CN101215261B - Method for synthesizing of 2-oxo-3-pyridine formic acid ester and derivatives thereof - Google Patents
Method for synthesizing of 2-oxo-3-pyridine formic acid ester and derivatives thereof Download PDFInfo
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- CN101215261B CN101215261B CN2008100193282A CN200810019328A CN101215261B CN 101215261 B CN101215261 B CN 101215261B CN 2008100193282 A CN2008100193282 A CN 2008100193282A CN 200810019328 A CN200810019328 A CN 200810019328A CN 101215261 B CN101215261 B CN 101215261B
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- 238000000034 method Methods 0.000 title claims abstract description 17
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 title description 4
- 235000019253 formic acid Nutrition 0.000 title description 2
- 230000002194 synthesizing effect Effects 0.000 title description 2
- 239000002253 acid Substances 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 239000002904 solvent Substances 0.000 claims abstract description 19
- 150000002576 ketones Chemical class 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 238000006845 Michael addition reaction Methods 0.000 claims abstract description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 4
- 239000000284 extract Substances 0.000 claims abstract description 4
- 238000010992 reflux Methods 0.000 claims abstract description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- -1 2-oxo-3-picolinic acid ester Chemical class 0.000 claims description 16
- PQCVYHSKABCYON-UHFFFAOYSA-N 2-oxo-1h-pyridine-3-carboxamide Chemical compound NC(=O)C1=CC=CN=C1O PQCVYHSKABCYON-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 239000012046 mixed solvent Substances 0.000 claims description 13
- 235000019260 propionic acid Nutrition 0.000 claims description 13
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 13
- WRIRWRKPLXCTFD-UHFFFAOYSA-N malonamide Chemical compound NC(=O)CC(N)=O WRIRWRKPLXCTFD-UHFFFAOYSA-N 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 8
- 239000011570 nicotinamide Substances 0.000 claims description 8
- 229960003966 nicotinamide Drugs 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 8
- 150000002505 iron Chemical class 0.000 claims description 6
- FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 238000010523 cascade reaction Methods 0.000 claims description 3
- 239000001117 sulphuric acid Substances 0.000 claims description 3
- 235000011149 sulphuric acid Nutrition 0.000 claims description 3
- 238000001308 synthesis method Methods 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 2
- 229940017219 methyl propionate Drugs 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 abstract 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 1
- KCLANYCVBBTKTO-UHFFFAOYSA-N Proparacaine Chemical compound CCCOC1=CC=C(C(=O)OCCN(CC)CC)C=C1N KCLANYCVBBTKTO-UHFFFAOYSA-N 0.000 abstract 1
- 229940087458 alcaine Drugs 0.000 abstract 1
- 238000005899 aromatization reaction Methods 0.000 abstract 1
- 150000001879 copper Chemical class 0.000 abstract 1
- 238000006356 dehydrogenation reaction Methods 0.000 abstract 1
- 238000010791 quenching Methods 0.000 abstract 1
- 230000000171 quenching effect Effects 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 7
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 229960001701 chloroform Drugs 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- PTPMVSMJQWEBHQ-UHFFFAOYSA-N 2-hydroxy-4-methyl-6-oxo-1-(3-propan-2-yloxypropyl)pyridine-3-carbonitrile Chemical compound CC(C)OCCCN1C(O)=C(C#N)C(C)=CC1=O PTPMVSMJQWEBHQ-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- UEYQJQVBUVAELZ-UHFFFAOYSA-N 2-Hydroxynicotinic acid Chemical compound OC(=O)C1=CC=CN=C1O UEYQJQVBUVAELZ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- URHFDFWUDKDOBN-UHFFFAOYSA-N C(C)OC(=O)C=1C(NC(=CC1C1=CC=CC=C1)C1=CC=C(C=C1)CN)=O Chemical compound C(C)OC(=O)C=1C(NC(=CC1C1=CC=CC=C1)C1=CC=C(C=C1)CN)=O URHFDFWUDKDOBN-UHFFFAOYSA-N 0.000 description 1
