CN106749235B - 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 the preparation methods of a kind of poly-substituted quinoline and azole derivatives.Amino chalcone and aldehyde, which are condensed, is made chalcone imines, then with glycinate imines, connected and be cyclized by Michael/Mannich, acidification, containing there are four the poly-substituted quinoline of chiral centre and azole derivatives shown in the production (I) of high cis-selectivity.The present invention is based on tandem reaction, have that environmental-friendly, synthesis step is easy, the advantage of Atom economy, cis-selectivity, and reaction condition is mild, substrate spectrum applicability is wide, safety easy to operate, is suitable for industrialized production.
Description
Technical field
The present invention relates to the preparation methods of a kind of poly-substituted quinoline and azole derivatives, belong to Synthetic Organic Chemistry technology neck
Domain.
Background technique
Quino azole derivatives are a kind of very important structural units, are widely present in biologically active chemical combination
In object and natural products.For example, Aplidiopsamine A is obtained by extracting in ascidian body, it can be used for the treatment of malaria
(J. Org. Chem.2010,75,8291-8294).5-HTRs Ligands-1(J. Med. Chem. 2012,55,
It 9446-9466) can be used as the regulator of 5-hydroxytryptamine receptor with 5-HTRs Ligands-2 (2006/0014778 A1 of US),
For the treatment of a variety of diseases, such as: metabolic disease comprising but it is not limited to obesity, diabetes, diabetic complication moves
Pulse atherosclerosis bears glucose tolerance and dyslipidemia;Central nervous system disease, including but not limited to anxiety, depression
Disease, obsessive-compulsive disorder, panic disorder, mental disease, schizophrenia, sleep disturbance, sexual dysfunction and social phobia headache;Migraine and
Enterogastric diseases.Cryptolepine is to extract and have been shown to have antibacterial, anti-hypertension, anti-muscarine from shrub plant
Etc. bioactivity natural materials (Bioorg. Med. Chem. 2011,19,7519-7525).
。
Roberto Di Santo, Roberta Costi et al. is with 3- O-Nitrophenylfluorone ethyl acrylate and to methylbenzene
Sulfonymethyl isonitrile is starting material, and 4- O-Nitrophenylfluorone -1H- pyrroles's -3- Ethyl formate is made under sodium hydride effect first；
Nitro is reduced to ammonia under the conditions of iron powder and 85 DEG C of acetic acid in gained intermediate 4- O-Nitrophenylfluorone -1H- pyrroles's -3- Ethyl formate
Base then occurs cyclization and obtains 2H- pyrroles [3,4, c] and quinoline -4 (5H) -one；It then is Asia by carbonyl reduction with lithium aluminium hydride
Methyl finally obtains quino azole compounds by elimination reaction.The synthesis is completed by four-step reaction, due to needing to use
The sodium hydride of strong basicity and higher reaction temperature, therefore, application be restricted (ARKIVOC. v, 2004,181-
195).
Liu Dong, Guo Tingting, Wang Weiping etc. report another synthetic route, which first will from 2-Pyrrolidone
Amino is protected, and is then hydroxyl by carbonyl reduction by DIBAL-H, is then passed through elimination reaction and obtain the 2,3- of N-protected
Pyrrolin；Resulting N-protected 2,3- pyrrolin and paranitroanilinum, glyoxylic acid ethyl ester will be prepared after tandem reaction
Quino azole compounds can be obtained with DDQ oxidation again.This method severe reaction conditions, and protection/deprotection steps are needed, synthesize road
Wire length increases synthesis cost (Acta Pharmaceutica Sinica, 51,2016,762-769).
In order to overcome drawbacks described above, present invention aims at open a kind of anti-based on Michael/Mannich series connection cyclisation
It answers, the method for the synthesis poly-substituted quinoline and azole derivatives of high cis-selectivity.The method raw material is cheap and easy to get, and route is short,
Simplify treatment process, it is only necessary to which primary purification, safety easy to operate are suitable for industrialized production.
Summary of the invention
The present invention can overcome the disadvantages that the shortcomings that existing synthetic method, efficiently synthesize quino azole derivatives.The purpose of the present invention
It is to disclose the synthetic method of a kind of poly-substituted quinoline and azole derivatives, this method raw material is easy to get, and preparation route is short, operation letter
It is single, it is at 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 tandem reaction constructs quinoline ring, hydrolyzes to obtain the quino pyrrole derivatives as shown in formula (I) through acid solution
Object.The present invention provides the preparation methods of a kind of simple, efficient poly-substituted quinoline and azole derivatives.
