRSHHPFBMLBT-OWOJBTEDSA-N (e)-3-(4-chlorophenyl)prop-2-enal Chemical compound ClC1=CC=C(\C=C\C=O)C=C1 HONRSHHPFBMLBT-OWOJBTEDSA-N 0.000 description 1
- VMSMELHEXDVEDE-HWKANZROSA-N 2-nitrocinnamaldehyde Chemical compound [O-][N+](=O)C1=CC=CC=C1\C=C\C=O VMSMELHEXDVEDE-HWKANZROSA-N 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 238000003445 Hantzsch reaction Methods 0.000 description 1
- 229910021617 Indium monochloride Inorganic materials 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 239000002879 Lewis base Substances 0.000 description 1
- WTHPMQSFSPASLP-YVMONPNESA-N N-[(Z)-but-2-en-2-yl]butan-1-amine Chemical compound C/C(=C/C)/NCCCC WTHPMQSFSPASLP-YVMONPNESA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910001914 chlorine tetroxide Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- ZMMRKRFMSDTOLV-UHFFFAOYSA-N cyclopenta-1,3-diene zirconium Chemical compound [Zr].C1C=CC=C1.C1C=CC=C1 ZMMRKRFMSDTOLV-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- APHGZSBLRQFRCA-UHFFFAOYSA-M indium(1+);chloride Chemical compound [In]Cl APHGZSBLRQFRCA-UHFFFAOYSA-M 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 239000011968 lewis acid catalyst Substances 0.000 description 1
- 150000007527 lewis bases Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- AXCXHFKZHDEKTP-UHFFFAOYSA-N para-methoxycinnamaldehyde Natural products COC1=CC=C(C=CC=O)C=C1 AXCXHFKZHDEKTP-UHFFFAOYSA-N 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a kind of bis cyclopentadienyl zirconium dichloride collaboration benzoic acids ligand catalysis synthesis 1, the method of 4- dihydrogen pyridine derivative, using bis cyclopentadienyl zirconium dichloride as catalyst, 3- nitrophthalic acid, 4- nitrophthalic acid, 5- methoxysalicylic acid, 5-NITROSALICYLIC ACID, 3,5- dinitrosalicylic acid etc. is used as ligand, so that enamine ester and cinnamic acid is carried out intermolecular cyclization and generates Isosorbide-5-Nitrae-dihydrogen pyridine derivative.Reaction condition of the present invention is mild, easy to operate, and the reaction time is short, reaction product is single, and Atom economy is high, only product need to be passed through simple column chromatography for separation after reaction, it can higher Isosorbide-5-Nitrae-dihydrogen pyridine derivative of the yield acquisition with extensive bioactivity and medical value.
Description
Technical field
The invention belongs to Isosorbide-5-Nitrae-dihydropyridine synthesis technical fields, and in particular to a kind of bis cyclopentadienyl zirconium dichloride collaboration benzoic acids
The method of ligand catalysis synthesis 1,4- dihydrogen pyridine derivative.
Background technique
Isosorbide-5-Nitrae-dihydropyridine (Isosorbide-5-Nitrae-DHPs) derivative has pharmacology abundant and biological characteristics, is widely present in natural
In product, in addition, synthetic intermediate useful, widely used in they or organic chemistry.Therefore, for Isosorbide-5-Nitrae-dihydro pyrrole
The synthesis of piperidine derivatives just has extensive research.The symmetrical foremost method of 1,4- dihydropyridine is prepared as classics
Hantzch synthetic method: condensation reaction occurs for two molecule β-carbonyl acid esters and a molecule aldehyde and a molecules of ammonia, obtains dihydropyridine and spreads out
Biology.Although Hantzsch reacts highly useful in the synthesis of dihydropyridine, N- aryl-Isosorbide-5-Nitrae-dihydropyridine and C5~
C6Unsubstituted 1,4- dihydropyridine cannot be synthesized by Hantzsch reaction scheme.Therefore, because these compounds is medicinal
Value and synthesis value, many scientists all over the world are making great efforts to develop other synthetic methods, these methods use
Miscellaneous catalyst, including lewis acid catalyst, such as FeCl3、Sc(OTf)3、Mg(ClO4)2、InCl、Cu
(OTf)2Deng；Bronsted acid catalyst, such as synthesize phosphoric acid, trifluoroacetic acid (TFA), trifluoromethanesulfonic acid (TfOH), L-PROLINE,
Cellulose sulfate (CAS), lactic acid (LA) etc..Certainly, lewis base or bronsted alkali can also be used as catalyst and is applied to conjunction
In reaction.
