CN109705098A - A kind of fragrance helical fold body and its preparation method and application - Google Patents
A kind of fragrance helical fold body and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of fragrant helical fold bodies and its preparation method and application.Fragrance helical fold body provided by the present invention is dimethyl 8,8'- ((8,8'- (((pyridine -2,6- dicarbapentaborane) bis- (azepine diyls)) bis- (carbonyls)) bis- (4- isobutoxy quinoline -2,2'- carbonyls)) bis- (azane diyls)) bis- (4- (2- (tert-butoxy) -2- oxoethoxy) quinaldic acid's tert-butyl esters).Synthetic method, 8 are prepared first, 8'- ((pyridine -2,6- dicarbapentaborane) is bis- (azepine diyl)) bis- (carbonyls)) bis- (4- isobutoxy quinoline -2- phosgenes), then prepare target fragrance helical fold body.Currently, helical structure shows that unprecedented potentiality, the present invention successfully synthesize fragrant helical fold body in fields such as chiral separation, molecular recognition, display materials, new thinking and approach are provided for fragrant constructing for helical structure.
Description
Technical field
The invention belongs to the designs of helical fold body to synthesize field, specifically a kind of fragrant helical fold body and its system
Preparation Method and application.
Background technique
Helical structure is nuclear structure important in organism, their function is exquisite and complicated.Widely known can control
The DNA of system heredity is exactly double-spiral structure, it can complete the storage and transmitting of hereditary information.Additionally, there are in memebrane protein
α spiral, it can be achieved that inside and outside cell membrane substance transmission and specific recognition.These helical structures are all in the life entity of people
Play highly important role.So rationally designing and constructing artificial spiral, the function of imitating natural helix is current research
Heat subject.
There are huge application potentials, such as Zeng Huaqiang et al. to utilize helical structure structure in all various aspects for artificial helical structure
Moisture subchannel is built, Huc et al. realizes Selective recognition and the encapsulation to carbohydrate by the helical structure of rational structure.
Yashima et al. has built the chiral column with controllable eluting order using the chiral memory characteristic of helical structure.
In recent years, the artificial helical structure of people's building can be divided into aromatics spiral, fat according to the difference of spiral skeleton
Class spiral, fragrance-fat hybridization spiral and supermolecule spiral.Wherein fatty spiral is due to its dependence to weak force, structure
It is extremely unstable.Hybridization spiral, usually fragrant plane and aliphatic chain are alternately arranged, although having both fragrant spiral and fatty spiral shell
The double grading of rotation, but the holding tool of its helical structure acquires a certain degree of difficulty.Supermolecule spiral, the building of structure compare above two
Although kind is simple, the research of its formation mechenism and the arrangement of specific conformation is but slightly aobvious difficult.And aromatics spiral, main chain knot
Aromatic ring in structure is connected and fixed by rigid key, per se with certain angle.In addition π-the π between lamella aromatic ring is acted on,
As the increase of molecular length forms helical structure.The helical structure is stable and predictable, no matter in liquid phase or solid phase all
It is able to maintain conformational stability.So fragrant spiral is the key object of research in the helical structure of numerous kinds.
Summary of the invention
The present invention provides a kind of fragrant helical fold bodies and its preparation method and application.The fragrance helical fold body point
Son, IUPAC name are as follows: dimethyl 8, ((8,8'- (((pyridine -2,6- dicarbapentaborane) is bis- (azepine diyl)) bis- (carbonyls)) are double by 8'-
(4- isobutoxy quinoline -2,2'- carbonyl)) bis- (azane diyls)) bis- (4- (2- (tert-butoxy) -2- oxoethoxy) quinoline -
2- carboxylic acid tert-butyl ester), new thinking and approach are provided for fragrant constructing for helical structure.
The technical scheme is that
A kind of fragrance helical fold body, fragrant helical fold body molecule, IUPAC name are as follows: dimethyl 8,8'- ((8,8'-
(((pyridine -2,6- dicarbapentaborane) is bis- (azepine diyl)) bis- (carbonyls)) is bis- (4- isobutoxy quinoline -2,2'- carbonyl)) bis- (azane
Diyl)) bis- (4- (2- (tert-butoxy) -2- oxoethoxy) quinaldic acid's tert-butyl esters), molecular formula is as follows:
A kind of preparation method of fragrance helical fold body, specific preparation process are as follows;
The synthetic route for preparing the tripolymer oligomer containing double acyl chlorides active groups is as follows:
Step A: 2- aminobenzamide is used and dimethyl butyn is fed intake with molar ratio 1:1.1~1.5, with methanol
For solvent, it is stirred at room temperature and is uniformly mixed to it, is heated to reflux 8 hours,
It standing to room temperature, and is put into -20 DEG C of refrigerator overnight, next day filter and washs filter cake repeatedly with ice methanol,
Until filtrate achromaticity and clarification, after the sufficiently drying of 30~40 DEG C of vacuum state, collection obtains pulverulent solids product 1,2- (2- amino
Fonnylphenyl) amino) dimethyl maleate;
Step B: prepare appropriate diphenyl ether, diphenyl ether quality: quality=21.5:1 of solid product 1 is slowly heated to 250
DEG C fluidized state, the quick thorough dried solid product 1 of investment later, sustained response 12~14 minutes,
Mixed solution is cooled to 50 DEG C or so, equal volume amounts petroleum ether, side stirring are added into diphenyl ether mixed solution