The invention discloses the preparation methods of a kind of poly-substituted quinoline of high cis-selectivity and azole derivatives, with letter
Single raw material aldehyde, amino chalcone and glycinate imines are that raw material is concatenated Michael and Mannich reaction, after acid processing
Obtain the quino azole derivatives as shown in formula (I), wherein R1For aromatic group, alkyl, R2For aromatic group, alkane
Base, R3For aromatic group, alkyl, hydrogen, R4For aromatic group, alkyl, hydrogen, R5For aromatic group, alkyl.
。
The preparation method of quino azole derivatives of the present invention, shown in reaction process formula (II):.
。
In the present invention, " the synthesis poly-substituted quinoline and azole derivatives of high cis-selectivity " referring to tool, there are four chiral
The quino azole derivatives at center, cis-selectivity are greater than 20:1.
Wherein, R1For phenyl, alkyl and with the phenyl of substituent group, R2For aromatic group, alkyl, R3For aromatic series base
Group, alkyl, hydrogen, R4For aromatic group, alkyl, hydrogen, R5For aromatic group, alkyl, compound 2 is that N- diphenyl methylene-is sweet
Propylhomoserin ester.
Preparation method of the present invention includes: that amino chalcone, aromatic aldehyde, magnesium sulfate and organic solvent are added in reaction flask,
Reaction is stirred at room temperature；Wherein, organic solvent additional amount is 2-5mL/mmol amino chalcone.Then, filter is concentrated after filtering
Liquid is added N- diphenyl methylene-tert-butyl glycinate, triethylamine and organic solvent, reacts at room temperature；Wherein, organic solvent adds
Entering amount is 10-20mL/mmol amino chalcone.Then filtrate is concentrated, organic solvent is added and dissolves reactant, adjusts pH into
Property, 10% aqueous citric acid solution is added, is stirred to react at room temperature, revolving removal solvent obtains crude product, chromatographs through column, obtains institute
State quino azole derivatives；Wherein organic solvent additional amount is 5-20mL/mmol amino chalcone, citric acid solution additional amount
For 4.5mL/mmol amino chalcone.
Wherein, the amino chalcone is E-3- (2- aminophenyl) -1- phenyl -2- propylene -1- ketone, which can be by
O-nitrobenzaldehyde and acetophenone reaction are prepared by the method for iron powder reducing again.(J. Org. Chem. 2014,79 is please referred to,
8440-8446)
In the present invention, N- diphenyl methylene-tert-butyl glycinate can be prepared by benzophenone imine and chloroacetic acid tert-butyl ester.
(please referring to Journal of Fluorine Chemistry. 2007,128,78-83).
Wherein, in the first step, the molar ratio of amino chalcone and aromatic aldehyde is 1:1；In second step, chalcone imines and N-
Diphenyl methylene-tert-butyl glycinate ratio is 1:1.
In the present invention, the aromatic aldehyde is P-methoxybenzal-dehyde, piperonal, fluorobenzaldehyde, and tolyl aldehyde is right
Bromobenzaldehyde, p-chlorobenzaldehyde, p-trifluoromethyl benzaldehyde, o-bromobenzaldehye, o-chlorobenzaldehyde, m-methoxybenzaldehyde are right
Fluorobenzaldehyde and benzaldehyde.Above compound is bought by market.
Wherein, the organic solvent is methylene chloride, toluene or tetrahydrofuran.
Benzaldehyde used in the present invention, acetophenone, the benzaldehyde containing substituent group, benzophenone imine, chloroacetic acid tert-butyl ester, lemon
Lemon acid, iron powder and organic solvent can market buy.
It is an object of that present invention to provide a kind of raw materials to be easy to get, and preparation route is short, easy to operate, atom economy height 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, generate poly-substituted quinoline and azole derivatives.First two steps are not required to purify, by simply separating, 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 the energy goods and materials such as reagent and solvent needed for changing operation, this method is environmentally protective, energy-efficient.In addition, the present invention is also
With good stereoselectivity, can the tool that obtains of high cis-selectivity there are four compound 1(dr > 20 of chiral centre:
1).