- 229940122820 Cannabinoid receptor antagonist Drugs 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 1
- 238000007167 Hofmann rearrangement reaction Methods 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- IQGYKBRUFBWVDF-UHFFFAOYSA-N NCC1=CC=C(C=C1)C1=C(C(NC(=C1)C1=CC=CC=C1)=O)C(=O)N Chemical compound NCC1=CC=C(C=C1)C1=C(C(NC(=C1)C1=CC=CC=C1)=O)C(=O)N IQGYKBRUFBWVDF-UHFFFAOYSA-N 0.000 description 1
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 238000010719 annulation reaction Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003536 cannabinoid receptor antagonist Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 1
- RRXOVXUHTGDSAA-UHFFFAOYSA-N ethyl 2-oxo-1h-pyridine-3-carboxylate Chemical compound CCOC(=O)C1=CC=CN=C1O RRXOVXUHTGDSAA-UHFFFAOYSA-N 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Chemical group [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 1
- 229910000398 iron phosphate Inorganic materials 0.000 description 1
- MVFCKEFYUDZOCX-UHFFFAOYSA-N iron(2+);dinitrate Chemical compound [Fe+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O MVFCKEFYUDZOCX-UHFFFAOYSA-N 0.000 description 1
- WBJZTOZJJYAKHQ-UHFFFAOYSA-K iron(3+) phosphate Chemical group [Fe+3].[O-]P([O-])([O-])=O WBJZTOZJJYAKHQ-UHFFFAOYSA-K 0.000 description 1
- RUTXIHLAWFEWGM-UHFFFAOYSA-H iron(3+) sulfate Chemical group [Fe+3].[Fe+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O RUTXIHLAWFEWGM-UHFFFAOYSA-H 0.000 description 1
- 229910000360 iron(III) sulfate Inorganic materials 0.000 description 1
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical group O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- FEONEKOZSGPOFN-UHFFFAOYSA-K tribromoiron Chemical compound Br[Fe](Br)Br FEONEKOZSGPOFN-UHFFFAOYSA-K 0.000 description 1
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- Pyridine Compounds (AREA)
Abstract
A process synthesizes 2-oxo-3-pyridine formic ether, which uses alpha-beta-unsaturated copper and 3-amido-3-oxopropionic ester as raw material with molar ratio of 1:1 to 1:5, and boils under the catalysis of triatomic malysite in acid solvent to synthesize according to following reaction formula. The synthesis process comprises conducting dehydrogenation aromatization tandem reactor between alpha, beta-unsaturated ketone and 3-amido-3-oxopropionic ester intermolecular Michael addition, and intramolecular ketone-acidamide cyclization and alkene-lactam, taking 0.1-5 equivalent weight of catalysis, using protonic acid solvent as reaction solvent, wherein carbon chain is C1-C4, reaction time is 10 minutes to 24 hours, and reaction temperature is controlled from ambient temperature to solvent reflux temperature, quenching with diluted acid solution to react after the reaction, wherein acid solution which is used is 0.1M-12M alcaine solution or 0.1M-6M sulfuric acid solution, then extracting organic solvent, and finally obtaining coarse product of 2-oxo-3-pyridine formic ether after being condensed extract.
Description
One, technical field
The present invention relates to the synthetic different 2-oxo-3-picolinic acid ester that replaces and the synthetic method of 2-oxo-3-pyridine carboxamide.
Two, background technology
2-oxo-3-pyridine carboxylic acid ester structure is present in and manyly has among the drug molecule.Show different biological activitys such as HIV (human immunodeficiency virus)-resistant activity (structural formula I) and kytoplasm and suppress active (structure I I).Optionally alkylation being carried out in the 2-position of specific replacement 2-oxo-3-picolinic acid ester parent nucleus modifies the molecule that obtains and can be used as Cannabinoid receptor antagonist (structural formula II I) and pesticide herbicide (structural formula IV).
