CN106749235A - The preparation method of poly-substituted quinoline and azole derivatives - Google Patents
The preparation method of poly-substituted quinoline and azole derivatives Download PDFInfo
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Abstract
The invention discloses a kind of poly-substituted quinoline and the preparation method of azole derivatives.The condensation of amino chalcone and aldehyde is obtained chalcone imines, then with glycinate imines, connected by Michael/Mannich and be cyclized, acidification, the production of cis-selectivity high（Ⅰ）It is shown containing four poly-substituted quinolines of chiral centre and azole derivatives.The present invention is based on cascade reaction, Atom economy, the advantage of cis-selectivity easy with environment-friendly, synthesis step, and reaction condition gently, and substrate spectrum applicability is wide, safety simple to operate, it is adaptable to industrialized production.
Description
Technical field
The present invention relates to a kind of poly-substituted quinoline and the preparation method of azole derivatives, belong to Synthetic Organic Chemistry technology neck
Domain.
Background technology
Quino azole derivatives are the very important construction units of a class, are widely present in the chemical combination with bioactivity
In thing and natural products.For example, Aplidiopsamine A are obtained by being extracted in ascidian body, can be used for the treatment of malaria
（J. Org. Chem.2010, 75, 8291-8294）.5-HTRs Ligands-1（J. Med. Chem. 2012, 55,
9446-9466）With 5-HTRs Ligands-2 (A1 of US 2006/0014778) can as the conditioning agent of 5-hydroxytryptamine receptor,
For the treatment of various diseases, for example：Metabolic disease, it includes but is not limited to obesity, and diabetes, diabetic complication is moved
Pulse atherosclerosis, bear glucose tolerance and dyslipidemia;Central nervous system disease, including but not limited to anxiety are depressed
Disease, obsession, panic disorder, mental disease, schizophrenia, sleep-disorder, sexual dysfunction and social phobia are had a headache;Antimigraine and
Enterogastric diseases.Cryptolepine is to extract and have been shown to have antibacterial, anti-hypertension, anti-muscarine from shrub plant
Etc. the natural materials of bioactivity（Bioorg. Med. Chem. 2011, 19, 7519-7525）.
。
Roberto Di Santo, Roberta Costi et al. is with 3- O-Nitrophenylfluorones ethyl acrylate and to methylbenzene
Sulfonymethyl isonitrile is initiation material, and 4- O-Nitrophenylfluorone -1H- pyrroles's -3- Ethyl formates are obtained under sodium hydride effect first；
Nitro is reduced to ammonia under the conditions of 85 DEG C of iron powder and acetic acid in gained intermediate 4- O-Nitrophenylfluorone -1H- pyrroles's -3- Ethyl formates
, then there is cyclization and obtain 2H- pyrroles [3,4, c] and quinoline -4 (5H) -one in base；Then with lithium aluminium hydride by carbonyl reduction as sub-
Methyl, eventually passes elimination reaction and obtains quino azole compounds.The synthesis is completed by four-step reaction, due to needing to use
The sodium hydride of strong basicity and reaction temperature higher, therefore, its application is restricted（ARKIVOC. v, 2004, 181-
195）.
Liu Dong, Guo Tingting, Wang Wei's equality report another synthetic route, and the route first will from 2-Pyrrolidone
Amino is protected, then by DIBAL-H by carbonyl reduction be hydroxyl, then pass through elimination reaction obtains N-protected 2,3-
Pyrrolin；By the N-protected 2,3- pyrrolin and paranitroanilinum, glyoxylic acid ethyl ester obtained by preparation by after cascade reaction
Being aoxidized with DDQ again can obtain quino azole compounds.This method severe reaction conditions, and protection/deprotection steps are needed, synthesize road
Line length, increased synthesis cost（Acta Pharmaceutica Sinica, 51, 2016, 762-769）.
In order to overcome drawbacks described above, present invention aim at open a kind of anti-based on Michael/Mannich series connection cyclisation
Should, the method for the synthesis poly-substituted quinoline and azole derivatives of cis-selectivity high.The method raw material is cheap and easy to get, and route is short,
Simplify processing procedure, it is only necessary to primary purification, safety simple to operate, it is adaptable to industrialized production.
The content of the invention
The present invention can overcome the disadvantages that the shortcoming of existing synthetic method, efficiently synthesize quino azole derivatives.The purpose of the present invention
It is the synthetic method for disclosing a kind of poly-substituted quinoline and azole derivatives, the method raw material is easy to get, and syntheti c route is short, operation letter
It is single, low cost, it is easy to industrialize.The present invention is occurred using method for the treatment of different things alike by chalcone imines and glycinate imines
Michael and Mannich cascade reactions build quinoline ring, are obtained such as formula through acid solution hydrolysis（Ⅰ）Shown quino pyrrole derivatives
Thing.The invention provides a kind of simple, efficient poly-substituted quinoline and the preparation method of azole derivatives.
The invention discloses a kind of poly-substituted quinoline of cis-selectivity high and the preparation method of azole derivatives, with letter
Single raw material aldehyde, amino chalcone and glycinate imines are concatenated Michael and Mannich reactions for raw material, after acid treatment
Obtain such as formula（Ⅰ）Shown quino azole derivatives, wherein, R1It is aromatic group, alkyl, R2It is aromatic group, alkane
Base, R3It is aromatic group, alkyl, hydrogen, R4It is aromatic group, alkyl, hydrogen, R5It is aromatic group, alkyl.