Specific embodiment
In conjunction with following specific embodiments, the present invention is described in further detail, and of the invention protects content not limit to
In following embodiment.Without departing from the spirit and scope of the invention, those skilled in the art it is conceivable that variation and excellent
Point is all included in the present invention, and using appended claims as protection scope.Implement process of the invention, condition,
Reagent, experimental method etc. are among the general principles and common general knowledge in the art, this hair in addition to what is specifically mentioned below
It is bright that there are no special restrictions to content.
The specific steps of preparation method of the present invention include: to weigh amino chalcone to react with the molar ratio of aldehyde for 1:1 addition
In bottle, the amount that magnesium sulfate is added is 1.176g/mmol, and addition organic solvent amount is 2-5mL/mmol, and reaction is stirred at room temperature
Overnight.Then, filtrate is concentrated after filtering, 1 equivalent N- diphenyl methylene-glycinate, 1 eq of triethylamine, organic solvent is added
Additional amount is 10-20mL/mmol, is reacted 24 hours at room temperature.Then filtrate is concentrated, organic solvent is added and dissolves reactant, adjusts
PH is saved to neutrality, 10% aqueous citric acid solution is added, is stirred to react at room temperature 24 hours, revolving removal solvent obtains crude product.It will
Crude product is ethyl acetate with volume ratio: petroleum ether=1:10 solution center pillar chromatography obtains the poly-substituted quinoline and pyrroles spreads out
Biological sterling.
Example 1 prepares tert-butyl 3,4- diphenyl -3a, 4,5,9b- tetrahydro-1 H-pyrrolo simultaneously [3,4-c] quinoline -1- carboxylic acid
Ester.
。
Weigh E-3- (2- aminophenyl) -1- phenyl -2- propylene -1- ketone (1.0mmol), benzaldehyde (1.0mmol), sulfuric acid
Magnesium (1.176g) is added in round-bottomed flask, and organic solvent 2mL is added, is stirred overnight at room temperature.Filtrate is concentrated after filtering, N- is added
Diphenyl methylene-tert-butyl glycinate (1.0mmol), triethylamine (1.0mmol) are added organic solvent 10mL, are stirred at room temperature 24
Hour.Then filtrate is concentrated, organic solvent is added and dissolves reactant, adjusts pH to neutrality, 10% aqueous citric acid solution, room is added
It is stirred to react under temperature 24 hours, revolving removal solvent, then passes through column chromatography (eluant, eluent: petroleum ether: ethyl acetate=10:1) separation
Quino azole derivatives A, yield 82%, dr > 20:1 are obtained out.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 tert-butyl 4- p-fluorophenyl -3- phenyl -3a, 4,5,9b- tetrahydro-1 H-pyrrolo simultaneously [3,4-c] quinoline
Quinoline -1- carboxylate.
。
Weigh E-3- (2- aminophenyl) -1- phenyl -2- propylene -1- ketone (1.0mmol), 4-Fluorobenzaldehyde (1.0mmol),
Magnesium sulfate (1.176g) is added in round-bottomed flask, and organic solvent 2mL is added, is stirred overnight at room temperature.Then, filter is concentrated after filtering
Liquid, is added N- diphenyl methylene-tert-butyl glycinate (1.0mmol), and organic solvent 10mL, room is added in triethylamine (1.0mmol)
Temperature stirring 24 hours.Then filtrate is concentrated, organic solvent is added and dissolves reactant, adjusts pH to neutrality, 10% citric acid water is added
Solution is stirred to react 24 hours at room temperature, revolving removal solvent, then by column chromatograph (eluant, eluent: petroleum ether: ethyl acetate=
It 10:1) isolates to 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 tert-butyl 4- m-methoxyphenyl -3- phenyl -3a, 4,5,9b- tetrahydro-1 H-pyrrolo simultaneously [3,4-c]
Quinoline -1- carboxylate.