It fills and in the petroleum ether of mixed solution equal volume amounts, places to Precipitation, filtering, and the filter that will be obtained while solution is poured into
Cake is sufficiently washed with petroleum ether until filtrate achromaticity and clarification, after the sufficiently drying of 30~35 DEG C of vacuum oven, collection obtains powder
Shape solid product 2,8- carbamoyl -4- oxyquinoline -2- carboxylate methyl ester;
Step C: by sufficiently dry solid product 2, triphenylphosphine and isobutanol with molar ratio 1:(1.1~1.3): (1.1
~1.5) it feeds intake, using tetrahydrofuran as solvent, system is sealed, be slowly added to while stirring into flask under condition of ice bath
The diisopropyl azodiformate of 2.2 times of equivalents after stirring 30~45 minutes or so, then is stirred at room temperature about 5 hours,
Remove solvent, solid residue is utilized methanol: chloroform volume ratio is (4~5): 1 solvent recrystallizes, most
Afterwards, obtained precipitating is filtered, filter cake is put into vacuum oven, sufficiently dries, obtains powdered solid under the conditions of 30~35 DEG C
Body product 3,8- carbamoyl -4- isobutoxy quinaldic acid's methyl esters;
Step D: with mass ratio being 1:(16.38~24.57 by 2,6- pyridine dicarboxylic acid and thionyl chloride) mixed solution
Back flow reaction 4~5 hours,
Heating under reduced pressure removes excessive thionyl chloride, obtains 4,2,6- dicarbapentaborane dichloropyridine of compound;
Step E: by 2,6- dicarbapentaborane dichloropyridine with solid product 3 with molar ratio 1:(2.2~2.5) it mixes, with drying
Chloroform be solvent, and be added 2.5~3 times of equivalents dry triethylamine, by solution under air-proof condition and nitrogen protection,
30 DEG C mechanical stirring 15~17 hours,
Organic phase washed with water and chloroform are washed, the organic phase merged, the solution that will be obtained utilizes chromatography
Column analytic approach, with methylene chloride: methanol is 100:1 as leacheate using volume ratio and is separated that obtained solution is revolved through evaporation
It is dry, then it is sufficiently dried to obtain powdery product 5, dimethyl 8,8'- (((pyridine -2,6- dicarbapentaborane) is bis- (azepine diyl))
Bis- (carbonyls)) bis- (4- isobutoxy quinaldic acid esters);
Step F: powdery product 5 is dissolved in tetrahydrofuran solution, and the NaOH of 4~4.5 times of equivalents is dissolved in
It in a small amount of methanol, instills in former solution under stirring, stirs 5~6 hours at room temperature,
PH is adjusted to 6.0 with appropriate hydrochloric acid (1.0mol/L), solvent is evaporated to dryness, residue is sufficiently washed with water,
Filtering, finally dries, obtains powdery product 6,8,8'- (((pyridine -2,6- dicarbapentaborane) is bis- (azepine diyl)) bis- (carbonyls))
Bis- (4- isobutoxy quinaldic acids);
Step G: with mass ratio being 1:(16.38~24.57 by powdery product 6 and thionyl chloride) mixed solution reflux
Reaction 4~5 hours,
Heating under reduced pressure removes excessive thionyl chloride, obtains (((pyridine -2, the 6- dicarbapentaborane) bis- (nitrogen of compound 7,8,8'-
Miscellaneous diyl)) bis- (carbonyls)) bis- (4- isobutoxy quinoline -2- phosgenes);
The synthesis step for preparing the strong-hydrophobicity helical fold body that aromatic structure is skeleton is as follows:
Step H: by compound 8 (4- hydroxyl -8- nitro -2- 2-methyl naphthoate) and 2- bromo-acetic acid tert-butyl with molar ratio 1:
(1.2~1.5) feed intake, and the KI of catalytic amount is added, and appropriate acetonitrile is added later and flows back 6~9 hours,
After fully reacting, remove solvent, and with methylene chloride: methanol is 50:1 as leacheate using volume ratio and carries out column layer
Analysis separation, obtained solution are spin-dried for through evaporation, sufficiently dry, obtain powdery product 9,4- (2- (tert-butoxy) -2- oxo
Ethyoxyl) -8- nitro -2- 2-methyl naphthoate;
Step I: it is the ethyl acetate of 2:1:0.3, in first alcohol and water that compound 9, which is well dispersed in volume ratio, to solution
The middle pd/C that catalytic amount is added, the ammonium formate of 5 times of quality are finally rapidly added the ammonium metavanadate of 1.3~1.5 times of quality, will hold
Device sealing, stirring at normal temperature 2~3 hours,
Mixed solution is filtered, sufficiently washs filter cake with ethyl acetate, until the filtrate of outflow is almost colourless, collects filtrate,
Water phase is separated, the solvent in organic phase is removed, is extracted with saturated sodium bicarbonate solution and methylene chloride, obtained organic phase
After being evaporated, dry powdered compounds 10,8- amino -4- (2- (tert-butoxy) -2- oxoethoxy) -2- naphthalene can be obtained
Methyl formate;
Step J: by the compound 7 of above-mentioned acquisition and compound 10 with molar ratio 1:(2.2~2.5) ratio be added it is anhydrous
In chloroform, the triethylamine of 3 times of equivalents is then added, is stirred 48 hours under the conditions of 30 DEG C,
Obtained organic phase is washed with water after first being washed with ethyl acetate, and organic phase is merged, and it is solid that anhydrous magnesium sulfate is added
Body is dried, and by the solution after drying, after heating in vacuum is evaporated, using column chromatographic assays, with methylene chloride: methanol is with body
Than being that 30:1 is separated as leacheate, obtained solution is spin-dried for through evaporation, then is sufficiently dried to obtain powdered products product
Object 11, dimethyl 8,8'- ((8,8'- (((pyridine -2,6- dicarbapentaborane) is bis- (azepine diyl)) bis- (carbonyls)) bis- (4- isobutoxies
Quinoline -2,2'- carbonyl)) bis- (azane diyls)) bis- (4- (2- (tert-butoxy) -2- oxoethoxy) tertiary fourths of quinaldic acid
Ester).