。
The preparation method of quino azole derivatives of the present invention, its course of reaction formula（Ⅱ）It is shown：.
。
In the present invention, " the synthesis poly-substituted quinoline and azole derivatives of cis-selectivity high " refers to four chiralitys
The quino azole derivatives at center, its cis-selectivity is more than 20:1.
Wherein, R1Phenyl for phenyl, alkyl and with substituted base, R2It is aromatic group, alkyl, R3It is aromatic series base
Group, alkyl, hydrogen, R4It is aromatic group, alkyl, hydrogen, R5It is aromatic group, alkyl, compound 2 is N- diphenyl methylenes-sweet
Propylhomoserin ester.
Preparation method of the present invention includes：By amino chalcone, aromatic aldehyde, magnesium sulfate and organic solvent add reaction bulb in,
Reaction is stirred at room temperature；Wherein, organic solvent addition is 2-5mL/mmol amino chalcones.Then, filter is concentrated after filtering
Liquid, adds N- diphenyl methylenes-tert-butyl glycinate, triethylamine and organic solvent, reacts at room temperature；Wherein, organic solvent adds
Enter amount for 10-20mL/mmol amino chalcones.Then filtrate is concentrated, organic solvent dissolving reactant is added, pH is into for regulation
Property, 10% aqueous citric acid solution being added, at room temperature stirring reaction, revolving removal solvent obtains crude product, through column chromatography, obtains institute
State quino azole derivatives；Wherein organic solvent addition is 5-20mL/mmol amino chalcones, citric acid solution addition
It is 4.5mL/mmol amino chalcones.
Wherein, the amino chalcone is E-3- (2- aminophenyls) -1- phenyl -2- propylene -1- ketone, and the compound can be by
O-nitrobenzaldehyde and acetophenone reaction are prepared by the method for iron powder reducing again.（J. Org. Chem. 2014,79 are referred to,
8440-8446）
In the present invention, N- diphenyl methylenes-tert-butyl glycinate can be prepared by benzophenone imine and chloroacetic acid tert-butyl ester.（Please
Refering to Journal of Fluorine Chemistry. 2007,128,78-83）.
Wherein, in the first step, amino chalcone is 1 with the mol ratio of aromatic aldehyde:1；In second step, chalcone imines and N-
The ratio of diphenyl methylene-tert-butyl glycinate is 1:1.
In the present invention, the aromatic aldehyde is P-methoxybenzal-dehyde, and piperonal a, fluorobenzaldehyde a, tolyl aldehyde is right
Bromobenzaldehyde, 4-chloro-benzaldehyde, p-trifluoromethyl benzaldehyde, o-bromobenzaldehye, o-chlorobenzaldehyde, m-methoxybenzaldehyde is right
Fluorobenzaldehyde and benzaldehyde.Above-claimed cpd is bought by market.
Wherein, the organic solvent is dichloromethane, toluene or tetrahydrofuran.
Benzaldehyde used of the invention, acetophenone, the benzaldehyde containing substitution base, benzophenone imine, chloroacetic acid tert-butyl ester, lemon
Lemon acid, iron powder and organic solvent can market buy.
It is easy to get present invention aim at a kind of raw material is provided, syntheti c route is short, simple to operate, atom economy is high and green ring
The poly-substituted quinoline of guarantor and the synthetic method of azole derivatives.In order to realize the purpose, the present invention uses one kettle way, by simple
Three-step reaction, generation poly-substituted quinoline and azole derivatives.First two steps are not required to purifying, are separated by simple, continuous charging,
Three-step reaction only need to carry out primary purification to final product, greatly shorten synthesis cycle, simplify operation.It is pure due to reducing multistep
The consumption of reagent and solvent equal energy source goods and materials needed for changing operation, the method environmental protection is energy-efficient.Additionally, the present invention is also
With good stereoselectivity, can cis-selectivity high obtain there are four compounds 1 of chiral centre（dr > 20:
1）.
Specific embodiment
With reference to specific examples below, the present invention is described in further detail, of the invention to protect content not limit to
In following examples.Under the spirit and scope without departing substantially from inventive concept, those skilled in the art it is conceivable that change and excellent
Point is all included in the present invention, and with appending claims as protection domain.Implement process of the invention, condition,
Reagent, experimental technique etc., in addition to the following special content for referring to, are the universal knowledege and common knowledge of this area, this hair
It is bright that content is not particularly limited.
The specific steps of preparation method of the present invention include：It is 1 that amino chalcone is weighed with the mol ratio of aldehyde:1 adds reaction
In bottle, the amount for adding magnesium sulfate is 1.176g/mmol, and it is 2-5mL/mmol to add organic solvent amount, and reaction is stirred at room temperature
Overnight.Then, filtrate is concentrated after filtering, 1 equivalent N- diphenyl methylenes-glycinate, 1 eq of triethylamine, organic solvent is added
Addition is 10-20mL/mmol, is reacted 24 hours at room temperature.Then filtrate is concentrated, organic solvent dissolving reactant is added, is adjusted
Section pH adds 10% aqueous citric acid solution, at room temperature stirring reaction 24 hours to neutrality, and revolving removal solvent obtains crude product.Will
Crude product volume ratio is ethyl acetate:Petroleum ether=1:Column chromatography in 10 solution, obtains the poly-substituted quinoline and pyrroles spreads out
Biological sterling.
Example 1 prepares the tert-butyl group 3,4- diphenyl -3a, 4,5,9b- tetrahydro-1 H-pyrrolo simultaneously [3,4-c] quinoline -1- carboxylic acids
Ester.