。
Weigh E-3- (2- aminophenyl) -1- phenyl -2- propylene -1- ketone (1.0mmol), m-methoxybenzaldehyde
(1.0mmol), magnesium sulfate (1.176g) are added in round-bottomed flask, and organic solvent 2mL is added, is stirred overnight at room temperature.Then, mistake
Filtrate is concentrated after filter, N- diphenyl methylene-tert-butyl glycinate (1.0mmol) is added, triethylamine (1.0mmol) is added organic
Solvent 10mL is stirred at room temperature 24 hours.Then filtrate is concentrated, organic solvent is added and dissolves reactant, adjusts pH to neutrality, is added
10% aqueous citric acid solution is stirred to react 24 hours at room temperature, revolving removal solvent, then by column chromatograph (eluant, eluent: petroleum ether:
Ethyl acetate=10:1) it isolates to 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 tert-butyl 4- Chloro-O-Phenyl -3- phenyl -3a, 4,5,9b- tetrahydro-1 H-pyrrolo simultaneously [3,4-c] quinoline
Quinoline -1- carboxylate.
。
Weigh E-3- (2- aminophenyl) -1- phenyl -2- propylene -1- ketone (1.0mmol), o-chlorobenzaldehyde (1.0mmol),
Magnesium sulfate (1.176g) is added in round-bottomed flask, and organic solvent 2mL is added, is stirred overnight at room temperature.Then, filter is concentrated after filtering
Liquid, is added N- diphenyl methylene-tert-butyl glycinate (1.0mmol), and organic solvent 10mL, room is added in triethylamine (1.0mmol)
Temperature stirring 24 hours.Then filtrate is concentrated, organic solvent is added and dissolves reactant, adjusts pH to neutrality, 10% citric acid water is added
Solution is stirred to react 24 hours at room temperature, revolving removal solvent, then by column chromatograph (eluant, eluent: petroleum ether: ethyl acetate=
It 10:1) isolates to 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 tert-butyl 4- o-bromophenyl -3- phenyl -3a, 4,5,9b- tetrahydro-1 H-pyrrolo simultaneously [3,4-c] quinoline
Quinoline -1- carboxylate.
。
Weigh E-3- (2- aminophenyl) -1- phenyl -2- propylene -1- ketone (1.0mmol), o-bromobenzaldehye (1.0mmol),
Magnesium sulfate (1.176g) is added in round-bottomed flask, and organic solvent 2mL is added, is stirred overnight at room temperature.Then, filter is concentrated after filtering
Liquid, is added N- diphenyl methylene-tert-butyl glycinate (1.0mmol), and organic solvent 10mL, room is added in triethylamine (1.0mmol)
Temperature stirring 24 hours.Then filtrate is concentrated, organic solvent is added and dissolves reactant, adjusts pH to neutrality, 10% citric acid water is added
Solution is stirred to react 24 hours at room temperature, revolving removal solvent, then by column chromatograph (eluant, eluent: petroleum ether: ethyl acetate=
It 10:1) isolates to 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 tert-butyl 4- p-trifluoromethyl phenyl -3- phenyl -3a, 4,5,9b- tetrahydro-1 H-pyrrolo simultaneously [3,4-
C] quinoline -1- carboxylate.
。
Weigh E-3- (2- aminophenyl) -1- phenyl -2- propylene -1- ketone (1.0mmol), p-trifluoromethyl benzaldehyde
(1.0mmol), magnesium sulfate (1.176g) are added in round-bottomed flask, and organic solvent 2mL is added, is stirred overnight at room temperature.Then, mistake
Filtrate is concentrated after filter, N- diphenyl methylene-tert-butyl glycinate (1.0mmol) is added, triethylamine (1.0mmol) is added organic
Solvent 10mL is stirred at room temperature 24 hours.Then filtrate is concentrated, organic solvent is added and dissolves reactant, adjusts pH to neutrality, is added
10% aqueous citric acid solution is stirred to react 24 hours at room temperature, revolving removal solvent, then by column chromatograph (eluant, eluent: petroleum ether:
Ethyl acetate=10:1) it isolates to 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 tert-butyl 4- rubigan -3- phenyl -3a, 4,5,9b- tetrahydro-1 H-pyrrolo simultaneously [3,4-c] quinoline
Quinoline -1- carboxylate.