Structural formula
2-oxo-3-pyridine carboxamide (structural formula V) can be counted as the derivative of 2-oxo-3-picolinic acid ester.And the Hofmann rearrangement product 2-oxo-3-pyridine amine of 2-oxo-3-pyridine carboxamide has effective pharmaceutical active: as specificity HIV-1 contrary specially transcriptase inhibitors (structural formula VI) and thrombin inhibitors (structural formula VII).
Structural formula
Bibliographical information Synthetic 2-oxo-3-picolinic acid ester method mainly comprises: method one, following and ethyl cyanoacetate annulation (A.Alberola etal.J.Heterocyclic Chem.1987,24,709. from β-enamine ketone (structural formula VIII) alkaline condition; F.Bondavallietal.Synthesis 1999,1169.).Method two, from 2-oxo-3-pyridine carbonitrile (structural formula IX) acidic conditions be hydrolyzed into carboxylic acid then esterification become ester (L.C.Meuer etal.Bioorg.Med.Chem.Lett.2005,15,645).Method three, selectivity is removed acid amides aromizing effect Synthetic 2-oxo-3-pyridine carboxylic acid ethyl ester (G.Yu etal.Synthesis 2004,1021. under alkene-lactan (structural formula X) alkaline condition; S.Wang etal.Org.Biomol.Chem.2004,2,1573.).And the synthetic method of 2-oxo-3-pyridine carboxamide is single relatively, normally synthesizes (L.Sircar etal.J.Med.Chem.1987,30,1023.) from corresponding from 2-oxo-3-pyridine carbonitrile (structural formula IX) partial hydrolysis.
Structural formula
There are methodological limitation in Synthetic 2-oxo-3-picolinic acid ester and 2-oxo-3-pyridine carboxamide as can be seen from the existing synthetic method of document.Employed starting raw material such as β-enamine ketone and alkene-lactan character is unstable or synthetic through multistep; And it is not high from 2-oxo-3-pyridine carbonitrile through the obvious combined coefficient of method that the cyano group derivatize converts ester and acid amides to.Therefore, proposition synthetic route initial from simple raw material, that meet Atom economy is necessary.
Three, summary of the invention
The objective of the invention is to overcome the limitation of aforesaid method, the synthetic method of a kind of Synthetic 2-oxo-3-picolinic acid ester and 2-oxo-3-pyridine carboxamide is provided.It is catalysts that new synthetic method adopts catalytic amount or molar weight trivalent iron salt, realizes from α, alpha, beta-unsaturated ketone and 3-amido-3-oxo propionic ester or Malonamide ' treat different things alike ' Synthetic 2-oxo-3-picolinic acid ester and 2-oxo-3-pyridine carboxamide.
The object of the present invention is achieved like this: the method for Synthetic 2-oxo-3-picolinic acid ester is ' to treat different things alike ' under the trivalent iron salt catalysis acid solvent from α, alpha, beta-unsaturated ketone and 3-amido-3-oxo propionic ester to synthesize (reaction formula 1).This ' treating different things alike ' synthesis method comprises the cascade reactions such as dehydroaromatizationof of α, alpha, beta-unsaturated ketone and the intermolecular Michael addition of 3-amido-3-oxo propionic ester, intramolecularly ketone-acid amides Cheng Huan and alkene-lactan.
Under same reaction conditions (acid solvent and trivalent iron salt catalyzer), from α, alpha, beta-unsaturated ketone and Malonamide Synthetic 2-oxo-3-pyridine carboxamide.