Although lewis acid has very big application in terms of being catalyzed the synthesis of Isosorbide-5-Nitrae-dihydrogen pyridine derivative, sometimes
But face severe reaction conditions, reaction selectivity are poor, reaction efficiency is low, substrate applicability is weak, solvent not environmentally the problems such as, Blang
This special acid is more stable for lewis acid, cheap, but is synthesizing Isosorbide-5-Nitrae-dihydropyridine compound sometimes
The defects of catalyst need to be prefabricated in advance, reaction step is more can be faced.And if both acid can be combined, it is sour excellent using two kinds
Gesture, the shortcomings that avoiding them, pass through the synergistic effect of lewis acid and bronsted acid and realize Isosorbide-5-Nitrae-dihydrogen pyridine derivative
Synthesis further increases the selectivity of reaction efficiency and reaction, improves Atom economy, develops easy, efficient, environmental-friendly
Synthetic method synthesizes Isosorbide-5-Nitrae-dihydrogen pyridine derivative, it will provides more choosings for Isosorbide-5-Nitrae-dihydrogen pyridine derivative synthetic method
It selects, new development and prospect is brought to various fields.
Summary of the invention
Technical problem to be solved by the present invention lies in overcome existing 1,4- dihydropyridine compounds preparation method to exist
The shortcomings that, provide that a kind of mild condition, easy to operate, the reaction time is short, reaction product is single, good substrate applicability, efficiently system
The method of standby 1,4- dihydropyridine compounds.
Solving technical solution used by above-mentioned technical problem is: by cortex cinnamomi shown in enamine ester shown in Formulas I and Formula II
Aldehyde compound is added in organic solvent, and bis cyclopentadienyl zirconium dichloride and benzoic acids ligand is added, and reacts at 30~60 DEG C, reacts
Product is isolated and purified after complete, obtains Isosorbide-5-Nitrae-dihydropyridine compounds shown in formula Ш；
In formula, R1Represent benzyl, halogeno-benzyl, C1~C4Alkyl substituted benzyl base, C1~C4Alkoxy substituted benzyl, benzene second
Base, phenylpropyl, C1~C6Any one in alkyl, R2Represent C1~C4Alkyl, R3Represent H, C1~C4Alkoxy, nitro, in halogen
Any one.
Above-mentioned benzoic acids ligand be 3- nitrophthalic acid, 4- nitrophthalic acid, 5- methoxysalicylic acid,
Any one in 5-NITROSALICYLIC ACID, 3,5- dinitrosalicylic acid, preferably 5-NITROSALICYLIC ACID or 3,5- dinitrosalicylic acid.
In above-mentioned synthetic method, the molar ratio of the enamine ester and cortex cinnamomi aldehyde compound is 1:1~1.5.
In above-mentioned synthetic method, the additional amount of the bis cyclopentadienyl zirconium dichloride is the 3%~10% of enamine ester mole, preferably two
The additional amount of chlorine zirconocene is the 5%~6% of enamine ester mole.
In above-mentioned synthetic method, the additional amount of the benzoic acids ligand is the 8%~20% of enamine ester mole, excellent
The additional amount for selecting benzoic acids ligand is the 10%~15% of enamine ester mole.
It in above-mentioned synthetic method, reacts 1~3 hour at 30~60 DEG C, is reacted 2 hours preferably at 50 DEG C.
In above-mentioned synthetic method, the organic solvent is to appoint in monochloro methane, methylene chloride, chloroform, ethyl alcohol etc.
It anticipates one kind.
For the present invention using bis cyclopentadienyl zirconium dichloride as catalyst, 5-NITROSALICYLIC ACID is ligand, and chloroform is solvent, makes enamine
Ester and cinnamic acid carry out intermolecular cyclization and generate 1,4- dihydropyridine compounds.Reaction condition of the present invention is mild, easy to operate,
Reaction time is short, and reaction product is single, and Atom economy is high, only product need to be passed through simple column chromatography for separation after reaction
?.Obtained 1,4- dihydropyridine compounds have extensive bioactivity and medical value.
Specific embodiment
Below with reference to embodiment, the present invention is described in more detail, but invention which is intended to be protected is not limited only to this
A little embodiments.