。
Weigh E-3- (2- aminophenyls) -1- phenyl -2- propylene -1- ketone（1.0mmol）, benzaldehyde（1.0mmol）, sulfuric acid
Magnesium（1.176g）, add in round-bottomed flask, organic solvent 2mL is added, it is stirred overnight at room temperature.Filtrate is concentrated after filtering, N- is added
Diphenyl methylene-tert-butyl glycinate（1.0mmol）, triethylamine（1.0mmol）, organic solvent 10mL is added, it is stirred at room temperature 24
Hour.Then filtrate is concentrated, adds organic solvent dissolving reactant, regulation pH to neutrality to add 10% aqueous citric acid solution, room
The lower stirring reaction of temperature 24 hours, revolving removal solvent, then by column chromatography（Eluant, eluent:Petroleum ether:Ethyl acetate=10:1）Separate
Go out to obtain quino azole derivatives A, yield 82%, dr> 20:1.1H NMR (600 MHz, CDCl3) δ7.31 (d,J = 7.7 Hz, 2H), 7.22 (d, J = 7.5 Hz, 1H), 7.15 (t, J = 7.1 Hz, 3H), 7.10
(t, J = 7.2 Hz, 2H), 7.08 – 7.04 (m, 2H), 7.01 (t, J = 7.6 Hz, 2H), 6.79 (t,J = 7.4 Hz, 1H), 6.66 (d, J = 7.9 Hz, 1H), 4.64 (d, J = 9.2 Hz, 1H), 4.16 (s,
1H), 3.98 (d, J = 9.9 Hz, 1H), 3.93 (t, J = 8.5 Hz, 1H), 3.73 – 3.67 (m, 1H),
1.60 (s, 9H); 13C NMR (151 MHz, CDCl3) δ 177.51, 171.79, 144.22, 141.15,
133.81, 129.88, 129.73, 128.32, 128.09, 127.66, 127.63, 127.53, 120.98,
118.56, 114.73, 81.90, 81.60, 77.24, 77.02, 76.81, 56.86, 52.54, 43.92,
28.21; HRMS:Calculated value: C28H28N2O2, [M+Na]+447.2043;Measured value: 447.2042.
Example 2 prepares the tert-butyl group 4- p-fluorophenyl -3- phenyl -3a, 4,5,9b- tetrahydro-1 H-pyrrolo simultaneously [3,4-c] quinoline
Quinoline -1- carboxylates.
。
Weigh E-3- (2- aminophenyls) -1- phenyl -2- propylene -1- ketone（1.0mmol）, 4-Fluorobenzaldehyde（1.0mmol）,
Magnesium sulfate（1.176g）, add in round-bottomed flask, organic solvent 2mL is added, it is stirred overnight at room temperature.Then, filter is concentrated after filtering
Liquid, adds N- diphenyl methylenes-tert-butyl glycinate（1.0mmol）, triethylamine（1.0mmol）, add organic solvent 10mL, room
Temperature stirring 24 hours.Then filtrate is concentrated, adds organic solvent dissolving reactant, regulation pH to neutrality to add 10% citric acid water
Solution, stirring reaction 24 hours, rotate removal solvent at room temperature, then by column chromatography（Eluant, eluent:Petroleum ether:Ethyl acetate=
10:1）Isolate and obtain quino azole derivatives B, yield 57%, dr> 20:1.1H NMR (600 MHz, CDCl3) δ
7.24 (s, 1H), 7.23 (s, 1H), 7.17 – 7.10 (m, 2H), 7.04 (dd, J = 14.6, 8.3 Hz,
3H), 6.98 (t, J = 7.6 Hz, 2H), 6.73 (t, J = 7.4 Hz, 1H), 6.67 (t, J = 8.5 Hz,
2H), 6.59 (d, J = 7.9 Hz, 1H), 4.55 (d, J = 9.3 Hz, 1H), 4.03 (s, 1H), 3.88
(d, J = 10.0 Hz, 1H), 3.86 (d, J = 9.0 Hz, 1H), 3.58 (t, J = 8.7 Hz, 1H),
1.53 (s, 9H);13C NMR (151 MHz, CDCl3) δ 177.21, 171.69, 163.29, 161.66,
144.07, 136.95, 133.83, 130.03, 129.74, 129.24, 129.19, 128.06, 127.70,
127.54, 121.02, 118.80, 115.17, 115.03, 114.80, 81.93, 81.69, 56.28, 52.76,
43.81, 28.19; HRMS:Calculated value: C28H27FN2O2, [M+Na]+465.1949;Measured value: 465.1952.
Example 3 prepares the tert-butyl group 4- m-methoxyphenyl -3- phenyl -3a, 4,5,9b- tetrahydro-1 H-pyrrolo simultaneously [3,4-c]
Quinoline -1- carboxylates.
