CN103028115A - Programmed-drug-release azobenzene derivative carrier, and preparation method and application thereof - Google Patents
Programmed-drug-release azobenzene derivative carrier, and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a programmed-drug-release azobenzene derivative carrier, and a preparation method and application thereof. One end of azobenzene and derivative thereof of the carrier compound is connected with a cholesteryl group, and the other end is connected with a nitrogen heterocycle group. The chemical structural formula is disclosed in the specification, wherein R is alkyl group, aromatic ring group or H, R' is C1-3 alkyl group or H, n=1 or 2, and x=2-10. The preparation method comprises the following steps: diazo coupling, substitution, esterification, azanylation and the like. The novel azobenzene derivative can be used in the aspects of programmed-drug-release carriers and other photosensitive or temperature-sensitive stimulus-responsive materials. Compared with the prior art, the method provided by the invention is simple and easy to implement; and the prepared compound can be used in programmed-drug-release carriers and other photosensitive or temperature-sensitive stimulus-responsive materials, and has wide application prospects.
Description
Technical field
But the present invention relates to azobenzene derivatives carrier of a kind of program release and preparation method thereof, be specifically related to an a kind of end and connect the cholesterol group, but an end connects azobenzene compound synthetic of nitrogen heterocyclic ring group and in the application of the stimulating responsive Material Fields such as program drug release carrier and other photaesthesia, temp. sensitive.
Background technology
Azobenzene and its derivatives contains-the N=N-group, trans (trans) can occur to the transformation of cis (cis) configuration at the light-initiated lower of specific wavelength, and can occur reversible change at the light-initiated lower configuration of heat or another wavelength.It is in the anti-configuration of " V " font and bar-shaped cis-configuration transition process, and not only large variation occurs molecular dimension, has also changed distance between macromolecular chain simultaneously, thereby has had special molecular switch function.The characteristic of reversible cis-trans isomerization conversion can occur in the azobenzene chemical compound under the effect of light or heat, as a kind of stimuli responsive function monomer, in the biological medicine material sciences such as controlled release drug especially procedural release, all be subject to extensive concern (J.Photochem.Photobiol., A:Chem.182 (2006), 250-261; Adv.Mater.24 (2012), 2069-26103).
Cholesterol is a kind of lipid, as biomembranous important component part, has the biomembranous flowability of adjusting, increases biomembranous mechanical strength and reduces biomembranous infiltrative function.Cholesterol is incorporated in the azobenzene group, not only can utilize the photic or warm isomery performance that causes of azo group, and can keep the intrinsic biophysical properties of cholesterol, as the stimulating responsive molecular switch, to be used well in the bio-medical material of procedural control release that (Biochemitry 39 (2000), 843-849; Chem.Mater.17 (2005), 2792-2795).
The people such as Wang Jinye have reported the patent of invention (publication number: CN1526723A) of a class " cholesterol derivative that contains azobenzene group ", its diphenyl diimide is not with substituent group, one end of diphenyl diimide is the trialkyl fatty amine of short carbon chain, patent of invention (publication number: CN1850844A) with a class " cholesterol derivative that contains azobenzene group ", its diphenyl diimide is not with substituent group, and an end of diphenyl diimide is the dialkyl group fatty amine of short carbon chain.Yet for containing the diphenyl diimide functional material, the structure of azobenzene compound will affect the performance of material.The present invention transforms with regard to the structure of azobenzene compound, to further expand the substrate spectrum of this compounds, expands it in the range of application of the aspects such as program release bio-medical material.
Summary of the invention
But purpose of the present invention is exactly to provide azobenzene derivatives carrier of a kind of program release and its preparation method and application for the defective that overcomes above-mentioned prior art existence.
Purpose of the present invention can be achieved through the following technical solutions: but a kind of azobenzene derivatives carrier of program release is characterized in that an end of this carrier connects the cholesterol group, the other end connects the nitrogen heterocyclic ring group, and its chemical structural formula is:
In the formula, R is alkyl, aromatic ring yl or H, and R ' is C
1～3Alkyl or H, n=1 or 2, x=2～10.