Embodiment 1
The following 1- benzyl -2- methyl 4-phenyl -1,4- dihydropyridine -3- carboxylic acid, ethyl ester of preparation structure formula
0.2238g (1mmol) (Z) -3- (benzylamino) but-2-ene acetoacetic ester, 146 μ L are added into 20mL reaction flask
(1.2mmol) cinnamic acid, 0.0125g (0.05mmol) bis cyclopentadienyl zirconium dichloride, 0.0181g (0.1mmol) 5-NITROSALICYLIC ACID, 3mL
Chloroform is stirred to react 2 hours at 50 DEG C, stops reaction, is down to room temperature naturally, and rotary evaporation removes chloroform, is used
Silica gel post separation (eluant, eluent is that the volume ratio of ethyl acetate and petroleum ether is the mixed liquor of 1:10), obtains 1- benzyl -2- methyl -
4- phenyl-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acid, ethyl ester, yield 96%, characterize data are as follows:1H NMR(600MHz,CDCl3)δ
7.35 (t, J=7.5Hz, 2H), 7.27 (dd, J=14.7,5.9Hz, 5H), 7.22 (d, J=7.4Hz, 2H), 7.17-7.13
(m, 1H), 5.95 (d, J=7.6Hz, 1H), 4.97 (dd, J=7.6,5.5Hz, 1H), 4.68-4.54 (m, 3H), 3.97 (q, J
=7.1Hz, 2H), 2.41 (s, 3H), 1.08 (t, J=7.1Hz, 3H)；13C NMR(151MHz,CDCl3)δ169.04,
148.87,148.84,138.11,129.46,128.90, 128.23,127.50,126.23,125.99,108.07,
100.42,59.31,53.73,40.34,15.97,14.17.
Embodiment 2
In the present embodiment, with the 5-NITROSALICYLIC ACID in equimolar 3- nitrophthalic acid alternative embodiment 1, other steps
It is rapid same as Example 1,1- benzyl -2- methyl 4-phenyl-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acid, ethyl ester is obtained, yield is
84%.
Embodiment 3
In the present embodiment, with the 5-NITROSALICYLIC ACID in equimolar 4- nitrophthalic acid alternative embodiment 1, other steps
It is rapid same as Example 1,1- benzyl -2- methyl 4-phenyl-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acid, ethyl ester is obtained, yield is
90%.
Embodiment 4
In the present embodiment, with the 5-NITROSALICYLIC ACID in equimolar 5- methoxysalicylic acid alternative embodiment 1, other steps
It is same as Example 1, obtain 1- benzyl -2- methyl 4-phenyl-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acid, ethyl ester, yield 92%.
Embodiment 5
In the present embodiment, with equimolar 3,5-NITROSALICYLIC ACID in 5- dinitrosalicylic acid alternative embodiment 1, other steps
It is rapid same as Example 1,1- benzyl -2- methyl 4-phenyl-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acid, ethyl ester is obtained, yield is
95%.
Embodiment 6
In the present embodiment, the dosage of 5-NITROSALICYLIC ACID is 0.009g (0.05mmol), other steps and 1 phase of embodiment
Together, 1- benzyl -2- methyl 4-phenyl-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acid, ethyl ester, yield 96% are obtained.
Embodiment 7
In the present embodiment, the dosage of 5-NITROSALICYLIC ACID is 0.0054g (0.03mmol), other steps and 1 phase of embodiment
Together, 1- benzyl -2- methyl 4-phenyl-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acid, ethyl ester, yield 83% are obtained.
Embodiment 8
The following 1- benzyl -2- methyl 4-phenyl -1,4- dihydropyridine -3- carboxylate methyl ester of preparation structure formula
In the present embodiment, used in equimolar (Z) -3- (benzylamino) but-2-ene acid methyl esters alternative embodiment 1
(Z) -3- (benzylamino) but-2-ene acetoacetic ester, other steps are same as Example 1, obtain 1- benzyl -2- methyl -4- benzene
Base-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylate methyl ester, yield 86%, characterize data are as follows:1H NMR(600MHz, CDCl3)δ7.34
(t, J=7.5Hz, 2H), 7.28-7.24 (m, 5H), 7.20 (d, J=7.4Hz, 2H), 7.15 (t, J=6.6Hz, 1H), 5.95
(d, J=7.6Hz, 1H), 4.99 (dd, J=7.6,5.7Hz, 1H), 4.66-4.61 (m, 2H), 4.56 (d, J=16.9Hz,
1H),3.52(s,3H),2.41(s,3H)；13C NMR(151MHz,CDCl3)δ 168.39,148.07,147.54,136.96,
128.49,127.82,127.23,126.43,126.27,125.14,124.97, 106.99,98.99,52.66,49.62,
39.00,14.97.