It is a kind of fragrance helical fold body chiral separation, molecular recognition and display material field application.
The beneficial effects of the present invention are:
The present invention provides a kind of novel fragrant helical fold body dimethyl 8,8'- ((8,8'- (((pyridines -2,6- bis-
Carbonyl) bis- (azepine diyls)) bis- (carbonyls)) bis- (4- isobutoxy quinoline -2,2'- carbonyls)) bis- (azane diyls)) bis- (4- (2-
(tert-butoxy) -2- oxoethoxy) quinaldic acid's tert-butyl ester) and its construct the preparation method of primitive.Primitive 8 is constructed,
8'- (((pyridine -2,6- dicarbapentaborane) is bis- (azepine diyl)) bis- (carbonyls)) bis- (4- isobutoxy quinoline -2- phosgenes) and 8- ammonia
It is entirely fragrance that base -4- (2- (tert-butoxy) -2- oxoethoxy) -2- 2-methyl naphthoate, which is keyed by amide and to form skeleton,
The helical fold body of structure, the benzene ring structure of adjacent phenyl rings and the intermolecular large volume of quinoline form strong pi-pi accumulation effect,
It is bent so that forming height between spatial slices and lamella, being stacked under effect between aromatic group obtains stable
Helical structure.It is because of helical fold body oligomerization that pyridine and quinoline molecular series, which are selected, as the primitive of constructing for forming helical structure
The folding behavior of object in the solution can be studied by the simple means such as UV-vis and fluorescence spectrum.In addition, quinoline point
Isobutyl sidechain and tert-butyl acetate side chain are introduced on son four respectively to increase the solubility of rigid oligomer.In detail
For, hydrogen on the intermolecular amido bond nitrogen of quinoline respectively with shape under the action of the nitrogen-atoms of adjacent quinoline molecule in the molecule hydrogen bond
At stable five-membered ring, effect that the hydrogen on the nitrogen-atoms of intermediate Pyridine Molecules and neighboring amide key nitrogen passes through intramolecular hydrogen bond
Two stable five-membered rings are formd, to limit the conformation of chain when chain folding, form it into stable helical structure.
Aromatics spiral, backbone structure are rigid aromatic ring structure, compared with traditional fatty spiral and hybridization spiral its
Helical structure is more stable, is easier to maintain in the liquid phase, in addition having between aromatic ring steady between certain angle and lamella
Fixed π-π effect, the helical structure of formation is stable and predictable, no matter conformational stability can be kept in liquid phase or solid phase.
Fragrant helical fold body prepared by the present invention, due to aromatic ring structure and the strong conjugation of piece interlayer, so that
It is of great significance to the research and development of photoelectric material with good light, electrical property.It introduces chiral radicals appropriate or passes through structure
The pharmaceutical intermediate raceme for being difficult to split can be separated as controlling obtained chiral helical structure, is had in chiral separation field
Huge application value.And be the extremely strong nitrogen-atoms of polarity and oxygen atom in the cavity of fragrant helical fold body, utilize its cavity
Interaction between interior atom and guest molecule, and by the control of helical molecule pore size, can be realized to molecule
Specific recognition has huge application prospect in molecular recognition field.Primitive is constructed using new simultaneously, for fragrant spiral knot
Constructing for structure provides new thinking and approach.
Detailed description of the invention
Fig. 1 is 5 dimethyl 8 of product, and bis- (4- is different by 8'- (((pyridine -2,6- dicarbapentaborane) is bis- (azepine diyl)) bis- (carbonyls))
Butoxy quinaldic acid ester) nuclear magnetic resonance spectroscopy spectrogram;
Fig. 2 is the nuclear-magnetism of 10 8- amino -4- of compound (2- (tert-butoxy) -2- oxoethoxy) -2- 2-methyl naphthoate
The hydrogen that resonates composes spectrogram;
Fig. 3 is 11 dimethyl 8 of product, 8'- ((8,8'- (((pyridine -2,6- dicarbapentaborane) is bis- (azepine diyl)) bis- (carbonyls
Base)) bis- (4- isobutoxy quinoline -2,2'- carbonyls)) bis- (azane diyls)) bis- (4- (2- (tert-butoxy) -2- oxo ethoxies
Base) quinaldic acid's tert-butyl ester) nuclear magnetic resonance spectroscopy spectrogram;
Fig. 4 is 11 dimethyl 8 of product, 8'- ((8,8'- (((pyridine -2,6- dicarbapentaborane) is bis- (azepine diyl)) bis- (carbonyls
Base)) bis- (4- isobutoxy quinoline -2,2'- carbonyls)) bis- (azane diyls)) bis- (4- (2- (tert-butoxy) -2- oxo ethoxies
Base) quinaldic acid's tert-butyl ester) Matrix-assisted laser desorption ionization spectrogram.
Fig. 5 a is 11 dimethyl 8 of product being calculated, 8'- ((8,8'- (((pyridine -2,6- dicarbapentaborane) bis- (azepines two
Base)) bis- (carbonyls)) bis- (4- isobutoxy quinoline -2,2'- carbonyls)) bis- (azane diyls)) bis- (4- (2- (tert-butoxy) -2-
Oxoethoxy) quinaldic acid's tert-butyl ester) most stable state when front shape illustrate.
Fig. 5 b is 11 dimethyl 8 of product being calculated, 8'- ((8,8'- (((pyridine -2,6- dicarbapentaborane) bis- (azepines two
Base)) bis- (carbonyls)) bis- (4- isobutoxy quinoline -2,2'- carbonyls)) bis- (azane diyls)) bis- (4- (2- (tert-butoxy) -2-
Oxoethoxy) quinaldic acid's tert-butyl ester) most stable state when reverse side shape illustrate.