。
Weigh E-3- (2- aminophenyl) -1- phenyl -2- propylene -1- ketone (1.0mmol), p-chlorobenzaldehyde (1.0mmol),
Magnesium sulfate (1.176g) is added in round-bottomed flask, and organic solvent 2mL is added, is stirred overnight at room temperature.Then, filter is concentrated after filtering
Liquid, is added N- diphenyl methylene-tert-butyl glycinate (1.0mmol), and organic solvent 17mL, room is added in triethylamine (1.0mmol)
Temperature stirring 24 hours.Then filtrate is concentrated, organic solvent is added and dissolves reactant, adjusts pH to neutrality, 10% citric acid water is added
Solution is stirred to react 24 hours at room temperature, revolving removal solvent, then by column chromatograph (eluant, eluent: petroleum ether: ethyl acetate=
It 10:1) isolates to 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 tert-butyl 4- p-bromophenyl -3- phenyl -3a, 4,5,9b- tetrahydro-1 H-pyrrolo simultaneously [3,4-c] quinoline
Quinoline -1- carboxylate.
。
Weigh E-3- (2- aminophenyl) -1- phenyl -2- propylene -1- ketone (1.0mmol), p-bromobenzaldehyde (1.0mmol),
Magnesium sulfate (1.176g) is added in round-bottomed flask, and organic solvent 2mL is added, is stirred overnight at room temperature.Then, filter is concentrated after filtering
Liquid, is added N- diphenyl methylene-tert-butyl glycinate (1.0mmol), and organic solvent 17mL, room is added in triethylamine (1.0mmol)
Temperature stirring 24 hours.Then filtrate is concentrated, organic solvent is added and dissolves reactant, adjusts pH to neutrality, 10% citric acid water is added
Solution is stirred to react 24 hours at room temperature, revolving removal solvent, then by column chromatograph (eluant, eluent: petroleum ether: ethyl acetate=
It 10:1) isolates to 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: it calculates
Value: C28H27BrN2O2, [M+Na]+525.1148;Measured value: 525.1146.
Example 9 prepares between tert-butyl 4- tolyl -3- phenyl -3a, 4,5,9b- tetrahydro-1 H-pyrrolo simultaneously [3,4-c] quinoline
Quinoline -1- carboxylate.
。
Weigh E-3- (2- aminophenyl) -1- phenyl -2- propylene -1- ketone (1.0mmol), tolyl aldehyde
(1.0mmol), magnesium sulfate (1.176g) are added in round-bottomed flask, and organic solvent 2mL is added, is stirred overnight at room temperature.Then, mistake
Filtrate is concentrated after filter, N- diphenyl methylene-tert-butyl glycinate (1.0mmol) is added, triethylamine (1.0mmol) is added organic
Solvent 10mL is stirred at room temperature 24 hours.Then filtrate is concentrated, organic solvent is added and dissolves reactant, adjusts pH to neutrality, is added
10% aqueous citric acid solution is stirred to react 24 hours at room temperature, revolving removal solvent, then by column chromatograph (eluant, eluent: petroleum ether:
Ethyl acetate=10:1) it isolates to 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: it calculates
Value: C29H30N2O2, [M+Na]+461.2199;Measured value: 461.2200.
Example 10 prepares between tert-butyl 4- fluorophenyl -3- phenyl -3a, 4,5,9b- tetrahydro-1 H-pyrrolo simultaneously [3,4-c] quinoline
Quinoline -1- carboxylate.
。
Weigh E-3- (2- aminophenyl) -1- phenyl -2- propylene -1- ketone (1.0mmol), fluorobenzaldehyde (1.0mmol),
Magnesium sulfate (1.176g) is added in round-bottomed flask, and organic solvent 2mL is added, is stirred overnight at room temperature.Then, filter is concentrated after filtering
Liquid, is added N- diphenyl methylene-tert-butyl glycinate (1.0mmol), and organic solvent 20mL, room is added in triethylamine (1.0mmol)
Temperature stirring 24 hours.Then filtrate is concentrated, organic solvent is added and dissolves reactant, adjusts pH to neutrality, 10% citric acid water is added
Solution is stirred to react 24 hours at room temperature, revolving removal solvent, then by column chromatograph (eluant, eluent: petroleum ether: ethyl acetate=
It 10:1) isolates to 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 prepares tert-butyl 4- (1,3- (methylene-dioxy) -5- phenyl) -3- phenyl -3a, 4,5,9b- tetrahydro -
1H- pyrrolo- [3,4-c] quinoline -1- carboxylate.