。
Weigh E-3- (2- aminophenyls) -1- phenyl -2- propylene -1- ketone（1.0mmol）, m-methoxybenzaldehyde
（1.0mmol）, magnesium sulfate（1.176g）, add in round-bottomed flask, organic solvent 2mL is added, it is stirred overnight at room temperature.Then, mistake
Filtrate is concentrated after filter, N- diphenyl methylenes-tert-butyl glycinate is added（1.0mmol）, triethylamine（1.0mmol）, add organic
Solvent 10mL, is stirred at room temperature 24 hours.Then filtrate is concentrated, adds organic solvent dissolving reactant, regulation pH to neutrality to add
10% aqueous citric acid solution, stirring reaction 24 hours, rotate removal solvent at room temperature, then by column chromatography（Eluant, eluent:Petroleum ether:
Ethyl acetate=10:1）Isolate and obtain quino azole derivatives C, yield 67%, dr> 20:1.1H NMR (600
MHz, CDCl3) δ 7.28 (s, 1H), 7.27 (s, 1H), 7.15 (d, J = 7.5 Hz, 1H), 7.11 (t,J = 7.3 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 6.97 (t, J = 7.7 Hz, 2H), 6.93 (t,J = 8.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.71 (d, J = 7.4 Hz, 1H), 6.59 (d,J = 7.9 Hz, 1H), 6.57 (s, 2H), 4.56 (d, J = 9.2 Hz, 1H), 4.09 (s, 1H), 3.88
(d, J = 10.0 Hz, 1H), 3.85 (d, J = 8.7 Hz, 1H), 3.60 (t, J = 8.7 Hz, 1H),
3.50 (s, 3H), 1.53 (s, 9H);13C NMR (151 MHz, CDCl3) δ 177.39, 171.74, 159.61,
144.15, 142.76, 133.99, 129.91, 129.72, 129.43, 128.03, 127.61, 127.52,
121.00, 119.79, 118.59, 114.74, 114.22, 113.06, 81.86, 81.63, 56.91, 55.17,
52.55, 43.89, 28.20; HRMS:Calculated value: C29H30N2O3, [M+Na]+477.2148;Measured value:
477.2154。
Example 4 prepares the tert-butyl group 4- Chloro-O-Phenyl -3- phenyl -3a, 4,5,9b- tetrahydro-1 H-pyrrolo simultaneously [3,4-c] quinoline
Quinoline -1- carboxylates.
。
Weigh E-3- (2- aminophenyls) -1- phenyl -2- propylene -1- ketone（1.0mmol）, o-chlorobenzaldehyde（1.0mmol）,
Magnesium sulfate（1.176g）, add in round-bottomed flask, organic solvent 2mL is added, it is stirred overnight at room temperature.Then, filter is concentrated after filtering
Liquid, adds N- diphenyl methylenes-tert-butyl glycinate（1.0mmol）, triethylamine（1.0mmol）, add organic solvent 10mL, room
Temperature stirring 24 hours.Then filtrate is concentrated, adds organic solvent dissolving reactant, regulation pH to neutrality to add 10% citric acid water
Solution, stirring reaction 24 hours, rotate removal solvent at room temperature, then by column chromatography（Eluant, eluent:Petroleum ether:Ethyl acetate=
10:1）Isolate and obtain quino azole derivatives D, yield 74%, dr> 20:1.1H NMR (600 MHz, CDCl3) δ
7.64 (d, J = 7.8 Hz, 1H), 7.41 (s, 1H), 7.40 (s, 1H), 7.23 (d, J = 7.5 Hz,
1H), 7.21 (d, J = 7.6 Hz, 1H), 7.18 (t, J = 7.4 Hz, 1H), 7.09 (t, J = 7.6 Hz,
1H), 7.05 (t, J = 7.7 Hz, 2H), 7.01 (dd, J = 12.1, 4.7 Hz, 1H), 6.87 (d, J =
8.0 Hz, 1H), 6.80 (t, J = 7.5 Hz, 1H), 6.65 (d, J = 7.9 Hz, 1H), 4.70 (d, J =
8.9 Hz, 1H), 4.67 (d, J = 9.4 Hz, 1H), 4.04 (s, 1H), 3.93 (t, J = 8.3 Hz,
1H), 3.75 (t, J = 8.6 Hz, 1H), 1.60 (s, 9H);13C NMR (151 MHz, CDCl3) δ 176.80,
171.85, 144.23, 138.81, 133.72, 133.42, 129.95, 129.66, 129.29, 128.98,
128.60, 128.20, 127.52, 127.42, 127.18, 121.38, 118.92, 114.99, 81.85, 81.75,
52.27, 51.69, 44.08, 28.20; HRMS:Calculated value: C28H27ClN2O2, [M+Na]+481.1653;Measurement
Value: 481.1656.
Example 5 prepares the tert-butyl group 4- o-bromophenyl -3- phenyl -3a, 4,5,9b- tetrahydro-1 H-pyrrolo simultaneously [3,4-c] quinoline
Quinoline -1- carboxylates.
。
Weigh E-3- (2- aminophenyls) -1- phenyl -2- propylene -1- ketone（1.0mmol）, o-bromobenzaldehye（1.0mmol）,
Magnesium sulfate（1.176g）, add in round-bottomed flask, organic solvent 2mL is added, it is stirred overnight at room temperature.Then, filter is concentrated after filtering
Liquid, adds N- diphenyl methylenes-tert-butyl glycinate（1.0mmol）, triethylamine（1.0mmol）, add organic solvent 10mL, room
Temperature stirring 24 hours.Then filtrate is concentrated, adds organic solvent dissolving reactant, regulation pH to neutrality to add 10% citric acid water
Solution, stirring reaction 24 hours, rotate removal solvent at room temperature, then by column chromatography（Eluant, eluent:Petroleum ether:Ethyl acetate=
10:1）Isolate and obtain quino azole derivatives E, yield 50%, dr> 20:1.1H NMR (600 MHz, CDCl3) δ
7.65 (d, J = 7.8 Hz, 1H), 7.42 (s, 1H), 7.41 (s, 1H), 7.30 (t, J = 7.5 Hz,
1H), 7.21 (d, J = 7.7 Hz, 1H), 7.18 (t, J = 7.1 Hz, 1H), 7.12 – 7.02 (m, 1H),
6.95 (t, J = 7.6 Hz, 4H), 6.81 (t, J = 7.4 Hz, 1H), 6.66 (d, J = 7.9 Hz, 1H),
4.70 (d, J = 9.1 Hz, 1H), 4.65 (d, J = 9.5 Hz, 1H), 4.06 (s, 1H), 3.94 (t, J = 8.4 Hz, 1H), 3.73 (t, J = 8.6 Hz, 1H), 1.60 (s, 9H);13C NMR (151 MHz, CDCl3)
δ 176.82, 171.55, 145.13, 143.79, 133.71, 130.54, 130.32, 130.11, 129.73,
128.02, 127.91, 127.76, 127.61, 125.16, 125.14, 124.62, 121.08, 119.09,
114.95, 82.01, 81.78, 56.70, 52.79, 43.61, 28.19; HRMS:Calculated value: C28H27BrN2O2,
[M+Na]+525.1148;Measured value: 525.1149.