But a kind of preparation method of azobenzene derivatives carrier of program release is characterized in that, is to obtain through diazo coupling, replacement, esterification and N-alkylation reaction, and its concrete steps are:
(1) diazo coupling
Will be by para-amino benzoic acid and NaNO
2The diazol that reaction obtains joins in the aqueous slkali of phenol and its derivatives, and the control reaction temperature is at 0～5 ℃, and the response time is 2～10 hours, obtains chemical compound 1, para-amino benzoic acid, NaNO
2, phenol and its derivatives mol ratio be 1: 1-5: 0.8-3; Its reaction equation is:
In the formula, R ' is C
1～3Alkyl or H;
(2) nucleophilic substitution
In alcohols solvent or ketones solvent, add alkali and catalyst, the control reaction temperature is at 15～100 ℃, and the response time is 10～72 hours, chemical compound 1 and dialkyl group bromine reaction make chemical compound 2, and the mol ratio of chemical compound 1, dialkyl group bromine, alkali, catalyst is 1: 2-8: 2-8: 0.01-0.1; Its reaction equation is:
In the formula, R ' is C
1～3Alkyl or H, x=2～10;
(3) esterification
In halogenated hydrocarbon solvent or benzene kind solvent, take dicyclohexylcarbodiimide as dehydrant, DMAP is catalyst, the control reaction temperature is at 0～40 ℃, response time is 5～20 hours, chemical compound 2 and lentochol reaction make chemical compound 3, and the mol ratio of chemical compound 2, cholesterol, dicyclohexylcarbodiimide, DMAP is 1: 1-2: 1-1.5: 0.01-0.1; Its reaction equation is;
In the formula, R ' is C
1～3Alkyl or H, x=2～10;
(4) N-alkylation reaction
In alcohols solvent or ether solvent, the control reaction temperature is at 50～120 ℃, and the response time is 5～80 hours, adds catalyst KI, chemical compound 3 and nitrogen-containing heterocycle compound reaction make chemical compound 4, and the mol ratio of chemical compound 3 and nitrogen-containing heterocycle compound is 1: 1-10; Its reaction equation is:
In the formula, R is alkyl, aromatic ring yl or H, and R ' is C
1～3Alkyl or H, n=1 or 2, x=2～10.
The described para-amino benzoic acid of step (1), NaNO
2, phenol and its derivatives mol ratio be 1: 1-2: 1-2.
The derivant of the described phenol of step (1) is its ortho position alkyl substituent, and alkyl is methyl, ethyl, propyl group or isopropyl.
The described alcohols solvent of step (2) comprises methanol, ethanol, propanol or butanols, and described ketones solvent comprises acetone, butanone or methyl ethyl ketone; Described alkali is alkali-metal tert-butyl group oxide, hydride, hydroxide, carbonate or bicarbonate, and described catalyst is potassium iodide, hexaoxacyclooctadecane-6-6 or tetrabutylammonium iodide.
Described alkali comprises t-BuoK, NaH, KH, NaOH, KOH, K
2CO
3Perhaps NaHCO
3
The described halogenated hydrocarbon solvent of step (3) comprises dichloromethane, chloroform, tetrachloromethane or 1,2-dichloroethanes, and described benzene kind solvent comprises chlorobenzene or toluene.
The described alcohols solvent of step (4) comprises methanol, ethanol, propanol or butanols, and described ether solvent comprises oxolane or methyltetrahydrofuran; The mol ratio of described chemical compound 3, nitrogen-containing heterocycle compound and KI is 1: 2-5: 0.001-0.05.
Described nitrogen-containing heterocycle compound is that five-membered ring, hexatomic ring or the multi-ring and upper hydrogen of ring are by the alkyl substituent.
But a kind of application of azobenzene derivatives carrier of program release, it is characterized in that, this azobenzene derivatives carrier can be used for the stimulating responsive material aspect of procedural drug release carrier and other photaesthesia or temp. sensitive, and described azobenzene derivatives all has good response performance to light and temperature.
Compared with prior art, the present invention has the following advantages:
1. the invention provides a kind of cholesterol derivative that contains azobenzene group of structure novel, wherein diphenyl diimide can be the alkyl substituents such as methyl, ethyl, propyl group or isopropyl, the contained azacyclo-of an end of diphenyl diimide can be on pyridine ring, quinoline ring, isoquinolin ring, indole ring, pyrrole ring and the ring thereof hydrogen by alkyl substituent etc.
Simple, the easy operating of preparation method of the present invention, raw material is cheap and easy to get, reaction condition is gentle, be suitable for applying.