Reaction formula 1
In the process of ' treating different things alike ' method Synthetic 2-oxo-3-picolinic acid ester and 2-oxo-3-pyridine carboxamide: the molar ratio of raw material α, alpha, beta-unsaturated ketone and 3-amido-3-oxo propionic ester or Malonamide is 1: 1 to 1: 5, and wherein substrate 3-amido-3-oxo propionic ester can be 3-amido-3-oxo methyl propionate, 3-amido-3-oxo ethyl propionate and 3-amido-3-oxo benzyl propionate.Using catalyzer to be trivalent iron salt, can be iron trichloride, ferric bromide, iron nitrate, tertiary iron phosphate, ferric sulfate and ferric oxide etc.; Catalyst levels is 0.1 equivalent to 5 equivalent.Reaction solvent is the protonic acid solvent, and carbochain is C
1-C
4Can be formic acid, acetate, trifluoroacetic acid, propionic acid and butyric acid.Reaction times is 10 minutes to 24 hours.Temperature of reaction is that room temperature (25 ℃) is to the solvent refluxing temperature.Need after the reaction with dilute acid soln cancellation reaction; The acidic solution that uses can be 0.1M to a 12M hydrochloric acid soln, perhaps 0.1M to 6M sulphuric acid soln.The mixed solvent of halogenated hydrocarbon solvents such as organic solvent extracts then, and solvent comprises methylene dichloride, trichloromethane and 1, the 2-ethylene dichloride or above-mentioned solvent and methyl alcohol, the blending ratio of halohydrocarbon and methyl alcohol is 10: 1 to 1: 1.After extracting solution concentrated, concentrated solution was the thick product of 2-oxo-3-picolinic acid ester and 2-oxo-3-pyridine carboxamide.
Thick product uses the mixed solvent recrystallization.Mixed solvent is acid and pure.Wherein acid can be acetate, propionic acid; The pure carbochain of using is C
1-C
4And isomer, comprise methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol and the trimethyl carbinol.The blending ratio of acid and alcohol is 1: 10 to 1: 1.
Characteristics of the present invention are: the method for constructing 2-oxo-3-pyridine ring with traditional alkaline condition down is obviously different, the present invention uses acid solvent and molysite catalyzer, realizes synthesizing the 2-oxo-3-picolinic acid ester and the 2-oxo-3-pyridine carboxamide of different replacements respectively from raw material α, alpha, beta-unsaturated ketone and 3-amido-3-oxo ethyl propionate or Malonamide.Mild condition, simple and feasible is particularly suitable for containing in the synthetic molecules 2-oxo-3-picolinic acid ester and the 2-oxo-3-pyridine carboxamide of alkaline sensitive group.Thick product 2-oxo-3-picolinic acid ester and 2-oxo-3-pyridine carboxamide are purified by acid/pure mixed solvent recrystallization.
Four, embodiment
Embodiment 1:1,2-dihydro-4,6-phenylbenzene-2-oxo-3-pyridine carboxylic acid ethyl ester (a) synthetic of structural formula XII
α, the roughly kind of alpha, beta-unsaturated ketone: 1-(4-aminomethyl phenyl)-3-phenyl-2-propylene-1-ketone (structural formula XI b), 1-(4-chloro-phenyl-)-3-phenyl-2-propylene-1-ketone (structural formula XI c), 1-phenyl-3-(4-phenyl)-2-propylene-1-ketone (structural formula XI d), 1-phenyl-3-(4-chloro-phenyl-)-2-propylene-1-ketone (structural formula XI e), 1-(4-p-methoxy-phenyl)-3-phenyl-2-propylene-1-ketone (structural formula XI f), 1-(3-chloro-phenyl-)-3-phenyl-2-propylene-1-ketone (structural formula XI g), 1-(2-chloro-phenyl-)-3-phenyl-2-propylene-1-ketone (structural formula XI h), 1-phenyl-3-(4-aminomethyl phenyl)-2-propylene-1-ketone (structural formula XI i), 1-phenyl-3-(4-p-methoxy-phenyl)-2-propylene-1-ketone (structural formula XI j), 1-phenyl-3-(2, the 5-dichlorophenyl)-2-propylene-1-ketone (structural formula XI k), 1-phenyl-3-(2, the 4-3,5-dimethylphenyl)-2-propylene-1-ketone (structural formula XI 1), 1-(3, the 4-dichlorophenyl)-4-(aminomethyl phenyl)-2-propylene-1-ketone (structural formula XIII) etc.