Example 6 prepares the tert-butyl group 4- p-trifluoromethyl phenyl -3- phenyl -3a, 4,5,9b- tetrahydro-1 H-pyrrolo simultaneously [3,4-
C] quinoline -1- carboxylates.
。
Weigh E-3- (2- aminophenyls) -1- phenyl -2- propylene -1- ketone（1.0mmol）, p-trifluoromethyl benzaldehyde
（1.0mmol）, magnesium sulfate（1.176g）, add in round-bottomed flask, organic solvent 2mL is added, it is stirred overnight at room temperature.Then, mistake
Filtrate is concentrated after filter, N- diphenyl methylenes-tert-butyl glycinate is added（1.0mmol）, triethylamine（1.0mmol）, add organic
Solvent 10mL, is stirred at room temperature 24 hours.Then filtrate is concentrated, adds organic solvent dissolving reactant, regulation pH to neutrality to add
10% aqueous citric acid solution, stirring reaction 24 hours, rotate removal solvent at room temperature, then by column chromatography（Eluant, eluent:Petroleum ether:
Ethyl acetate=10:1）Isolate and obtain quino azole derivatives F, yield 55%, dr> 20:1.1H NMR (600
MHz, CDCl3) δ 7.30 (s, 1H), 7.28 (s, 1H), 7.26 (s, 2H), 7.25 (s, 2H), 7.23
(s, 1H), 7.17 (t, J = 7.3 Hz, 1H), 7.11 (t, J = 7.3 Hz, 1H), 7.01 (t, J = 7.6
Hz, 2H), 6.82 (t, J = 7.3 Hz, 1H), 6.68 (d, J = 7.8 Hz, 1H), 4.64 (d, J = 9.1
Hz, 1H), 4.14 (s, 1H), 4.02 (d, J = 9.8 Hz, 1H), 3.95 (t, J = 8.4 Hz, 1H),
3.67 (t, J = 8.5 Hz, 1H), 1.60 (s, 9H);13C NMR (151 MHz, CDCl3) δ 176.82,
171.55, 145.13, 143.79, 133.71, 130.54, 130.32, 130.11, 129.73, 128.02,
127.91, 127.76, 127.61, 125.16, 125.14, 124.62, 121.08, 119.09, 114.95,
82.01, 81.78, 56.70, 52.79, 43.61, 28.19; HRMS:Calculated value: C29H27F3N2O2, [M+Na]+
515.1917;Measured value: 515.1918.
Example 7 prepares the tert-butyl group 4- rubigan -3- phenyl -3a, 4,5,9b- tetrahydro-1 H-pyrrolo simultaneously [3,4-c] quinoline
Quinoline -1- carboxylates.
。
Weigh E-3- (2- aminophenyls) -1- phenyl -2- propylene -1- ketone（1.0mmol）, 4-chloro-benzaldehyde（1.0mmol）,
Magnesium sulfate（1.176g）, add in round-bottomed flask, organic solvent 2mL is added, it is stirred overnight at room temperature.Then, filter is concentrated after filtering
Liquid, adds N- diphenyl methylenes-tert-butyl glycinate（1.0mmol）, triethylamine（1.0mmol）, add organic solvent 17mL, room
Temperature stirring 24 hours.Then filtrate is concentrated, adds organic solvent dissolving reactant, regulation pH to neutrality to add 10% citric acid water
Solution, stirring reaction 24 hours, rotate removal solvent at room temperature, then by column chromatography（Eluant, eluent:Petroleum ether:Ethyl acetate=
10:1）Isolate and obtain quino azole derivatives G, yield 77%, dr> 20:1.1H NMR (600 MHz, CDCl3) δ
7.30 (d, J = 7.6 Hz, 2H), 7.22 (d, J = 4.8 Hz, 1H), 7.21 (d, J = 4.4 Hz, 1H),
7.11 – 7.08 (m, 1H), 7.07 (d, J = 1.4 Hz, 1H), 7.06 (s, 2H), 7.04 (s, 1H),
7.01 (s, 1H), 7.00 (s, 1H), 6.80 (t, J = 7.4 Hz, 1H), 6.66 (d, J = 7.9 Hz,
1H), 4.61 (d, J = 9.2 Hz, 1H), 4.11 (s, 1H), 3.94 (d, J = 3.3 Hz, 1H), 3.92
(d, J = 10.3 Hz, 1H), 3.64 (t, J = 8.8 Hz, 1H), 1.59 (s, 9H);13C NMR (151 MHz,
CDCl3) δ 177.10, 171.65, 143.98, 139.69, 133.82, 133.77, 130.05, 129.71,
128.94, 128.38, 128.07, 127.75, 127.57, 121.08, 118.88, 114.89, 81.95, 81.73,
56.37, 52.77, 43.72, 28.20; HRMS:Calculated value: C28H27ClN2O2, [M+Na]+481.1653;Measurement
Value: 481.1652.