3. novel stimulating responsive azobenzene derivatives of the present invention all has good response performance and the regulatable switch performance of program to light and temperature.
4. novel stimulating responsive azobenzene derivatives carrier of the present invention can be used for procedural drug release carrier, and as stimulating responsive materials such as other photaesthesia, temp. sensitives, is with a wide range of applications.
Description of drawings
Fig. 1 is the hydrogen spectrogram of azobenzene derivatives of the present invention;
Fig. 2 is for to penetrate the ultraviolet-visible spectrogram of lower cis-trans isomerism in different light.
Fig. 3 is the ultraviolet-visible spectrogram of cis-trans isomerism under different temperatures.
The specific embodiment
The specific embodiment of the present invention below is provided, 3 embodiment and 2 Application Examples are provided, but be noted that enforcement of the present invention is not limited to following embodiment.
Embodiment 1
The preparation of a kind of azobenzene derivatives 4a
(1) diazo coupling
With cold NaNO
2Aqueous solution (60mmol) joins in the hydrochloric acid solution of para-amino benzoic acid (50mmol) (2mol/L) lentamente, keeps reaction temperature to be no more than 5 ℃.After half an hour, this diazonium salt solution is joined lentamente in the NaOH aqueous solution of phenol (50mmol) (1mol/L), keep reaction temperature to be no more than 5 ℃ of reactions 5 hours, neutralization reaction liquid filters water and methanol wash, NaHCO to acid
3The aqueous solution recrystallization gets chemical compound 1a, yellow acicular crystal, productive rate 80%.
(2) nucleophilic substitution
Chemical compound 1a (4mmol), K
2CO
3(9mmol), KI (0.1mmol), 1,4-dibromobutane (16mmol) and anhydrous propanone (100mL) join in the there-necked flask that condensing reflux pipe drying is housed (250mL) back flow reaction 40 hours in 60 ℃ oil bath, stopped reaction also is cooled to room temperature, filter, filtrate is spin-dried for, and the rapid column chromatography purification gets chemical compound 2a, yellow solid, productive rate 80%.
(3) esterification
In the there-necked flask of 250mL, chemical compound 2a (4mmol) and cholesterol (4.8mmol) are dissolved in CH
2Cl
2(60mL), logical nitrogen deoxygenation slowly added 30mL and contains dicyclohexylcarbodiimide (5mmol) and DMAP (0.08mmol) after 30 minutes, was sealed in 20 ℃ of reactions after 20 hours, filter, filtrate is used hydrochloric acid (0.1mol/L), NaHCO successively
3(saturated) washing, anhydrous MgSO
4Drying, solvent is spin-dried for, and the rapid column chromatography purification gets chemical compound 3a, yellow solid, productive rate 60%.
(4) N-alkylation reaction
Chemical compound 3a (4mmol), pyridine (10mmol), KI (0.02mmol) and anhydrous tetrahydro furan (60mL) join in the there-necked flask that condensing reflux pipe drying is housed (100mL) back flow reaction 10 hours in 70 ℃ oil bath, stopped reaction also is cooled to room temperature, filter, the ether washing, the rapid column chromatography purification, get chemical compound 4a, yellow solid, productive rate 75%.
C49H66N3O3Br
1H?NMR(400MHz，CDCl
3)：δ(ppm)9.49(2H，d，J＝8.0Hz)，8.46(1H，t，J＝8.0Hz)，8.16(2H，d，J＝8.0Hz)，8.10(2H，t，J＝8.0Hz)，7.97-7.88(4H，m)，6.99(2H，d，J＝8.0Hz)，5.43(1H，s)，5.16(1H，d，J＝8.0Hz)，4.17(2H，t，J＝5.8Hz)，2.50-0.69(49H，m).MS(ESI)：744(M
+-79).IR(KBr)υ/cm
-1：3383，2930，2860，1713，1637，1597，1496，1461，1263，1101，1027，802，688.