With 1 of 2.08g (10mmol), (structural formula XI a), back flow reaction is after 0.5 hour (TLC tracking) in propionic acid (20mL) solution for (12mmol) 3-amido-3-oxo ethyl propionate and 3.25g (20mmol) FERRIC CHLORIDE ANHYDROUS, and underpressure distillation goes out propionic acid 10mL for 3-phenylbenzene-2-propylene-1-ketone.Be cooled to room temperature then, in system, add 30mL hydrochloric acid (1.0M), use dichloromethane extraction (30mL * 3) then.The methylene dichloride organic phase is through saturated aqueous sodium carbonate washing, washing and anhydrous magnesium sulfate drying.Concentrating under reduced pressure, enriched material obtain the 2.0g crystal after with acetate/ethanol (1: 1) mixed solvent recrystallization.mp?202-204℃.IR(KBr)：1724，1629cm
-1.
1H?NMR(300MHz，CDCl
3)：δ13.13(1H，s)，7.91-7.87(2H，m)，7.52-7.44(8H，m)，6.55(1H，s)，4.17(2H，q，J＝7.1Hz)，1.06(3H，t，J＝7.1Hz).
13C?NMR(75MHz，CDCl
3)：δ166.9，163.1，153.6，148.4，138.6，133.2，130.9，129.5，128.9，127.9，127.5，121.6，107.2，61.6，14.2.MS：m/z?320(M+1，20)，319(M
+，88)，245(100).Anal.Calcd?for?C
20H
17NO
3：C，75.22；H，5.37；N，4.39.Found：C，75.42；H，5.27；N，4.34.
Embodiment 2:1,2-dihydro-4,6-phenylbenzene-2-oxo-3-pyridine carboxylic acid ethyl ester (a) synthetic of structural formula XII
With 1 of 2.08g (10mmol), (structural formula XI a), back flow reaction is after 1.0 hours (TLC tracking) in propionic acid (20 mL) solution for (15mmol) 3-amido-3-oxo ethyl propionate and 4.88g (30mmol) FERRIC CHLORIDE ANHYDROUS, and underpressure distillation goes out propionic acid 10mL for 3-phenylbenzene-2-propylene-1-ketone.Be cooled to room temperature then, in system, add 30mL hydrochloric acid (1.0M), use dichloromethane extraction (30mL * 3) then.The methylene dichloride organic phase is through saturated aqueous sodium carbonate washing, washing and anhydrous magnesium sulfate drying.Concentrating under reduced pressure, enriched material obtain the 1.6g crystal after with acetate/ethanol (1: 1) mixed solvent recrystallization.
Embodiment 3:1,2-dihydro-4,6-phenylbenzene-2-oxo-3-pyridine carboxylic acid ethyl ester (a) synthetic of structural formula XII
With 1 of 2.08g (10mmol), (structural formula XI a), back flow reaction is after 2.0 hours (TLC tracking) in propionic acid (20mL) solution for (10mmol) 3-amido-3-oxo ethyl propionate and 1.62g (10mmol) FERRIC CHLORIDE ANHYDROUS, and underpressure distillation goes out propionic acid 10mL for 3-phenylbenzene-2-propylene-1-ketone.Be cooled to room temperature then, in system, add 30mL sulfuric acid (1.0M), use chloroform extraction (30mL * 3) then.The trichloromethane organic phase is through saturated aqueous sodium carbonate washing, washing and anhydrous magnesium sulfate drying.Concentrating under reduced pressure, enriched material obtain the 1.2g crystal after with acetate/ethanol (1: 1) mixed solvent recrystallization.