Example 8 prepares the tert-butyl group 4- p-bromophenyl -3- phenyl -3a, 4,5,9b- tetrahydro-1 H-pyrrolo simultaneously [3,4-c] quinoline
Quinoline -1- carboxylates.
。
Weigh E-3- (2- aminophenyls) -1- phenyl -2- propylene -1- ketone（1.0mmol）, p-bromobenzaldehyde（1.0mmol）,
Magnesium sulfate（1.176g）, add in round-bottomed flask, organic solvent 2mL is added, it is stirred overnight at room temperature.Then, filter is concentrated after filtering
Liquid, adds N- diphenyl methylenes-tert-butyl glycinate（1.0mmol）, triethylamine（1.0mmol）, add organic solvent 17mL, room
Temperature stirring 24 hours.Then filtrate is concentrated, adds organic solvent dissolving reactant, regulation pH to neutrality to add 10% citric acid water
Solution, stirring reaction 24 hours, rotate removal solvent at room temperature, then by column chromatography（Eluant, eluent:Petroleum ether:Ethyl acetate=
10:1）Isolate and obtain quino azole derivatives H, yield 67%, dr> 20:1.1H NMR (600 MHz, CDCl3) δ
7.30 (s, 1H), 7.29 (s, 1H), 7.22 (t, J = 7.9 Hz, 2H), 7.17 (s, 1H), 7.16 (s,
1H), 7.09 (t, J = 8.3 Hz, 1H), 7.06 (t, J = 7.7 Hz, 2H), 7.02 (s, 1H), 7.00
(s, 1H), 6.80 (t, J = 7.5 Hz, 1H), 6.66 (d, J = 7.9 Hz, 1H), 4.61 (d, J = 9.1
Hz, 1H), 4.10 (s, 1H), 3.92 (t, J = 8.6 Hz, 2H), 3.64 (t, J = 8.7 Hz, 1H),
1.60 (s, 9H);13C NMR (151 MHz, CDCl3) δ 177.07, 171.63, 143.94, 140.21,
133.74, 131.35, 130.04, 129.71, 129.26, 128.06, 127.77, 127.57, 121.89,
121.10, 118.91, 114.89, 81.95, 81.74, 56.43, 52.78, 43.68, 28.19; HRMS:Calculate
Value: C28H27BrN2O2, [M+Na]+525.1148;Measured value: 525.1146.
Example 9 prepares between the tert-butyl group 4- tolyl -3- phenyl -3a, 4,5,9b- tetrahydro-1 H-pyrrolo simultaneously [3,4-c] quinoline
Quinoline -1- carboxylates.
。
Weigh E-3- (2- aminophenyls) -1- phenyl -2- propylene -1- ketone（1.0mmol）, a tolyl aldehyde
（1.0mmol）, magnesium sulfate（1.176g）, add in round-bottomed flask, organic solvent 2mL is added, it is stirred overnight at room temperature.Then, mistake
Filtrate is concentrated after filter, N- diphenyl methylenes-tert-butyl glycinate is added（1.0mmol）, triethylamine（1.0mmol）, add organic
Solvent 10mL, is stirred at room temperature 24 hours.Then filtrate is concentrated, adds organic solvent dissolving reactant, regulation pH to neutrality to add
10% aqueous citric acid solution, stirring reaction 24 hours, rotate removal solvent at room temperature, then by column chromatography（Eluant, eluent:Petroleum ether:
Ethyl acetate=10:1）Isolate and obtain quino azole derivatives I, yield 69%, dr> 20:1.1H NMR (600
MHz, CDCl3) δ 7.31 (s, 1H), 7.30 (s, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.15 (t,J = 7.4 Hz, 1H), 7.09 (dd, J = 11.2, 4.0 Hz, 1H), 7.02 (dd, J = 15.0, 7.5 Hz,
3H), 6.98 (t, J = 7.7 Hz, 1H), 6.88 (d, J = 7.4 Hz, 1H), 6.86 (s, 1H), 6.78
(t, J = 7.4 Hz, 1H), 6.66 (d, J = 7.9 Hz, 1H), 4.63 (d, J = 9.0 Hz, 1H), 4.15
(s, 1H), 3.96 – 3.88 (m, 2H), 3.70 – 3.61 (m, 1H), 2.07 (s, 3H), 1.60 (s,
9H);13C NMR (151 MHz, CDCl3) δ 177.55, 171.82, 144.30, 140.97, 137.93, 134.04,
129.82, 129.75, 128.80, 128.67, 128.32, 128.02, 127.50, 124.29, 121.00,
118.50, 114.72, 81.83, 81.65, 56.85, 52.62, 43.93, 28.21, 21.00; HRMS:Calculate
Value: C29H30N2O2, [M+Na]+461.2199;Measured value: 461.2200.
Example 10 prepares between the tert-butyl group 4- fluorophenyl -3- phenyl -3a, 4,5,9b- tetrahydro-1 H-pyrrolo simultaneously [3,4-c] quinoline
Quinoline -1- carboxylates.