Embodiment 9
Following 1- benzyl -2- methyl -4- (4- the methoxyphenyl) -1,4- dihydropyridine -3- carboxylic acid second of preparation structure formula
Ester
In the present embodiment, the cinnamic acid used in equimolar 4- methoxycinnamic aldehyde alternative embodiment 1, other steps with
Embodiment 1 is identical, obtains 1- benzyl -2- methyl -4- (4- methoxyphenyl)-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acid, ethyl ester, yield
It is 80%, characterize data are as follows:1H NMR(600MHz,CDCl3) δ 7.24 (t, J=7.5Hz, 2H), 7.16 (t, J=7.3Hz,
1H), 7.09 (dd, J=16.8,8.0Hz, 4H), 6.71 (d, J=8.5Hz, 2H), 5.84 (d, J=7.6 Hz, 1H), 4.85
(dd, J=7.4,5.7Hz, 1H), 4.51 (dd, J=11.3,5.4Hz, 2H), 4.43 (d, J=16.9 Hz, 1H), 3.89 (q, J
=7.1Hz, 2H), 3.65 (s, 3H), 2.30 (s, 3H), 1.01 (t, J=7.1Hz, 3H)；13C NMR(151MHz,CDCl3)δ
169.12,157.96,148.50,141.39,138.20,129.37,128.91, 128.55,127.50,126.28,
113.62,108.20,100.81,59.32,55.25,53.72,39.41,16.02,14.29.
Embodiment 10
Following 1- benzyl -2- methyl -4- (4- the nitrobenzophenone) -1,4- dihydropyridine -3- carboxylic acid, ethyl ester of preparation structure formula
In the present embodiment, cinnamic acid, other steps and reality used in equimolar 4- nitro cinnamaldehyde alternative embodiment 1
It is identical to apply example 1, obtains 1- benzyl -2- methyl -4- (4- nitrobenzophenone)-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acid, ethyl ester, yield is
93%, characterize data are as follows:1H NMR(600MHz,CDCl3) δ 8.02 (d, J=8.5Hz, 2H), 7.29 (dd, J=17.3,
8.1Hz, 4H), 7.21 (t, J=7.3Hz, 1H), 7.12 (d, J=7.5Hz, 2H), 5.93 (d, J=7.6Hz, 1H), 4.84
(dd, J=7.4,5.7Hz, 1H), 4.70 (d, J=5.5Hz, 1H), 4.55 (dd, J=56.7,16.8Hz, 2H), 3.90 (q, J
=7.0Hz, 2H), 2.37 (s, 3H), 1.00 (t, J=7.1Hz, 3H)；13C NMR(151MHz, CDCl3)δ168.36,
155.98,149.92,146.29,137.70,130.42,129.00,128.21,127.74,126.25, 123.67,
106.62,99.28,59.55,53.86,40.59,16.06,14.21.
Embodiment 11
Following 1- benzyl -2- methyl -4- (2- the nitrobenzophenone) -1,4- dihydropyridine -3- carboxylic acid, ethyl ester of preparation structure formula
In the present embodiment, cinnamic acid, other steps and reality used in equimolar 2- nitro cinnamaldehyde alternative embodiment 1
It is identical to apply example 1, obtains 1- benzyl -2- methyl -4- (2- nitrobenzophenone)-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acid, ethyl ester, yield is
96%, characterize data are as follows:1H NMR(600MHz,CDCl3) δ 7.61 (d, J=8.1Hz, 1H), 7.46 (d, J=7.8Hz, 1H),
7.42 (t, J=7.5Hz, 1H), 7.28 (t, J=7.5Hz, 2H), 7.21 (t, J=7.3Hz, 1H), 7.16 (t, J=8.1Hz,
3H), 5.89 (d, J=7.6Hz, 1H), 5.14-5.03 (m, 2H), 4.53 (q, J=16.9 Hz, 2H), 3.74 (q, J=
7.1Hz, 2H), 2.40 (s, 3H), 0.80 (t, J=7.1Hz, 3H)；13C NMR(151 MHz,CDCl3)δ168.01,150.70,
147.70,143.58,137.83,133.09,131.24,130.23,128.98, 127.67,126.51,126.27,
123.14,106.89,99.42,59.35,53.96,36.40,15.78,13.81.
Embodiment 12
Following 1- benzyl -2- methyl -4- (4- the chlorphenyl) -1,4- dihydropyridine -3- carboxylic acid, ethyl ester of preparation structure formula
In the present embodiment, the cinnamic acid used in equimolar 4- chlorocinnamaldehyde alternative embodiment 1, other steps and implement
Example 1 is identical, obtains 1- benzyl -2- methyl -4- (4- chlorphenyl)-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acid, ethyl ester, yield 93%,
Characterize data are as follows:1H NMR(600MHz,CDCl3) δ 7.36 (t, J=7.5Hz, 2H), 7.30 (d, J=7.3 Hz, 1H), 7.21
(t, J=8.3Hz, 4H), 7.17 (d, J=8.4Hz, 2H), 5.97 (d, J=7.6Hz, 1H), 4.94 (dd, J=7.6,
5.5Hz, 1H), 4.68-4.55 (m, 3H), 3.99 (q, J=7.1Hz, 2H), 2.42 (s, 3H), 1.10 (t, J=7.1Hz,
3H)；13C NMR(151MHz,CDCl3)δ168.79,149.14,147.42,137.98,131.60, 129.80,128.95,
128.31,127.61,126.27,107.60,100.12,59.42,53.77,39.83,16.03,14.26.