Embodiment 4:1,2-dihydro-4,6-phenylbenzene-2-oxo-3-pyridine carboxamide (a) synthetic of structural formula XIV
With 1 of 2.08g (10mmol), (structural formula XI a), back flow reaction is after 0.5 hour (TLC tracking) in propionic acid (20mL) solution for (12mmol) Malonamide and 3.25g (20mmol) FERRIC CHLORIDE ANHYDROUS, and underpressure distillation goes out propionic acid 10mL for 3-phenylbenzene-2-propylene-1-ketone.Be cooled to room temperature then, in system, add 30mL hydrochloric acid (1.0M), use chloroform extraction (30mL * 3) then.The trichloromethane organic phase is through saturated aqueous sodium carbonate washing, washing and anhydrous magnesium sulfate drying.Concentrating under reduced pressure, enriched material obtain the 1.9g crystallization after with acetate/ethanol (1: 1) mixed solvent recrystallization.mp?228-230℃.IR(KBr)：1662，1629cm
-1.
1H?NMR(300MHz，DMSO-d
6)：δ12.04(1H，s)，7.86-7.83(2H，m)，7.73(1H，s)，7.60-7.57(2H，m)，7.50-7.42(6H，m)，7.29(1H，s)，6.63(1H，s).MS：m/z?290(M+，1)，289(M-1，8)，272(100).Anal.Calcd?forC
18H
14N
2O
2：C，74.47；H，4.86；N，9.65.Found：C，74.49；H，4.83；N，9.68.
Embodiment 5:1,2-dihydro-4,6-phenylbenzene-2-oxo-3-pyridine carboxamide (a) synthetic of structural formula XIV
With 1 of 2.08g (10mmol), (structural formula XI a), back flow reaction is after 0.5 hour (TLC tracking) in propionic acid (20mL) solution for (10mmol) Malonamide and 1.62g (10mmol) FERRIC CHLORIDE ANHYDROUS, and underpressure distillation goes out propionic acid 10mL for 3-phenylbenzene-2-propylene-1-ketone.Be cooled to room temperature then, in system, add 30mL hydrochloric acid (1.0M), use methylene chloride (10/1) mixed solvent to extract (30mL * 3) then.Organic phase is through saturated aqueous sodium carbonate washing, washing and anhydrous magnesium sulfate drying.Concentrating under reduced pressure, enriched material obtain the 1.4g crystallization after with acetate/ethanol (1: 1) mixed solvent recrystallization.Raw material of the present invention and molecular proportion of catalyst scope are insensitive, even also all can realize the present invention in wideer scope, and temperature condition is as the same, and room temperature condition or slightly heat all can.
Embodiment 6: structural formula XII b-1 compound synthetic
With embodiment 1 under the similar condition of composite structure formula XII a, from corresponding 1,3-diaryl-2-propylene-1-ketone (structural formula XI b-1) obtains compounds X II b-1:1,2-dihydro-4-(4-aminomethyl phenyl)-6-phenyl-2-oxo-3-pyridine carboxylic acid ethyl ester (structural formula XIIb); 1,2-dihydro-4-(4-chloro-phenyl-)-6-phenyl-2-oxo-3-pyridine carboxylic acid ethyl ester (structural formula XII c); 1,2-dihydro-4-phenyl-6-(4-phenyl)-2-oxo-3-pyridine carboxylic acid ethyl ester (structural formula XII d); 1,2-dihydro-4-phenyl-6-(4-chloro-phenyl-)-2-oxo-3-pyridine carboxylic acid ethyl ester (structural formula XII e); 1,2-dihydro-4-(4-p-methoxy-phenyl)-6-phenyl-2-oxo-3-pyridine carboxylic acid ethyl ester (structural formula XIIf); 1,2-dihydro-4-(3-chloro-phenyl-)-6-phenyl-2-oxo-3-pyridine carboxylic acid ethyl ester (structural formula XII g); 1,2-dihydro-4-(2-chloro-phenyl-)-6-phenyl-2-oxo-3-pyridine carboxylic acid ethyl ester (structural formula XII h); 1,2-dihydro-4-phenyl-6-(4-aminomethyl phenyl)-2-oxo-3-pyridine carboxylic acid ethyl ester (structural formula XII i); 1,2-dihydro-4-phenyl-6-(4-p-methoxy-phenyl)-2-oxo-3-pyridine carboxylic acid ethyl ester (structural formula XII j); 1,2-dihydro-4-phenyl-6-(2, the 5-dichlorophenyl)-2-oxo-3-pyridine carboxylic acid ethyl ester (structural formula XII k); 1,2-dihydro-4-phenyl-6-(2, the 4-3,5-dimethylphenyl)-2-oxo-3-pyridine carboxylic acid ethyl ester (structural formula XII 1).