。
Weigh E-3- (2- aminophenyls) -1- phenyl -2- propylene -1- ketone（1.0mmol）, a fluorobenzaldehyde（1.0mmol）,
Magnesium sulfate（1.176g）, add in round-bottomed flask, organic solvent 2mL is added, it is stirred overnight at room temperature.Then, filter is concentrated after filtering
Liquid, adds N- diphenyl methylenes-tert-butyl glycinate（1.0mmol）, triethylamine（1.0mmol）, add organic solvent 20mL, room
Temperature stirring 24 hours.Then filtrate is concentrated, adds organic solvent dissolving reactant, regulation pH to neutrality to add 10% citric acid water
Solution, stirring reaction 24 hours, rotate removal solvent at room temperature, then by column chromatography（Eluant, eluent:Petroleum ether:Ethyl acetate=
10:1）Isolate and obtain quino azole derivatives J, yield 62%, dr> 20:1.1H NMR (600 MHz, CDCl3) δ
7.33 (d, J = 7.4 Hz, 2H), 7.22 (d, J = 7.6 Hz, 1H), 7.18 (t, J = 7.4 Hz, 1H),
7.09 (t, J = 7.6 Hz, 1H), 7.06 (t, J = 7.7 Hz, 2H), 6.99 – 6.94 (m, 1H), 6.93
(d, J = 9.7 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.82 – 6.78 (m, 1H), 6.77 (dd,J = 8.3, 2.0 Hz, 1H), 6.66 (d, J = 7.9 Hz, 1H), 4.62 (d, J = 9.1 Hz, 1H),
4.14 (s, 1H), 3.99 – 3.94 (m, 1H), 3.92 (d, J = 8.6 Hz, 1H), 3.67 (dd, J =
12.9, 4.6 Hz, 1H), 1.59 (s, 9H);13C NMR (151 MHz, CDCl3) δ 177.11, 171.64,
163.61, 161.98, 143.93, 143.79, 143.74, 133.88, 130.09, 129.81, 129.75,
129.71, 127.96, 127.75, 127.58, 123.50, 123.48, 121.04, 118.88, 114.98,
114.89, 114.84, 114.55, 114.41, 81.94, 81.73, 56.52, 52.57, 43.76, 28.20;
HRMS:Calculated value: C28H27FN2O2, [M+Na]+465.1949;Measured value: 465.1948.
Example 11 prepare tert-butyl group 4- (1,3- (methylene-dioxy) -5- phenyl) -3- phenyl -3a, 4,5,9b- tetrahydrochysene -
1H- pyrrolo-es [3,4-c] quinoline -1- carboxylates.
。
Weigh E-3- (2- aminophenyls) -1- phenyl -2- propylene -1- ketone（1.0mmol）, piperonal（1.0mmol）, sulfuric acid
Magnesium（1.176g）, add in round-bottomed flask, organic solvent 2mL is added, it is stirred overnight at room temperature.Then, filtrate is concentrated after filtering, plus
Enter N- diphenyl methylenes-tert-butyl glycinate（1.0mmol）, triethylamine（1.0mmol）, organic solvent 10mL is added, room temperature is stirred
Mix 24 hours.Then filtrate is concentrated, adds organic solvent dissolving reactant, regulation pH to neutrality to add 10% citric acid water-soluble
Liquid, stirring reaction 24 hours, rotate removal solvent at room temperature, then by column chromatography（Eluant, eluent:Petroleum ether:Ethyl acetate=10:
1）Isolate and obtain quino azole derivatives K, yield 40%, dr> 20:1.1H NMR (600 MHz, CDCl3) δ
7.37 (d, J = 7.5 Hz, 2H), 7.21 (t, J = 7.7 Hz, 2H), 7.09 (t, J = 7.7 Hz, 3H),
6.79 (t, J = 7.4 Hz, 1H), 6.70 (d, J = 1.2 Hz, 1H), 6.65 (d, J = 7.9 Hz, 1H),
6.55 (dd, J = 7.9, 1.3 Hz, 1H), 6.43 (d, J = 7.9 Hz, 1H), 5.86 (d, J = 1.1
Hz, 1H), 5.79 (d, J = 1.1 Hz, 1H), 4.61 (d, J = 9.2 Hz, 1H), 4.10 (s, 1H),
3.94 – 3.89 (m, 1H), 3.87 (d, J = 9.9 Hz, 1H), 3.62 (t, J = 8.4 Hz, 1H), 1.60
(s, 9H);13C NMR (151 MHz, CDCl3) δ 177.45, 171.77, 147.63, 147.29, 144.22,
134.97, 134.10, 129.86, 129.74, 128.09, 127.62, 127.50, 121.23, 121.03,
118.64, 114.78, 107.87, 107.85, 100.89, 81.87, 81.66, 56.68, 52.86, 43.88,
28.20; HRMS:Calculated value: C29H28N2O4, [M+Na]+491.1941;Measured value: 491.1944.
Example 12 prepares the tert-butyl group 4- p-methoxyphenyl -3- phenyl -3a, 4,5,9b- tetrahydro-1 H-pyrrolo simultaneously [3,4-
C] quinoline -1- carboxylates.