Specific embodiment
Technical solution of the present invention is further explained and is illustrated in a manner of specific embodiment below.
The method that the application prepares the helical fold body comprising following steps:
Step 1: include the steps that preparing the tripolymer oligomer containing double acyl chlorides active groups, have the tripolymer both ends
There is the function of can be used for that condensation reaction is carried out with amino;
Step 2: including by double acid chloride groups on tripolymer and with amino active group and strong hydrophobic side chain acetic acid
The quinoline molecule of the tert-butyl ester reacts, and generates strong-hydrophobicity helical fold body (the application that aromatic structure is skeleton
Target product) the step of.
Embodiment 1
The synthetic route for preparing the tripolymer oligomer containing double acyl chlorides active groups is as follows:
Specific step is as follows for the preparation method of tripolymer oligomer containing double acyl chlorides active groups:
Step A: 10g 2- aminobenzamide is dissolved in round-bottomed flask with 30ml anhydrous methanol, by 2- aminobenzoic
Amide 10g and dimethyl butyn are fed intake with molar ratio 1:1.1, first by dimethyl butyn be dissolved in 15ml without water beetle
In alcohol, then it is slowly added drop-wise in round-bottomed flask, is stirred at room temperature and is uniformly mixed to it, is heated to reflux 8 hours.
It stands to room temperature, is put into -20 DEG C of refrigerator overnight.Next day is filtered and is carried out repeatedly to filter cake with ice methanol
Washing, until filtrate achromaticity and clarification.It is collected after the sufficiently drying of 30 DEG C of vacuum state and obtains glassy yellow product 1,2- (2- carbamoyl
Phenyl) amino) dimethyl maleate.
Step B: being slowly heated to 250 DEG C of fluidized states for 500ml diphenyl ether, afterwards rapidly produces 25g dry glassy yellow
Object 1 is added, and sustained response 13 minutes.
When mixed solution is cooled to 50 DEG C or so, equivalent petroleum ether is added into diphenyl ether mixed solution, while stirring
Solution is poured into the large beaker for filling 1000ml petroleum ether, is placed to Precipitation, filtering, and the filter cake petroleum that will be obtained
Ether sufficiently washs until filtrate achromaticity and clarification.Heating under reduced pressure is dried to abundant, and collects obtained brown solid 2,8- ammonia
Base formoxyl -4- oxyquinoline -2- carboxylate methyl ester.
Step C: by sufficiently dry solid product 2 (5g) and triphenylphosphine and isobutanol with molar ratio 1:1.1:1.1
It feeds intake, the dry tetrahydrofuran of 50ml is added later.System is sealed, is slowly added into flask while stirring under condition of ice bath
Enter the diisopropyl azodiformate of 2.2 times of equivalents, stirring is stirred at room temperature 5 hours again after 30 minutes or so.
Solvent is removed, using volume ratio be methanol by solid residue: chloroform is that the solvent of 4:1 recrystallizes.Finally, will
Obtained precipitating filtering, filter cake heating under reduced pressure is dried, powdery product 3,8- carbamoyl -4- isobutoxy are obtained
Quinaldic acid's methyl esters.
Step D: by 2,6- pyridine dicarboxylic acid 1.0g and mixed solution back flow reaction 4 hours of 16.4g thionyl chloride.
Heating under reduced pressure removes excessive thionyl chloride later, obtains 4,2,6- dicarbapentaborane dichloropyridine of compound;
Step E: 2,6- dicarbapentaborane dichloropyridine is mixed with powdery product 3 with molar ratio 1:2.2, with dry trichlorine
Methane is solvent, and the dry triethylamine of 2.5 times of equivalents is added.By solution sealing 30 DEG C and nitrogen protection under mechanical stirring 15
Hour.
And wash organic phase washed with water and chloroform, the organic phase merged, the solution that will be obtained utilizes column
Chromatographic assays, with methylene chloride: methanol is separated for 100:1 as leacheate using volume ratio, obtained solution, through evaporating
It is spin-dried for, then is sufficiently dried to obtain powdery product 5, dimethyl 8,8'- (((pyridine -2,6- dicarbapentaborane) bis- (azepines two
Base)) bis- (carbonyls)) bis- (4- isobutoxy quinaldic acid esters).
Tripolymer oligomer is carried out1H-NMR analysis, as shown in Figure 1, has determined the correctness of product structure.
1H NMR(500MHz,CDCl3) δ 14.46 (s, 2H), 8.83 (d, J=7.3Hz, 2H), 8.59 (d, J=7.7Hz,
2H), 8.24-8.18 (m, 3H), 7.67 (t, J=7.7Hz, 2H), 6.54 (s, 2H), 3.69 (d, J=6.5Hz, 10H), 2.31-
2.24 (m, 2H), 1.22 (d, J=6.7Hz, 12H)
Step F: powdery product 5 is dissolved in tetrahydrofuran solution, and the NaOH of 4 times of equivalents is dissolved in a small amount of methanol
In, it instills in former solution under stirring, stirs 5 hours at room temperature.
PH is adjusted to 6.0 with hydrochloric acid (1.0mol/L).Solvent is evaporated to dryness, residue is washed with water, and filtering is used in combination
Water sufficiently washs, last sufficiently dry, obtains powdered 6,8,8'- (((pyridine -2,6- dicarbapentaborane) bis- (azepines two of target product
Base)) bis- (carbonyls)) bis- (4- isobutoxy quinaldic acids).
Step G: by compound 6 (1.0g) and mixed solution back flow reaction 4 hours of 16.4g thionyl chloride.
Heating under reduced pressure removes excessive thionyl chloride later, obtains (((bis- carbonyl of pyridine -2,6- of target compound 7,8,8'-
Base) bis- (azepine diyls)) bis- (carbonyls)) bis- (4- isobutoxy quinoline -2- phosgenes).