Embodiment 2
The preparation of a kind of azobenzene derivatives 4b
(1) diazo coupling
With cold NaNO
2Aqueous solution (75mmol) joins in the hydrochloric acid solution of para-amino benzoic acid (50mmol) (2.5mol/L) lentamente, keeps reaction temperature to be no more than 5 ℃.After half an hour, this diazonium salt solution is joined lentamente in the NaOH aqueous solution of 2,6-xylenol (60mmol) (1.5mol/L), keep reaction temperature to be no more than 5 ℃ of reactions 7 hours, neutralization reaction liquid filters to acid, water and methanol wash, NaHCO
3The aqueous solution recrystallization gets chemical compound 1b, yellow acicular crystal, productive rate 80%.
(2) nucleophilic substitution
Chemical compound 1b (4mmol), K
2CO
3(24mmol), KI (0.2mmol), 1,6-dibromobutane (28mmol) and anhydrous propanone (130mL) join in the there-necked flask that condensing reflux pipe drying is housed (250mL) back flow reaction 60 hours in 60 ℃ oil bath, stopped reaction also is cooled to room temperature, filter, filtrate is spin-dried for, and the rapid column chromatography purification gets chemical compound 2b, yellow solid, productive rate 80%.
(3) esterification
In the there-necked flask of 250mL, chemical compound 2b (4mmol) and cholesterol (5.2mmol) are dissolved in CHCl
3(80mL), logical nitrogen deoxygenation slowly added 50mL and contains dicyclohexylcarbodiimide (5.2mmol) and DMAP (0.1mmol) after 30 minutes, was sealed in 25 ℃ of reactions after 15 hours, filter, filtrate is used hydrochloric acid (0.1mol/L), NaHCO successively
3(saturated) washing, anhydrous MgSO
4Drying, solvent is spin-dried for, and the rapid column chromatography purification gets chemical compound 3b, yellow solid, productive rate 65%.
(4) N-alkylation reaction
Chemical compound 3b (4mmol), isoquinolin (12mmol), KI (0.04mmol) and dry methyltetrahydrofuran (70mL) join in the there-necked flask that condensing reflux pipe drying is housed (100mL) back flow reaction 20 hours in 85 ℃ oil bath, stopped reaction also is cooled to room temperature, filter, the ether washing, the rapid column chromatography purification, get chemical compound 4b, yellow solid, productive rate 70%.
Embodiment 3
The preparation of a kind of azobenzene derivatives 4c
(1) diazo coupling
With cold NaNO
2Aqueous solution (75mmol) joins in the hydrochloric acid solution of para-amino benzoic acid (50mmol) (2.5mol/L) lentamente, keeps reaction temperature to be no more than 5 ℃.After half an hour, this diazonium salt solution is joined lentamente in the NaOH aqueous solution of 2,6-dipropyl phenol (65mmol) (1.5mol/L), keep reaction temperature to be no more than 5 ℃ of reactions 7 hours, neutralization reaction liquid filters to acid, water and methanol wash, NaHCO
3The aqueous solution recrystallization gets chemical compound 1c, yellow acicular crystal, productive rate 75%.
(2) nucleophilic substitution
Chemical compound 1c (4mmol), K
2CO
3(28mmol), tetrabutylammonium iodide (0.2mmol), 1,4-dibromobutane (28mmol) and dehydrated alcohol (130mL) join in the there-necked flask that condensing reflux pipe drying is housed (250mL) back flow reaction 60 hours in 80 ℃ oil bath, stopped reaction also is cooled to room temperature, filter, filtrate is spin-dried for, and the rapid column chromatography purification gets chemical compound 2c, yellow solid, productive rate 80%.
(3) esterification
In the there-necked flask of 250mL, chemical compound 2c (4mmol) and cholesterol (6mmol) are dissolved in CHCl
3(80mL), logical nitrogen deoxygenation slowly added 50mL and contains dicyclohexylcarbodiimide (5.2mmol) and DMAP (0.12mmol) after 30 minutes, was sealed in 25 ℃ of reactions after 15 hours, filter, filtrate is used hydrochloric acid (0.1mol/L), NaHCO successively
3(saturated) washing, anhydrous MgSO
4Drying, solvent is spin-dried for, and the rapid column chromatography purification gets chemical compound 3c, yellow solid, productive rate 65%.
(4) N-alkylation reaction
Chemical compound 3c (4mmol), pyrroles (10mmol), KI (0.08mmol) and dry oxolane (80mL) join in the there-necked flask that condensing reflux pipe drying is housed (100mL) back flow reaction 10 hours in 65 ℃ oil bath, stopped reaction also is cooled to room temperature, filter, the ether washing, the rapid column chromatography purification, get chemical compound 4c, yellow solid, productive rate 70%.