。
Weigh E-3- (2- aminophenyls) -1- phenyl -2- propylene -1- ketone（1.0mmol）, p-tolyl aldehyde
（1.0mmol）, magnesium sulfate（1.176g）, add in round-bottomed flask, organic solvent 2mL is added, it is stirred overnight at room temperature.Then, mistake
Filtrate is concentrated after filter, N- diphenyl methylenes-tert-butyl glycinate is added（1.0mmol）, triethylamine（1.0mmol）, add organic
Solvent 12mL, is stirred at room temperature 24 hours.Then filtrate is concentrated, adds organic solvent dissolving reactant, regulation pH to neutrality to add
10% aqueous citric acid solution, stirring reaction 24 hours, rotate removal solvent at room temperature, then by column chromatography（Eluant, eluent:Petroleum ether:
Ethyl acetate=10:1）Isolate and obtain quino azole derivatives L, yield 43%, dr> 20:1.1H NMR (600
MHz, CDCl3) δ 7.32 (d, J = 7.9 Hz, 2H), 7.21 (d, J = 7.5 Hz, 1H), 7.16 (t, J = 7.0 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 7.04 (dd, J = 13.3, 7.3 Hz, 3H),
6.78 (t, J = 7.4 Hz, 1H), 6.65 (d, J = 7.9 Hz, 1H), 6.59 (d, J = 7.4 Hz, 2H),
4.62 (d, J = 9.3 Hz, 1H), 4.11 (s, 1H), 3.92 (t, J = 9.0 Hz, 2H), 3.69 (d, J = 1.0 Hz, 3H), 3.67 – 3.61 (m, 1H), 1.60 (s, 9H);13C NMR (151 MHz, CDCl3) δ
177.58, 171.83, 159.53, 144.35, 133.96, 133.30, 129.79, 129.74, 128.67,
128.19, 127.61, 127.49, 121.06, 118.51, 114.73, 113.80, 81.85, 81.66, 56.28,
55.36, 52.82, 43.94, 28.22; HRMS:Calculated value: C29H30N2O3, [M+Na]+477.2148;Measured value:
477.2152。
Finally illustrate, preferred embodiment above is merely illustrative of the technical solution of the present invention and unrestricted, although logical
Cross above preferred embodiment to be described in detail the present invention, it is to be understood by those skilled in the art that can be
Various changes are made to it in form and in details, without departing from claims of the present invention limited range.
Claims (7)
1. the preparation method of poly-substituted quinoline and azole derivatives, it is characterised in that be condensed first with amino chalcone and aldehyde
Chalcone imines is obtained, is then gone here and there by Michael additions and Mannich as raw material with chalcone imines and glycinate imines
Connection cyclization, prepares such as formula through peracid treatment（Ⅰ）Shown poly-substituted quinoline and azole derivatives；
Wherein, R1It is aromatic group, alkyl, R2It is aromatic group, alkyl, R5It is aromatic group, alkyl；
The preparation method such as formula（Ⅱ）It is shown,
Wherein, R1It is aromatic group, alkyl, R2It is aromatic group, alkyl, R3It is aromatic group, alkyl, hydrogen, R4It is virtue
Fragrant race's group, alkyl, hydrogen, R5It is aromatic group, alkyl；
Comprise the following steps：
Step（1）, raw material is weighed, by amino chalcone：Aldehyde：Glycinate imines:Alkali:Magnesium sulfate:The mol ratio of acid is 1:1:
1:1:9.8:2.6；
Step（2）, the amino chalcone and aldehyde are obtained imine intermediate through magnesium sulfate dehydration；
Step（3）, by gained imine intermediate, glycinate imines and alkali soluble in organic solvent, it is stirred at room temperature 24 hours；
Step（4）, gained mixture is adjusted into pH to neutrality, aqueous acid is added, at room temperature stirring reaction 24 hours, except molten
Agent, quino azole derivatives are obtained by column chromatography；
Wherein, the alkali is achirality organic base；Acid is achiral carboxylic acids or sulfonic acid；The solvent is dichloromethane, tetrahydrochysene furan
Mutter, 1,2- dichloroethanes, chloroform, toluene, paraxylene, a trimethylbenzene, acetonitrile or ether.
2. preparation method as claimed in claim 1, it is characterised in that the amino chalcone:Aldehyde:Glycinate imines:Alkali:
Magnesium sulfate:The mol ratio of acid is 1:1:1:1:9.8:2.6.
3. preparation method as claimed in claim 1, it is characterised in that the amino chalcone is trans ketenes.
4. preparation method as claimed in claim 1, it is characterised in that the consumption of the solvent is the amino chalcone consumption
50-100 times.
5. preparation method as claimed in claim 1, it is characterised in that the substitution base is substituted or non-substituted aryl.
6. preparation method as claimed in claim 1, it is characterised in that the aldehyde is substituted or non-substituted aromatic aldehyde.
7. preparation method as claimed in claim 1, it is characterised in that the reaction yield of the preparation method is 40%-82%.
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| CN108440365A (en) * | 2018-06-28 | 2018-08-24 | 淮阴师范学院 | The preparation method of polysubstituted pyrrole derivative |
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| ROBERTO DI SANTO ET AL.: "A general, versatile synthesis of 2H-pyrrolo[3,4-c]quinolines via tosylmethylisocyanide reaction", 《ARKIVOC》 * |
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| CN107501136A (en) * | 2017-09-19 | 2017-12-22 | 西南大学 | A kind of method prepared together with diaryl methylamines |
| CN108440365A (en) * | 2018-06-28 | 2018-08-24 | 淮阴师范学院 | The preparation method of polysubstituted pyrrole derivative |
| CN108440365B (en) * | 2018-06-28 | 2021-10-29 | 淮阴师范学院 | Process for preparing polysubstituted pyrrole derivatives |
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