The synthetic route for preparing the strong-hydrophobicity helical fold body that aromatic structure is skeleton is as follows:
The aromatic structure is that specific step is as follows for the preparation method of strong-hydrophobicity helical fold body of skeleton:
Step H: by 2g compound 8 (4- hydroxyl -8- nitro -2- 2-methyl naphthoate) and 2- bromo-acetic acid tert-butyl with molar ratio
1:1.2 feeds intake, and the KI of 0.2 times of equivalent is added, and 20mL acetonitrile is added later and flows back 6 hours.
After fully reacting, remove solvent, and with methylene chloride: methanol is 50:1 as leacheate using volume ratio and is divided
From obtained solution is spin-dried for through evaporation, then is sufficiently dried to obtain powdery product 9,4- (2- (tert-butoxy) -2- oxo
Ethyoxyl) -8- nitro -2- 2-methyl naphthoate.
Step I: powdery product 9 (1.0g) is well dispersed in 20ml ethyl acetate, later be added 10ml methanol and
3ml water is uniformly mixed.The pd/C of 0.2 times of equivalent is added into solution, 5g ammonium formate is finally rapidly added 1.3g ammonium metavanadate,
Container is sealed, stirring at normal temperature 2 hours.
Mixed solution is filtered, sufficiently washs filter cake with ethyl acetate, until the filtrate of outflow is almost colourless.Filtrate is collected,
Separate water phase, remove the solvent in organic phase, after extracted with saturated sodium bicarbonate solution and methylene chloride, what is obtained is organic
After being mutually evaporated, dry yellow powdery solid 10,8- amino -4- (2- (tert-butoxy) -2- oxoethoxy) -2- naphthalene are obtained
Methyl formate.
Quinoline molecule with amino active group and strong hydrophobic side chain tert-butyl acetate is carried out1H-NMR
Analysis, as shown in Figure 2, has determined the correctness of product structure.
1H NMR(500MHz,CDCl3) δ 7.59 (d, J=8.4Hz, 1H), 7.42-7.37 (m, 2H), 6.95 (d, J=
7.6Hz,1H),4.79(s,2H),4.02(s,3H),1.51(s,12H).
Step J: nothing is added with the ratio of molar ratio 1:2.2 in the compound 7 of above-mentioned acquisition and yellow powdery solid 10
In the mixture of water chloroform, the triethylamine of 3 times of equivalents is then added, is stirred 48 hours under the conditions of 30 DEG C.
Obtained organic phase is washed with water after first being washed with ethyl acetate, and organic phase is merged, and it is solid that anhydrous magnesium sulfate is added
Body is dried.By the solution after drying, after heating in vacuum is evaporated, using chromatographic column analytic approach, with methylene chloride: methanol is with body
Than being that 30:1 is separated as leacheate, obtained solution is spin-dried for through evaporation, then is sufficiently dried to obtain white powder product
Shape product 11, dimethyl 8,8'- ((8,8'- (((pyridine -2,6- dicarbapentaborane) is bis- (azepine diyl)) bis- (carbonyls)) bis- (4- isobutyls
Phenoxyl quinoline -2,2'- carbonyl)) bis- (azane diyls)) bis- (4- (2- (tert-butoxy) -2- oxoethoxy) quinaldic acids
The tert-butyl ester).
Fragrant helical fold body is carried out1H-NMR analysis, as shown in Figure 3, it is determined that the correctness of product structure.
1H NMR(500MHz,CDCl3) δ 13.56 (s, 2H), 11.00 (s, 2H), 8.97 (dd, J=7.2,1.5Hz, 2H),
8.87 (dd, J=7.7,1.1Hz, 2H), 8.31 (dd, J=8.2,1.5Hz, 2H), 7.81-7.77 (m, 4H), 7.61 (t, J=
8.0Hz, 3H), 7.14 (s, 2H), 6.78 (d, J=6.6Hz, 4H), 4.67 (s, 4H), 3.90-3.82 (m, 10H), 2.35-
2.31(m,2H),1.35–1.15(m,30H).
Meanwhile Matrix-assisted laser desorption ionization test has been carried out to white powder product 11, such as
Shown in Fig. 4, which clearly illustrates the molecular weight of target white powdery product 11 plus hydrogen plus sodium plus potassium, point
Son amount is consistent with calculated value, so that secondary evidence compound 11 is target compound again.
The white powder product 11 utilizes computer simulation, shows that its skeleton energy most stable state is helical fold body,
Shown in being the front of the fragrant helical fold body such as Fig. 5 a, Fig. 5 b is its reverse side diagram.
Embodiment 2
The synthetic route for preparing the tripolymer oligomer containing double acyl chlorides active groups is as follows:
Specific step is as follows for the trimer preparation method containing double acyl chlorides active groups:
Step A: 10g 2- aminobenzamide is dissolved in round-bottomed flask with 30ml anhydrous methanol, by 2- aminobenzoic
Amide 10g and dimethyl butyn are fed intake with molar ratio 1:1.3, first by dimethyl butyn be dissolved in 17ml without water beetle
In alcohol, then it is slowly added drop-wise in round-bottomed flask, is stirred at room temperature and is uniformly mixed to it, is heated to reflux 8 hours.
It stands to room temperature, and is put into -20 DEG C of refrigerator overnight.Next day filter and washs filter cake repeatedly with ice methanol,
Until filtrate achromaticity and clarification.Finally, filter cake is put into vacuum oven, after 30 DEG C of abundant dryings, collection obtains pulverulent solids
Product 1,2- (2- Carbamoylphenyl) amino) dimethyl maleate.