The hydrogen spectrogram of azobenzene derivatives of the present invention is seen accompanying drawing 1:
Its characteristic peak (9.49,8.46,8.16,8.10,7.97-7.88,6.99,5.43,5.16,4.17,2.50-0.69) proof: the synthetic of azobenzene derivatives is successfully.
The exploration of the photic isomery performance of azobenzene derivatives of Application Example embodiment 1 preparation
The azobenzene derivatives of the embodiment of 5mg preparation is dissolved in the chloroform, is configured to certain density solution, pipette 3mL in quartz colorimetric utensil, carry out the photometric mensuration of ultraviolet-visible.
Utilize 365nm length ultraviolet rayed to be contained in azobenzene derivatives solution in the quartz colorimetric utensil, the ultraviolet-visible spectrogram of gained is seen accompanying drawing 2 under different irradiation times:
Wherein, wavelength 356nm is the anti-configuration of diphenyl diimide, and wavelength 442nm is the cis-configuration of diphenyl diimide.
Along with the increase of irradiation time, the peak of wavelength 356nm weakens by force gradually, and the peak of wavelength 442nm strengthens by force gradually, and this shows: reversible cis-trans isomerism can occur through 365nm length ultraviolet rayed and change in azo-benzene units.
The azobenzene derivatives temperature of Application Example embodiment 2 preparations causes the exploration of isomery performance
The azobenzene derivatives of the embodiment of 5mg preparation is dissolved in the chloroform, is configured to certain density solution, pipette 3mL in quartz colorimetric utensil, carry out the photometric mensuration of ultraviolet-visible.
Utilize 365nm length ultraviolet rayed to be contained in azobenzene derivatives solution in the quartz colorimetric utensil, shine lucifuge after 20 minutes leaves standstill the different time gained under 37 ℃ ultraviolet-visible spectrogram and see accompanying drawing 3:
Wherein, wavelength 356nm is the anti-configuration of diphenyl diimide, and wavelength 442nm is the cis-configuration of diphenyl diimide.
Through irradiation under ultraviolet ray after 20 minutes lucifuge under 37 ℃, leave standstill different time, increase along with the time, the peak of wavelength 442nm weakens by force gradually, the peak of wavelength 356nm strengthens by force gradually, this shows: reversible cis-configuration can occur and turn back to anti-configuration under 37 ℃ in azo-benzene units lucifuge after 365nm length ultraviolet rayed.
Embodiment 4
The preparation method of a kind of novel azo benzene derivative, azobenzene derivatives are through series reaction such as diazo coupling, replacement, esterification and azanyls and obtain.Its concrete steps are:
(1) diazo coupling
Will be by para-amino benzoic acid and NaNO
2The diazol that reaction obtains joins in the aqueous slkali of phenol and its derivatives, and the control reaction temperature is at 0～2 ℃, and the response time is 7～8 hours, obtains chemical compound 1, para-amino benzoic acid, NaNO
2, phenol and its derivatives mol ratio be 1: 1: 0.8, the derivant of described phenol is its ortho position alkyl substituent, alkyl is methyl.Its reaction equation is:
In the formula, R ' is methyl.
(2) nucleophilic substitution
In methanol solvate, take NaH as alkali, potassium iodide is catalyst, the control reaction temperature is at 15～20 ℃, response time is 70～72 hours, and chemical compound 1 and dialkyl group bromine reaction make chemical compound 2, and the mol ratio of chemical compound 1, dialkyl group bromine, alkali, catalyst is 1: 2: 2: 0.01.Its reaction equation is:
In the formula, R ' is methyl, x=3.
(3) esterification
In dichloromethane solvent, take dicyclohexylcarbodiimide as dehydrant, DMAP is catalyst, the control reaction temperature is at 0～5 ℃, response time is 18～20 hours, chemical compound 2 and lentochol reaction make chemical compound 3, and the mol ratio of chemical compound 2, cholesterol, dicyclohexylcarbodiimide, DMAP is 1: 1: 1: 0.01.Its reaction equation is:
In the formula, R ' is methyl, x=3.