Embodiment 13
Following 1- benzyl -2- methyl -4- (4- the bromophenyl) -1,4- dihydropyridine -3- carboxylic acid, ethyl ester of preparation structure formula
In the present embodiment, the cinnamic acid used in equimolar 4- bromocinnamaldehyde alternative embodiment 1, other steps and implement
Example 1 is identical, obtains 1- benzyl -2- methyl -4- (4- bromophenyl)-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acid, ethyl ester, yield 90%,
Characterize data are as follows:1H NMR(600MHz,CDCl3) δ 7.38-7.31 (m, 4H), 7.26 (t, J=7.3Hz, 1H), 7.18 (d, J
=7.5Hz, 2H), 7.12 (dd, J=8.4,2.1Hz, 2H), 5.94 (d, J=7.6Hz, 1H), 4.91 (dd, J=7.5,
5.6Hz, 1H), 4.63-4.50 (m, 3H), 3.97 (q, J=7.1Hz, 2H), 2.40 (s, 3H), 1.08 (t, J=7.1Hz,
3H)；13C NMR(151MHz,CDCl3)δ168.76,149.16,147.89,137.96,131.26, 129.81,129.35,
128.95,127.62,126.27,119.76,107.53,100.05,59.43,53.78,39.90,16.04, 14.27.
Embodiment 14
The following 1- butyl -2- methyl 4-phenyl -1,4- dihydropyridine -3- carboxylic acid, ethyl ester of preparation structure formula
In the present embodiment, used in equimolar (Z) -3- (butylamino) but-2-ene acetoacetic ester alternative embodiment 1
(Z) -3- (benzylamino) but-2-ene acetoacetic ester, other steps are same as Example 1, obtain 1- butyl -2- methyl 4-phenyl -
Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acid, ethyl ester, yield 68%, characterize data are as follows:1H NMR(600MHz,CDCl3) δ7.1-7.14
(m, 4H), 7.05 (dt, J=8.3,1.6Hz, 1H), 5.80 (d, J=7.6Hz, 1H), 4.85 (dd, J=7.6,5.6Hz,
1H), 4.50 (d, J=5.6Hz, 1H), 3.90 (q, J=7.0Hz, 2H), 3.38 (dt, J=14.9,7.5 Hz, 1H), 3.15
(dt, J=14.8,7.5Hz, 1H), 2.37 (s, 3H), 1.50 (dt, J=15.2,7.5Hz, 2H), 1.28 (dt, J=15.0,
7.4Hz, 2H), 1.01 (t, J=7.1Hz, 3H), 0.87 (t, J=7.4Hz, 3H)；13C NMR(151 MHz,CDCl3)δ
169.09,149.20,148.78,128.86,128.16,127.40,125.91,107.88,99.61, 59.17,50.14,
40.23,32.42,19.92,15.70,14.21,13.86.
Embodiment 15
The following 1- of preparation structure formula (3- phenyl propyl) -2- methyl 4-phenyl -1,4- dihydropyridine -3- carboxylic acid, ethyl ester
In the present embodiment, with equimolar (Z) -3- ((3- phenyl propyl) amino) but-2-ene acetoacetic ester alternative embodiment 1
(Z) -3- (benzylamino) but-2-ene acetoacetic ester used, other steps are same as Example 1, obtain 1- (3- phenyl propyl) -
2- methyl 4-phenyl-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acid, ethyl ester, yield 75%, characterize data are as follows:1H NMR(600MHz,
CDCl3) δ 7.30 (t, J=7.6Hz, 3H), 7.25 (d, J=6.4Hz, 3H), 7.21 (d, J=7.2Hz, 1H), 7.18 (t, J
=9.1Hz, 3H), 5.86 (d, J=7.6Hz, 1H), 4.94 (dd, J=7.5,5.7Hz, 1H), 4.58 (d, J=5.6Hz,
1H), 3.97 (q, J=7.1Hz, 2H), 3.50 (dt, J=14.8,7.4Hz, 1H), 3.24 (dt, J=14.8,7.5Hz, 1H),
2.65 (dd, J=8.4,6.2Hz, 2H), 2.40 (s, 3H), 1.96-1.91 (m, 2H), 1.09 (t, J=7.1Hz, 3H)；13C
NMR(151MHz,CDCl3)δ169.08,149.17,148.73,140.98, 128.88,128.63,128.36,128.28,
127.46,126.27,126.02,108.04,99.91,59.27,49.75, 40.26,32.88,31.78,15.72,14.30.