Embodiment 7: structural formula XIV b-f compound synthetic
With embodiment 4 under the similar condition of composite structure formula XIV a, from corresponding 1,3-diaryl-2-propylene-1-ketone (structural formula XI b-e and XIII) obtains compounds X IV b-f:1,2-dihydro-4,6-phenylbenzene-2-oxo-3-pyridine carboxamide (structural formula XIV b); 1,2-dihydro-4-(4-aminomethyl phenyl)-6-phenyl-2-oxo-3-pyridine carboxamide (structural formula XIV c); 1,2-dihydro-4-(4-chloro-phenyl-)-6-phenyl-2-oxo-3-pyridine carboxamide (structural formula XIV c); 1,2-dihydro-4-phenyl-6-(4-phenyl)-2-oxo-3-pyridine carboxamide (structural formula XIV d); 1 ,-dihydro-4-phenyl-6-(4-chloro-phenyl-)-2-oxo-3-pyridine carboxamide (structural formula XIV e); 1,2-dihydro-4-(3, the 4-dichlorophenyl)-6-(4-aminomethyl phenyl)-2-oxo-3-pyridine carboxamide (structural formula XIV f).
Structural formula
Structural formula XI, XIII structural formula XIV
XI, XIII, XIV Ar
1Ar
2The productive rate of XIV (%)
a Ph Ph 70
b 4-CH
3C
6H
4 Ph 68
c 4-ClC
6H
4 Ph 75
d Ph 4-PhC
6H
4 65
e Ph 4-ClC
6H
4 60
XIII 3，4-Cl
2C
6H
3 4-CH
3C
6H
4 70
Claims (3)
1. the method for Synthetic 2-oxo-3-picolinic acid ester is characterized in that from α, alpha, beta-unsaturated ketone and 3-amino-3-oxo propionic ester be raw material, and the molar ratio of α, alpha, beta-unsaturated ketone and 3-amino-3-oxo propionic ester is 1: 1 to 1: 5; It is synthetic with following reaction formula ' to treat different things alike ' under the trivalent iron salt catalysis in acid solvent; This ' treating different things alike ' synthesis method comprises the dehydroaromatizationof cascade reaction of α, alpha, beta-unsaturated ketone and the intermolecular Michael addition of 3-amino-3-oxo propionic ester, intramolecularly ketone-acid amides Cheng Huan and alkene-lactan; Catalyst levels is 0.1 equivalent to 5 equivalent; Reaction solvent is the protonic acid solvent, and carbochain is C
1-C
4Reaction times is 10 minutes to 24 hours; Temperature of reaction is that room temperature is to the solvent refluxing temperature; React with the dilute acid soln cancellation reaction back; The dilute acid soln that uses is 0.1M to 12M hydrochloric acid soln or 0.1M to 6M sulphuric acid soln; Organic solvent extracts then; After extracting solution concentrated, concentrated solution was the thick product of 2-oxo-3-picolinic acid ester; α, the kind of alpha, beta-unsaturated ketone is: 1-(4-aminomethyl phenyl)-3-phenyl-2-propylene-1-ketone, 1-(4-chloro-phenyl-)-3-phenyl-2-propylene-1-ketone, 1-phenyl-3-(4-phenyl)-2-propylene-1-ketone, 1-phenyl-3-(4-chloro-phenyl-)-2-propylene-1-ketone, 1-(4-p-methoxy-phenyl)-3-phenyl-2-propylene-1-ketone, 1-(3-chloro-phenyl-)-3-phenyl-2-propylene-1-ketone, 1-(2-chloro-phenyl-)-3-phenyl-2-propylene-1-ketone, 1-phenyl-3-(4-aminomethyl phenyl)-2-propylene-1-ketone, 1-phenyl-3-(4-p-methoxy-phenyl)-2-propylene-1-ketone, 1-phenyl-3-(2, the 5-dichlorophenyl)-2-propylene-1-ketone, 1-phenyl-3-(2, the 4-3,5-dimethylphenyl)-2-propylene-1-ketone, 1-(3, the 4-dichlorophenyl)-4-(aminomethyl phenyl)-2-propylene-1-ketone; 3-amino-3-oxo propionic ester is 3-amino-3-oxo methyl propionate, 3-amino-3-oxo ethyl propionate or 3-amino-3-oxo benzyl propionate;