(4) N-alkylation reaction
In methanol solvate, the control reaction temperature is at 50～60 ℃, and the response time is 78～80 hours, chemical compound 3 and nitrogen heterocyclic ring reaction make chemical compound 4, add the KI of catalytic amount, the mol ratio of chemical compound 3, nitrogen heterocyclic ring and KI is 1: 1: 0.001, and described nitrogen heterocyclic ring is 2-picoline ring.Its reaction equation is:
In the formula, R is the 2-methyl, and R ' is methyl, n=2, x=3.
Embodiment 5
The preparation method of a kind of novel azo benzene derivative, azobenzene derivatives are through series reaction such as diazo coupling, replacement, esterification and azanyls and obtain.Its concrete steps are:
(1) diazo coupling
Will be by para-amino benzoic acid and NaNO
2The diazol that reaction obtains joins in the aqueous slkali of phenol and its derivatives, and the control reaction temperature is at 4～5 ℃, and the response time is 2～3 hours, obtains chemical compound 1, para-amino benzoic acid, NaNO
2, phenol and its derivatives mol ratio be 1: 5: 3, the derivant of described phenol is its ortho position alkyl substituent, alkyl is isopropyl etc.Its reaction equation is:
In the formula, R ' is isopropyl.
(2) nucleophilic substitution
In acetone solvent, take NaOH as alkali, tetrabutylammonium iodide is catalyst, the control reaction temperature is at 95～100 ℃, response time is 10～12 hours, and chemical compound 1 and dialkyl group bromine reaction make chemical compound 2, and the mol ratio of chemical compound 1, dialkyl group bromine, alkali, catalyst is 1: 8: 8: 0.1.Its reaction equation is:
In the formula, R ' is isopropyl, x=10.
(3) esterification
In chlorobenzene solvent, take dicyclohexylcarbodiimide as dehydrant, DMAP is catalyst, the control reaction temperature is at 38～40 ℃, response time is 5～6 hours, chemical compound 2 and lentochol reaction make chemical compound 3, and the mol ratio of chemical compound 2, cholesterol, dicyclohexylcarbodiimide, DMAP is 1: 2: 1.5: 0.1.Its reaction equation is:
In the formula, R ' is isopropyl, x=10.
(4) N-alkylation reaction
In methyl-tetrahydrofuran solvent, the control reaction temperature is at 60～120 ℃, and the response time is 5～6 hours, chemical compound 3 and nitrogen heterocyclic ring reaction make chemical compound 4, add the KI of catalytic amount, the mol ratio of chemical compound 3, nitrogen heterocyclic ring and KI is 1: 10: 0.05, and described nitrogen heterocyclic ring is indole ring.Its reaction equation is:
In the formula, R is phenyl ring, and R ' is isopropyl, n=2, x=10.
Embodiment 6
The preparation method of a kind of novel azo benzene derivative, azobenzene derivatives are through series reaction such as diazo coupling, replacement, esterification and azanyls and obtain.Its concrete steps are:
(1) diazo coupling
Will be by para-amino benzoic acid and NaNO
2The diazol that reaction obtains joins in the aqueous slkali of phenol, and the control reaction temperature is at 2～3 ℃, and the response time is 5～6 hours, obtains chemical compound 1, para-amino benzoic acid, NaNO
2, phenol and its derivatives mol ratio be 1: 2: 2, its reaction equation is:
In the formula, R ' is H.
(2) nucleophilic substitution
In acetone solvent, with K
2CO
3Be alkali, tetrabutylammonium iodide is catalyst, and the control reaction temperature is at 60～70 ℃, and the response time is 30～32 hours, and chemical compound 1 and dialkyl group bromine reaction make chemical compound 2, and the mol ratio of chemical compound 1, dialkyl group bromine, alkali, catalyst is 1: 6: 6: 0.05.Its reaction equation is:
In the formula, R ' is H, x=6.
(3) esterification
1, in the 2-dichloroethanes solvent, take dicyclohexylcarbodiimide as dehydrant, DMAP is catalyst, the control reaction temperature is at 20～25 ℃, response time is 8～10 hours, and chemical compound 2 and lentochol reaction make chemical compound 3, and the mol ratio of chemical compound 2, cholesterol, dicyclohexylcarbodiimide, DMAP is 1: 1.5: 1.2: 0.05.Its reaction equation is:
In the formula, R ' is H, x=6.