Embodiment 16
The following 1- of preparation structure formula (4- methylbenzyl) -2- methyl 4-phenyl -1,4- dihydropyridine -3- carboxylic acid, ethyl ester
In the present embodiment, with equimolar (Z) -3- ((4- methylbenzyl) amino) but-2-ene acetoacetic ester alternative embodiment 1
(Z) -3- (benzylamino) but-2-ene acetoacetic ester used, other steps are same as Example 1, obtain 1- (4- methylbenzyl) -
2- methyl 4-phenyl-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acid, ethyl ester, yield 83%, characterize data are as follows:1H NMR(600MHz,
CDCl3) δ 7.23 (dt, J=15.0,7.4Hz, 4H), 7.10 (d, J=8.2Hz, 3H), 7.06 (d, J=8.0Hz, 2H),
5.87 (d, J=7.7Hz, 1H), 4.91 (dd, J=7.5,5.6Hz, 1H), 4.66 (d, J=5.5 Hz, 1H), 4.46 (dd, J=
56.0,16.8Hz, 2H), 3.94 (qd, J=7.1,2.8Hz, 2H), 2.39 (s, 3H), 2.28 (s, 3H), 1.03 (s, 3H)；13C
NMR(151MHz,CDCl3)δ169.02,149.08,137.14,135.24, 129.65,128.32,127.66,126.36,
126.09,108.08,100.42,59.32,53.56,40.52,21.20,16.07, 14.32.
Embodiment 17
The following 1- of preparation structure formula (4- methoxy-benzyl) -2- methyl 4-phenyl -1,4- dihydropyridine -3- carboxylic acid second
Ester
In the present embodiment, is replaced and implemented with equimolar (Z) -3- ((4- methoxy-benzyl) amino) but-2-ene acetoacetic ester
(Z) -3- (benzylamino) but-2-ene acetoacetic ester used in example 1, other steps are same as Example 1, obtain 1- (4- methoxyl group
Benzyl) -2- methyl 4-phenyl-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acid, ethyl ester, yield 87%, characterize data are as follows:1H NMR
(600MHz,CDCl3) δ 7.25 (dd, J=11.7,5.1Hz, 4H), 7.14 (d, J=8.7Hz, 3H), 6.89 (d, J=
8.6Hz, 2H), 5.95 (d, J=7.6Hz, 1H), 4.97 (dd, J=7.6,5.5Hz, 1H), 4.64 (d, J=5.5 Hz, 1H),
4.55 (dd, J=53.5,16.6Hz, 2H), 3.98 (q, J=7.1Hz, 2H), 3.81 (s, 3H), 2.43 (s, 3H), 1.08 (t,
J=7.1Hz, 3H)；13C NMR(151MHz,CDCl3)δ169.03,159.06,148.99, 148.95,130.08,129.47,
128.25,127.59,127.55,126.02,114.31,108.05,100.36,59.30, 55.32,53.21,40.38,
16.02,14.23.
Embodiment 18
The following 1- of preparation structure formula (4- luorobenzyl) -2- methyl 4-phenyl -1,4- dihydropyridine -3- carboxylic acid, ethyl ester
In the present embodiment, with 1 institute of equimolar (Z) -3- ((4- luorobenzyl) amino) but-2-ene acetoacetic ester alternative embodiment
(Z) -3- (benzylamino) but-2-ene acetoacetic ester, other steps are same as Example 1, obtain 1- (4- luorobenzyl) -2-
Methyl 4-phenyl-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acid, ethyl ester, yield 83%, characterize data are as follows:1H NMR(600 MHz,
CDCl3) δ 7.13 (d, J=4.4Hz, 4H), 7.02 (dd, J=13.3,6.6Hz, 3H), 6.88 (t, J=8.6 Hz, 2H),
5.78 (d, J=7.6Hz, 1H), 4.84 (dd, J=7.6,5.5Hz, 1H), 4.55 (d, J=5.5Hz, 1H), 4.39 (dd, J=
56.0,16.8Hz, 2H), 3.84 (q, J=7.0Hz, 2H), 2.27 (s, 3H), 0.94 (t, J=7.1Hz, 3H)；13C NMR
(151MHz,CDCl3)δ168.91,162.98,161.36,148.82,148.63,134.00, 129.40,128.30,
128.02,127.97,127.53,126.10,115.85,115.71,108.22,100.72,59.36, 53.01,40.35,
15.93,14.21.