2. the method for Synthetic 2-oxo-3-pyridine carboxamide is characterized in that from α, alpha, beta-unsaturated ketone and Malonamide be raw material, and the molar ratio of α, alpha, beta-unsaturated ketone and Malonamide is 1: 1 to 1: 5; The following reaction formula of ' treating different things alike ' under the trivalent iron salt catalysis in acid solvent is synthetic; ' treating different things alike ' synthesis method comprises the dehydroaromatizationof cascade reaction of the intermolecular Michael addition of α, alpha, beta-unsaturated ketone and Malonamide, intramolecularly ketone-acid amides Cheng Huan and alkene-lactan; Catalyst levels is 0.1 equivalent to 5 equivalent; Reaction solvent is the protonic acid solvent, and carbochain is C
1-C
4Reaction times is 10 minutes to 24 hours; Temperature of reaction is that room temperature is to the solvent refluxing temperature; React with the dilute acid soln cancellation reaction back; The dilute acid soln that uses is 0.1M to a 12M hydrochloric acid soln, perhaps 0.1M to 6M sulphuric acid soln; Organic solvent extracts then; Organic solvent is the mixed solvent of halogenated hydrocarbon solvent or above-mentioned solvent and methyl alcohol, and the blending ratio of halohydrocarbon and methyl alcohol is 10: 1 to 1: 1; After extracting solution concentrated, concentrated solution was the thick product of 2-oxo-3-pyridine carboxamide; α, the kind of alpha, beta-unsaturated ketone is: 1-(4-aminomethyl phenyl)-3-phenyl-2-propylene-1-ketone, 1-(4-chloro-phenyl-)-3-phenyl-2-propylene-1-ketone, 1-phenyl-3-(4-phenyl)-2-propylene-1-ketone, 1-phenyl-3-(4-chloro-phenyl-)-2-propylene-1-ketone, 1-(4-p-methoxy-phenyl)-3-phenyl-2-propylene-1-ketone, 1-(3-chloro-phenyl-)-3-phenyl-2-propylene-1-ketone, 1-(2-chloro-phenyl-)-3-phenyl-2-propylene-1-ketone, 1-phenyl-3-(4-aminomethyl phenyl)-2-propylene-1-ketone, 1-phenyl-3-(4-p-methoxy-phenyl)-2-propylene-1-ketone, 1-phenyl-3-(2, the 5-dichlorophenyl)-2-propylene-1-ketone, 1-phenyl-3-(2, the 4-3,5-dimethylphenyl)-2-propylene-1-ketone, 1-(3, the 4-dichlorophenyl)-4-(aminomethyl phenyl)-2-propylene-1-ketone;
3. the method for Synthetic 2-oxo according to claim 1 and 2-3-pyridine carboxamide or manthanoate, it is characterized in that thick product uses the mixed solvent recrystallization: mixed solvent is acid and pure; Wherein acid is acetate, propionic acid; The pure carbochain of using is C
1-C
4And isomer, comprise methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol or the trimethyl carbinol; The blending ratio of acid and alcohol is 1: 10 to 1: 1.
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