Step B: preparing 300mL diphenyl ether, be slowly heated to 250 DEG C of fluidized states, and quickly investment 15g is thoroughly dried later
Good compound 1, sustained response 13 minutes.
Mixed solution is cooled to 50 DEG C or so, 300mL petroleum ether is added into diphenyl ether mixed solution, while stirring will
Solution pours into the petroleum ether of 600mL, places to Precipitation, filtering, and obtained filter cake is sufficiently washed directly with petroleum ether
To filtrate achromaticity and clarification.After the sufficiently drying of 30~35 DEG C of vacuum oven, collection obtains pulverulent solids product 2,8- amino first
Acyl group -4- oxyquinoline -2- carboxylate methyl ester.
Step C: by sufficiently dry pulverulent solids product 2, triphenylphosphine and isobutanol with molar ratio 1:1.3:1.5 throwing
Material, using tetrahydrofuran as solvent, system is sealed, is slowly added to 2.2 times of equivalents into flask while stirring under condition of ice bath
Diisopropyl azodiformate then be stirred at room temperature 5 hours after stirring 45 minutes or so.
Remove solvent, solid residue is utilized methanol: chloroform volume ratio is that the solvent of 4:1 recrystallizes.Finally, will
Filter cake is put into vacuum oven, sufficiently dries under the conditions of 35 DEG C, obtain pulverulent solids product 3,8- ammonia by the precipitating filtering arrived
Base formoxyl -4- isobutoxy quinaldic acid's methyl esters.
Step D: by 2g 2, mixed solution back flow reaction 5 hours of 6- pyridine dicarboxylic acid and 49.2g thionyl chloride.
Heating under reduced pressure removes excessive thionyl chloride, obtains 4,2,6- dicarbapentaborane dichloropyridine of compound.
Step E: 2,6- dicarbapentaborane dichloropyridine is mixed with solid product 3 with molar ratio 1:2.5, with three dry chloromethanes
Alkane is solvent, and the dry triethylamine of 3 times of equivalents is added.By solution under air-proof condition and nitrogen protection, 30 DEG C of mechanical stirrings
17 hours.
Organic phase washed with water and chloroform are washed, the organic phase merged, the solution that will be obtained utilizes chromatography
Column analytic approach, with methylene chloride: methanol is 100:1 as leacheate using volume ratio and is separated that obtained solution is revolved through evaporation
It is dry, then it is sufficiently dried to obtain powdery product 5, dimethyl 8,8'- (((pyridine -2,6- dicarbapentaborane) is bis- (azepine diyl))
Bis- (carbonyls)) bis- (4- isobutoxy quinaldic acid esters).
Tripolymer oligomer is carried out1H-NMR analysis, as shown in Figure 1, it is determined that the correctness of product structure.
1H NMR(500MHz,CDCl3) δ 14.46 (s, 2H), 8.83 (d, J=7.3Hz, 2H), 8.59 (d, J=7.7Hz,
2H), 8.24-8.18 (m, 3H), 7.67 (t, J=7.7Hz, 2H), 6.54 (s, 2H), 3.69 (d, J=6.5Hz, 10H), 2.31-
2.24 (m, 2H), 1.22 (d, J=6.7Hz, 12H).
Step F: powdery product 5 is dissolved in tetrahydrofuran solution, and the NaOH of 4.5 times of equivalents is dissolved on a small quantity
It in methanol, instills in former solution under stirring, stirs 6 hours at room temperature.
PH is adjusted to 6.0 with appropriate hydrochloric acid (1.0mol/L), solvent is evaporated to dryness, residue is sufficiently washed with water,
Filtering, finally dries, obtains powdery product 6,8,8'- (((pyridine -2,6- dicarbapentaborane) is bis- (azepine diyl)) bis- (carbonyls))
Bis- (4- isobutoxy quinaldic acids).
Step G: by 2g powdery product 6 and mixed solution back flow reaction 5 hours of 30mL thionyl chloride.Heating under reduced pressure removes
Excessive thionyl chloride is removed, it is double to obtain compound 7,8,8'- (((pyridine -2,6- dicarbapentaborane) is bis- (azepine diyl)) bis- (carbonyls))
(4- isobutoxy quinoline -2- phosgene).
The synthesis step for preparing the strong-hydrophobicity helical fold body that aromatic structure is skeleton is as follows:
Aromatic structure is that specific step is as follows for the preparation method of strong-hydrophobicity helical fold body of skeleton:
Step H: by 1g compound 8 (4- hydroxyl -8- nitro -2- 2-methyl naphthoate) and 2- bromo-acetic acid tert-butyl with molar ratio
1:1.5 feeds intake, and the KI of 0.2 times of equivalent is added, and 10mL acetonitrile is added later and flows back 9 hours.
After fully reacting, remove solvent, and with methylene chloride: methanol is 50:1 as leacheate using volume ratio and carries out column layer
Analysis separation, obtained solution are spin-dried for through evaporation, sufficiently dry, obtain powdery product 9,4- (2- (tert-butoxy) -2- oxo
Ethyoxyl) -8- nitro -2- 2-methyl naphthoate.
Step I: 2g powdery product 9 is well dispersed in volume ratio for the ethyl acetate of 2:1:0.3, in first alcohol and water.
The pd/C of 0.2 times of equivalent is added into solution, 10g ammonium formate is finally rapidly added 3g ammonium metavanadate, container is sealed, room temperature
Stirring 3 hours.
Mixed solution is filtered, sufficiently washs filter cake with ethyl acetate, until the filtrate of outflow is almost colourless.Filtrate is collected,
Water phase is separated, the solvent in organic phase is removed, is extracted with saturated sodium bicarbonate solution and methylene chloride, obtained organic phase
After being evaporated, dry powdered compounds 10,8- amino -4- (2- (tert-butoxy) -2- oxoethoxy) -2- naphthalene can be obtained
Methyl formate.