Embodiment 19
The following 1- of preparation structure formula (2- phenylethyl) -2- methyl 4-phenyl -1,4- dihydropyridine -3- carboxylic acid, ethyl ester
In the present embodiment, with equimolar (Z) -3- ((2- phenylethyl) amino) but-2-ene acetoacetic ester alternative embodiment 1
(Z) -3- (benzylamino) but-2-ene acetoacetic ester used, other steps are same as Example 1, obtain 1- (2- phenylethyl) -
2- methyl 4-phenyl-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acid, ethyl ester, yield 79%, characterize data are as follows:1H NMR(600MHz,
CDCl3) δ 7.29 (t, J=7.5Hz, 2H), 7.26-7.21 (m, 5H), 7.16 (d, J=7.2Hz, 2H), 7.13 (dd, J=
10.0,4.2Hz, 1H), 5.84 (d, J=7.7Hz, 1H), 4.92 (dd, J=7.6,5.5Hz, 1H), 4.59 (d, J=5.5Hz,
1H), 3.96 (q, J=7.1Hz, 2H), 3.70-3.63 (m, 1H), 3.48-3.42 (m, 1H), 2.88-2.82 (m, 2H), 2.41
(s, 3H), 1.06 (t, J=7.1Hz, 3H)；13C NMR(151MHz,CDCl3) δ169.06,149.12,148.44,138.07,
128.89,128.80,128.51,128.25,127.52,126.82,126.01, 108.28,100.10,59.27,51.91,
40.35,36.74,15.71,14.26.
Embodiment 20
Following 1- benzyl -2- methyl -4- (4- the nitrobenzophenone) -1,4- dihydropyridine -3- carboxylate methyl ester of preparation structure formula
In the present embodiment, with equimolar (Z) -3- (4- nitrobenzophenone) amino) but-2-ene acid methyl esters alternative embodiment 1
(Z) -3- (benzylamino) but-2-ene acetoacetic ester used, cortex cinnamomi used in equimolar 4- nitro cinnamaldehyde alternative embodiment 1
Aldehyde, other steps are same as Example 1, obtain 1- benzyl -2- methyl -4- (4- nitrobenzophenone)-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acid
Methyl esters, yield 85%, characterize data are as follows:1H NMR(600MHz,CDCl3) δ 8.12 (d, J=8.7Hz, 2H), 7.37
(dd, J=8.1,6.4Hz, 4H), 7.31 (t, J=7.3Hz, 1H), 7.20 (d, J=7.4Hz, 2H), 6.03 (d, J=
7.6Hz, 1H), 4.97-4.94 (m, 1H), 4.77 (d, J=5.6Hz, 1H), 4.64 (dd, J=57.3,16.8Hz, 2H),
3.54(s,3H),2.46(s,3H)；13C NMR(151MHz,CDCl3)δ168.79, 155.81,150.17,146.29,
137.70,130.53,128.99,128.14,127.73,126.26,123.71,106.61, 98.97,53.86,50.76,
40.39,16.13.
Embodiment 21
Following 1- benzyl -2- methyl -4- (4- the bromophenyl) -1,4- dihydropyridine -3- carboxylate methyl ester of preparation structure formula
In the present embodiment, used in equimolar (Z) -3- (benzylamino) but-2-ene acid methyl esters alternative embodiment 1
(Z) -3- (benzylamino) but-2-ene acetoacetic ester, cinnamic acid used in equimolar 4- bromocinnamaldehyde alternative embodiment 1 are other
Step is same as Example 1, obtains 1- benzyl -2- methyl -4- (4- bromophenyl)-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylate methyl ester, produces
Rate is 84%, characterize data are as follows:1H NMR(600MHz,CDCl3) δ 7.27 (dd, J=17.4,8.0 Hz, 4H), 7.20 (t, J=
7.3Hz, 1H), 7.10 (d, J=7.3Hz, 2H), 7.03 (d, J=8.4Hz, 2H), 5.88 (d, J=7.6Hz, 1H), 4.86
(dd, J=7.6,5.6Hz, 1H), 4.52 (dt, J=39.5,16.9Hz, 3H), 3.44 (s, 3H), 2.33 (s, 3H)；13C NMR
(151MHz,CDCl3)δ169.21,149.37,147.65,137.87,131.33, 129.86,129.19,128.95,
127.63,126.24,119.81,107.55,99.77,53.80,50.78,39.67,16.10. 。
Claims (10)
1. a kind of bis cyclopentadienyl zirconium dichloride collaboration benzoic acids ligand catalysis synthesizes Isosorbide-5-Nitrae-dihydropyridine compounds method, feature
It is: cortex cinnamomi aldehyde compound shown in enamine ester shown in Formulas I and Formula II is added in organic solvent, and two cyclopentadienyl of dichloro is added
Zirconium and benzoic acids ligand, react at 30~60 DEG C, isolate and purify product after having reacted, and obtain Isosorbide-5-Nitrae-dihydro shown in formula Ш
Pyridine compounds and their；
In formula, R1Represent benzyl, halogeno-benzyl, C1~C4Alkyl substituted benzyl base, C1~C4Alkoxy substituted benzyl, phenethyl, benzene
Propyl, C1~C6Any one in alkyl, R2Represent C1~C4Alkyl, R3Represent H, C1~C4It is alkoxy, nitro, any in halogen
It is a kind of；
Above-mentioned benzoic acids ligand is 3- nitrophthalic acid, 4- nitrophthalic acid, 5- methoxysalicylic acid, 5- nitre
Any one in base salicylic acid, 3,5- dinitrosalicylic acid.