。
Weigh E-3- (2- aminophenyl) -1- phenyl -2- propylene -1- ketone (1.0mmol), piperonal (1.0mmol), sulfuric acid
Magnesium (1.176g) is added in round-bottomed flask, and organic solvent 2mL is added, is stirred overnight at room temperature.Then, filtrate is concentrated after filtering, adds
Enter N- diphenyl methylene-tert-butyl glycinate (1.0mmol), organic solvent 10mL is added in triethylamine (1.0mmol), and room temperature is stirred
It mixes 24 hours.Then filtrate is concentrated, organic solvent is added and dissolves reactant, adjusts pH to neutrality, it is water-soluble that 10% citric acid is added
Liquid is stirred to react 24 hours at room temperature, revolving removal solvent, then by column chromatograph (eluant, eluent: petroleum ether: ethyl acetate=10:
1) it isolates to 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 tert-butyl 4- p-methoxyphenyl -3- phenyl -3a, 4,5,9b- tetrahydro-1 H-pyrrolo simultaneously [3,4-
C] quinoline -1- carboxylate.
。
Weigh E-3- (2- aminophenyl) -1- phenyl -2- propylene -1- ketone (1.0mmol), p-tolyl aldehyde
(1.0mmol), magnesium sulfate (1.176g) are added in round-bottomed flask, and organic solvent 2mL is added, is stirred overnight at room temperature.Then, mistake
Filtrate is concentrated after filter, N- diphenyl methylene-tert-butyl glycinate (1.0mmol) is added, triethylamine (1.0mmol) is added organic
Solvent 12mL is stirred at room temperature 24 hours.Then filtrate is concentrated, organic solvent is added and dissolves reactant, adjusts pH to neutrality, is added
10% aqueous citric acid solution is stirred to react 24 hours at room temperature, revolving removal solvent, then by column chromatograph (eluant, eluent: petroleum ether:
Ethyl acetate=10:1) it isolates to 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, it is stated that preferred embodiment above is only used to illustrate the technical scheme of the present invention and not to limit it, although logical
It crosses above preferred embodiment the present invention is described in detail, however, those skilled in the art should understand 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 (4)
1. the preparation method of poly-substituted quinoline and azole derivatives, which is characterized in that be condensed first with amino chalcone and aldehyde
Chalcone imines is made, is then that raw material passes through Michael addition and Mannich with chalcone imines and glycinate imines 2
The poly-substituted quinoline as shown in formula (I) and azole derivatives is prepared through peracid treatment in series connection cyclization；
Formula (I)
Wherein, R1For phenyl；R2For phenyl, p-fluorophenyl, m-methoxyphenyl, Chloro-O-Phenyl, o-bromophenyl, to trifluoromethyl
Phenyl, rubigan, p-bromophenyl, aminomethyl phenyl, fluorophenyl, p-methoxyphenyl and 1,3- (methylene-dioxy)-
5- phenyl；R5For tert-butyl；
The preparation method such as formula () shown in,
Process type ()
Wherein, R1For phenyl；R2For phenyl, p-fluorophenyl, m-methoxyphenyl, Chloro-O-Phenyl, o-bromophenyl, to trifluoromethyl
Phenyl, rubigan, p-bromophenyl, aminomethyl phenyl, fluorophenyl, p-methoxyphenyl and 1,3- (methylene-dioxy)-
5- phenyl；R3, R4For phenyl；R5For tert-butyl；
The following steps are included:
Step (1), weighs raw material, by amino chalcone: aldehyde: glycinate imines 2: alkali: magnesium sulfate: sour molar ratio is 1:1:
1:1:9.8:2.6；The amino chalcone and aldehyde are dehydrated through magnesium sulfate, imine intermediate is made；
Step (2) is stirred at room temperature 24 hours by gained imine intermediate, glycinate imines 2 and alkali soluble in organic solvent；
Gained mixture is adjusted pH to neutrality, aqueous acid is added, is stirred to react at room temperature 24 hours, except molten by step (3)
Agent chromatographs to obtain quino azole derivatives by column；
Wherein, the alkali is achirality organic base；Acid is achiral carboxylic acids or sulfonic acid；The solvent is methylene chloride, tetrahydro furan
It mutters, 1,2- dichloroethanes, chloroform, toluene, paraxylene, trimethylbenzene, acetonitrile or ether.
2. preparation method as described in claim 1, which is characterized in that the amino chalcone is trans- ketenes.
3. preparation method as described in claim 1, which is characterized in that the dosage of the solvent is the amino chalcone dosage
50-100 times.
4. preparation method as described in claim 1, which is characterized in that the reaction yield of the preparation method is 40%-82%.
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