Quinoline molecule with amino active group and strong hydrophobic side chain tert-butyl acetate is carried out1H-NMR
Analysis, as shown in Figure 2, has determined the correctness of product structure.
1H NMR(500MHz,CDCl3) δ 7.59 (d, J=8.4Hz, 1H), 7.42-7.37 (m, 2H), 6.95 (d, J=
7.6Hz,1H),4.79(s,2H),4.02(s,3H),1.51(s,12H).
Step J: anhydrous three chloromethane is added with the ratio of molar ratio 1:2.5 in the compound 7 of above-mentioned acquisition and compound 10
In alkane, the triethylamine of 3 times of equivalents is then added, is stirred 48 hours under the conditions of 30 DEG C.
Obtained organic phase is washed with water after first being washed with ethyl acetate, and organic phase is merged, and it is solid that anhydrous magnesium sulfate is added
Body is dried.By the solution after drying, after heating in vacuum is evaporated, using column chromatographic assays, with methylene chloride: methanol is with body
Than being that 30:1 is separated as leacheate, obtained solution is spin-dried for through evaporation, then is sufficiently dried to obtain powdered products product
Object 11, dimethyl 8,8'- ((8,8'- (((pyridine -2,6- dicarbapentaborane) is bis- (azepine diyl)) bis- (carbonyls)) bis- (4- isobutoxies
Quinoline -2,2'- carbonyl)) bis- (azane diyls)) bis- (4- (2- (tert-butoxy) -2- oxoethoxy) tertiary fourths of quinaldic acid
Ester).
Fragrant helical fold body is carried out1H-NMR analysis, as shown in Figure 3, it is determined that the correctness of product structure.
1H NMR(500MHz,CDCl3) δ 13.56 (s, 2H), 11.00 (s, 2H), 8.97 (dd, J=7.2,1.5Hz, 2H),
8.87 (dd, J=7.7,1.1Hz, 2H), 8.31 (dd, J=8.2,1.5Hz, 2H), 7.81-7.77 (m, 4H), 7.61 (t, J=
8.0Hz, 3H), 7.14 (s, 2H), 6.78 (d, J=6.6Hz, 4H), 4.67 (s, 4H), 3.90-3.82 (m, 10H), 2.35-
2.31(m,2H),1.35–1.15(m,30H).
Meanwhile substance assistant laser desorpted ionized flight time matter is carried out to powdery product fragrance helical fold body 11
Spectrum test, as shown in figure 4, the mass spectrogram clearly illustrates target compound fragrance helical fold body 11 plus hydrogen plus sodium, adds
The molecular weight of potassium, molecular weight are consistent with calculated value, thus secondary evidence powdery product fragrance helical fold body 11 again
For target compound.
The powdery product fragrance helical fold body 11 utilizes computer simulation, shows that its skeleton energy most stable state is spiral shell
Folded formation is revolved, shown in being the front of the fragrant helical fold body such as Fig. 5 a, Fig. 5 b is its reverse side diagram.
Claims (3)
1. a kind of fragrance helical fold body, it is characterised in that: fragrant helical fold body molecule, IUPAC name are as follows: dimethyl 8,
8'- ((8,8'- (((pyridine -2,6- dicarbapentaborane) is bis- (azepine diyl)) bis- (carbonyls)) bis- (4- isobutoxy quinoline -2,2'- carbonyls
Base)) bis- (azane diyls)) bis- (4- (2- (tert-butoxy) -2- oxoethoxy) quinaldic acid's tert-butyl esters), molecular formula
It is as follows:
2. a kind of preparation method of fragrant helical fold body according to claim 1, it is characterised in that: specific preparation process
It is as follows;
The synthetic route for preparing the tripolymer oligomer containing double acyl chlorides active groups is as follows:
Step A: 2- aminobenzamide being used and dimethyl butyn is fed intake with molar ratio 1:1.1~1.5, is molten with methanol
Agent is stirred at room temperature and is uniformly mixed to it, is heated to reflux 8 hours,
It standing to room temperature, and is put into -20 DEG C of refrigerator overnight, next day filter and washs filter cake repeatedly with ice methanol, until
Filtrate achromaticity and clarification, after the sufficiently drying of 30~40 DEG C of vacuum state, collection obtains pulverulent solids product 1,2- (2- carbamyl
Base phenyl) amino) dimethyl maleate;
Step B: prepare appropriate diphenyl ether, diphenyl ether quality: quality=21.5:1 of solid product 1 is slowly heated to 250 DEG C of boilings
State is risen, later the thorough dried solid product 1 of quick investment, sustained response 12~14 minutes,
Mixed solution is cooled to 50 DEG C or so, equal volume amounts petroleum ether is added into diphenyl ether mixed solution, while stirring will
Solution, which pours into, to be filled and in the petroleum ether of mixed solution equal volume amounts, places to Precipitation, filtering, and obtained filter cake is used
Petroleum ether sufficiently washs until filtrate achromaticity and clarification, after the sufficiently drying of 30~35 DEG C of vacuum oven, collection obtains powdered solid
Body product 2,8- carbamoyl -4- oxyquinoline -2- carboxylate methyl ester;
Step C: by sufficiently dry solid product 2, triphenylphosphine and isobutanol with molar ratio 1:(1.1~1.3): (1.1~
1.5) it feeds intake, using tetrahydrofuran as solvent, system is sealed, be slowly added to 2.2 into flask while stirring under condition of ice bath
The diisopropyl azodiformate of times equivalent after stirring 30~45 minutes or so, then is stirred at room temperature about 5 hours,
Remove solvent, solid residue is utilized methanol: chloroform volume ratio is (4~5): 1 solvent recrystallizes, finally, will
Filter cake is put into vacuum oven, sufficiently dries under the conditions of 30~35 DEG C, obtain pulverulent solids product by obtained precipitating filtering