2. bis cyclopentadienyl zirconium dichloride collaboration benzoic acids ligand catalysis synthesizes 1,4- dihydropyridine compounds according to claim 1
Method, it is characterised in that: the benzoic acids ligand be 5-NITROSALICYLIC ACID or 3,5- dinitrosalicylic acid.
3. bis cyclopentadienyl zirconium dichloride collaboration benzoic acids ligand catalysis according to claim 1 synthesizes 1,4- dihydropyridines chemical combination
The method of object, it is characterised in that: the molar ratio of the enamine ester and cortex cinnamomi aldehyde compound is 1:1~1.5.
4. bis cyclopentadienyl zirconium dichloride collaboration benzoic acids ligand catalysis according to claim 1 synthesizes 1,4- dihydropyridines chemical combination
The method of object, it is characterised in that: the additional amount of the bis cyclopentadienyl zirconium dichloride is the 3%~10% of enamine ester mole.
5. bis cyclopentadienyl zirconium dichloride collaboration benzoic acids ligand catalysis according to claim 4 synthesizes 1,4- dihydropyridines chemical combination
The method of object, it is characterised in that: the additional amount of the bis cyclopentadienyl zirconium dichloride is the 5%~6% of enamine ester mole.
6. bis cyclopentadienyl zirconium dichloride collaboration benzoic acids ligand catalysis according to claim 1 synthesizes 1,4- dihydropyridines chemical combination
The method of object, it is characterised in that: the additional amount of the benzoic acids ligand is the 8%~20% of enamine ester mole.
7. bis cyclopentadienyl zirconium dichloride collaboration benzoic acids ligand catalysis according to claim 6 synthesizes 1,4- dihydropyridines chemical combination
The method of object, it is characterised in that: the additional amount of the benzoic acids ligand is the 10%~15% of enamine ester mole.
8. bis cyclopentadienyl zirconium dichloride collaboration benzoic acids ligand catalysis according to claim 1 synthesizes 1,4- dihydropyridines chemical combination
The method of object, it is characterised in that: reacted 1~3 hour at 30~60 DEG C.
9. bis cyclopentadienyl zirconium dichloride collaboration benzoic acids ligand catalysis according to claim 8 synthesizes 1,4- dihydropyridines chemical combination
The method of object, it is characterised in that: reacted 2 hours at 50 DEG C.
10. bis cyclopentadienyl zirconium dichloride collaboration benzoic acids ligand catalysis according to claim 1 synthesizes 1,4- dihydropyridines
The method for closing object, it is characterised in that: the organic solvent is monochloro methane, methylene chloride, chloroform, any one in ethyl alcohol
Kind.
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| CN110483563A (en) * | 2019-09-06 | 2019-11-22 | 山西医科大学 | A kind of preparation method and application of novel ionic betanaphthol aldehyde schiff bases zirconium complex |
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| WO2006076020A2 (en) * | 2005-01-13 | 2006-07-20 | Fernandes Joseph B | Fuel compositions and methods thereof |
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| CN110483563A (en) * | 2019-09-06 | 2019-11-22 | 山西医科大学 | A kind of preparation method and application of novel ionic betanaphthol aldehyde schiff bases zirconium complex |
| CN110483563B (en) * | 2019-09-06 | 2021-12-28 | 山西医科大学 | Preparation method and application of novel ionic beta-naphthoic aldehyde Schiff base zirconium complex |
| CN110483223A (en) * | 2019-09-11 | 2019-11-22 | 陕西师范大学 | The method that pyridine palladium efficient catalytic prepares diaryl ketone compound |
| CN110483223B (en) * | 2019-09-11 | 2022-06-07 | 陕西师范大学 | Method for preparing diaryl ketone compound by high-efficiency catalysis of palladium pyridine |
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