3,8- carbamoyl -4- isobutoxy quinaldic acid's methyl esters;
Step D: with mass ratio being 1:(16.38~24.57 by 2,6- pyridine dicarboxylic acid and thionyl chloride) mixed solution reflux
Reaction 4~5 hours,
Heating under reduced pressure removes excessive thionyl chloride, obtains 4,2,6- dicarbapentaborane dichloropyridine of compound;
Step E: by 2,6- dicarbapentaborane dichloropyridine with solid product 3 with molar ratio 1:(2.2~2.5) it mixes, with dry three
Chloromethanes is solvent, and the dry triethylamine of 2.5~3 times of equivalents, by solution under air-proof condition and nitrogen protection, 30 DEG C is added
Mechanical stirring 15~17 hours,
Organic phase washed with water and chloroform are washed, the organic phase merged, the solution that will be obtained, utilizes chromatographic column point
Analysis method, with methylene chloride: methanol is 100:1 as leacheate using volume ratio and is separated that obtained solution is spin-dried for through evaporation,
It is sufficiently dried to obtain powdery product 5 again, dimethyl 8, (((pyridine -2,6- dicarbapentaborane) is bis- (azepine diyl)) are double by 8'-
(carbonyl)) bis- (4- isobutoxy quinaldic acid esters);
Step F: powdery product 5 is dissolved in tetrahydrofuran solution, and the NaOH of 4~4.5 times of equivalents is dissolved on a small quantity
It in methanol, instills in former solution under stirring, stirs 5~6 hours at room temperature, with appropriate hydrochloric acid (1.0mol/L) by pH
6.0 are adjusted to, solvent is evaporated to dryness, residue is sufficiently washed with water, and filtering is finally dried, obtains powdery product 6,8,
8'- (((pyridine -2,6- dicarbapentaborane) is bis- (azepine diyl)) bis- (carbonyls)) bis- (4- isobutoxy quinaldic acids);
Step G: with mass ratio being 1:(16.38~24.57 by powdery product 6 and thionyl chloride) mixed solution back flow reaction
4~5 hours,
Heating under reduced pressure removes excessive thionyl chloride, obtains (((pyridine -2, the 6- dicarbapentaborane) bis- (azepines two of compound 7,8,8'-
Base)) bis- (carbonyls)) bis- (4- isobutoxy quinoline -2- phosgenes);
The synthesis step for preparing the strong-hydrophobicity helical fold body that aromatic structure is skeleton is as follows:
Step H: by compound 8 (4- hydroxyl -8- nitro -2- 2-methyl naphthoate) and 2- bromo-acetic acid tert-butyl with molar ratio 1:(1.2
~1.5) it feeds intake, and the KI of catalytic amount is added, appropriate acetonitrile is added later and flows back 6~9 hours,
After fully reacting, remove solvent, and with methylene chloride: methanol is 50:1 as leacheate using volume ratio and carries out column chromatography point
From, obtained solution is spin-dried for through evaporation, and it is sufficiently dry, obtain powdery product 9,4- (2- (tert-butoxy) -2- oxo ethoxy
Base) -8- nitro -2- 2-methyl naphthoate;
Step I: it is the ethyl acetate of 2:1:0.3, in first alcohol and water that compound 9, which is well dispersed in volume ratio, into solution plus
Enter the pd/C of catalytic amount, the ammonium formate of 5 times of quality is finally rapidly added the ammonium metavanadate of 1.3~1.5 times of quality, and container is close
Envelope, stirring at normal temperature 2~3 hours,
Mixed solution is filtered, sufficiently washs filter cake with ethyl acetate, until the filtrate of outflow is almost colourless, filtrate is collected, separates
Water phase removes the solvent in organic phase, is extracted with saturated sodium bicarbonate solution and methylene chloride, obtained organic phase is evaporated
Afterwards, dry powdered compounds 10,8- amino -4- (2- (tert-butoxy) -2- oxoethoxy) -2- naphthoic acid can be obtained
Methyl esters;
Step J: by the compound 7 of above-mentioned acquisition and compound 10 with molar ratio 1:(2.2~2.5) ratio anhydrous trichlorine is added
In methane, the triethylamine of 3 times of equivalents is then added, is stirred 48 hours under the conditions of 30 DEG C,
Obtained organic phase is washed with water after first being washed with ethyl acetate, and organic phase is merged, be added anhydrous magnesium sulfate solid into
Row drying, by the solution after drying, after heating in vacuum is evaporated, using column chromatographic assays, with methylene chloride: methanol is with volume ratio
It is separated, obtained solution, is spin-dried for through evaporation, then be dried to obtain powdery product as leacheate sufficiently for 30:1
11, dimethyl 8,8'- ((8,8'- (((pyridine -2,6- dicarbapentaborane) is bis- (azepine diyl)) bis- (carbonyls)) bis- (4- isobutoxy quinolines
Quinoline -2,2'- carbonyl)) bis- (azane diyls)) bis- (4- (2- (tert-butoxy) -2- oxoethoxy) tertiary fourths of quinaldic acid
Ester).
3. a kind of fragrant helical fold body answering in chiral separation, molecular recognition and display material field described in claim 1
With.
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Non-Patent Citations (3)
Title |
---|
ARA M.ABRAMYAN ET AL.: "Mechanistic and dynamic insights into ligand encapsulation by helical arylamide foldamers", 《PHYS.CHEM.CHEM.PHYS.》 * |
HUA JIANG ET AL.: "Aromatic δ-Peptides", 《J.AM.CHEM.SOC.》 * |
XIAO LI ET AL.: "Pyridine–imide oligomers", 《CHEM.COMMUN.》 * |
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