(4) N-alkylation reaction
In methyltetrahydrofuran, the control reaction temperature is at 80～90 ℃, and the response time is 24～25 hours, the KI that adds catalytic amount, chemical compound 3 and trialkylamine reaction make chemical compound 4, and the mol ratio of chemical compound 3, nitrogen heterocyclic ring and KI is 1: 5: 0.01, and described nitrogen heterocyclic ring is isoquinolin.Its reaction equation is:
In the formula, R is phenyl ring, and R ' is isopropyl, n=2, x=6.
Claims (10)
1. but the azobenzene derivatives carrier of a program release is characterized in that, an end of this carrier connects the cholesterol group, and the other end connects the nitrogen heterocyclic ring group, and its chemical structural formula is:
In the formula, R is alkyl, aromatic ring yl or H, and R ' is C
1～3Alkyl or H, n=1 or 2, x=2～10.
2. but the preparation method of the azobenzene derivatives carrier of a program release as claimed in claim 1 is characterized in that, is to obtain through diazo coupling, replacement, esterification and N-alkylation reaction, and its concrete steps are:
(1) diazo coupling
Will be by para-amino benzoic acid and NaNO
2The diazol that reaction obtains joins in the aqueous slkali of phenol and its derivatives, and the control reaction temperature is at 0～5 ℃, and the response time is 2～10 hours, obtains chemical compound 1, para-amino benzoic acid, NaNO
2, phenol and its derivatives mol ratio be 1: 1-5: 0.8-3; Its reaction equation is:
In the formula, R ' is C
1～3Alkyl or H;
(2) nucleophilic substitution
In alcohols solvent or ketones solvent, add alkali and catalyst, the control reaction temperature is at 15～100 ℃, and the response time is 10～72 hours, chemical compound 1 and dialkyl group bromine reaction make chemical compound 2, and the mol ratio of chemical compound 1, dialkyl group bromine, alkali, catalyst is 1: 2-8: 2-8: 0.01-0.1; Its reaction equation is:
In the formula, R ' is C
1～3Alkyl or H, x=2～10;
(3) esterification
In halogenated hydrocarbon solvent or benzene kind solvent, take dicyclohexylcarbodiimide as dehydrant, DMAP is catalyst, the control reaction temperature is at 0～40 ℃, response time is 5～20 hours, chemical compound 2 and lentochol reaction make chemical compound 3, and the mol ratio of chemical compound 2, cholesterol, dicyclohexylcarbodiimide, DMAP is 1: 1-2: 1-1.5: 0.01-0.1; Its reaction equation is:
In the formula, R ' is C
1～3Alkyl or H, x=2～10;
(4) N-alkylation reaction
In alcohols solvent or ether solvent, the control reaction temperature is at 50～120 ℃, and the response time is 5～80 hours, adds catalyst KI, chemical compound 3 and nitrogen-containing heterocycle compound reaction make chemical compound 4, and the mol ratio of chemical compound 3 and nitrogen-containing heterocycle compound is 1: 1-10; Its reaction equation is:
In the formula, R is alkyl, aromatic ring yl or H, and R ' is C
1～3Alkyl or H, n=1 or 2, x=2～10.
3. but the synthetic method of a kind of program release azobenzene derivatives carrier according to claim 2 is characterized in that, the described para-amino benzoic acid of step (1), NaNO
2, phenol and its derivatives mol ratio be 1: 1-2: 1-2.
4. but the synthetic method of the azobenzene derivatives carrier of described a kind of program release according to claim 2 is characterized in that the derivant of the described phenol of step (1) is its ortho position alkyl substituent, and alkyl is methyl, ethyl, propyl group or isopropyl.
5. but the synthetic method of the azobenzene derivatives carrier of a kind of program release according to claim 2, it is characterized in that, the described alcohols solvent of step (2) comprises methanol, ethanol, propanol or butanols, and described ketones solvent comprises acetone, butanone or methyl ethyl ketone; Described alkali is alkali-metal tert-butyl group oxide, hydride, hydroxide, carbonate or bicarbonate, and described catalyst is potassium iodide, hexaoxacyclooctadecane-6-6 or tetrabutylammonium iodide.
6. but the synthetic method of the azobenzene derivatives carrier of a kind of program release according to claim 5 is characterized in that, described alkali comprises t-BuoK, NaH, KH, NaOH, KOH, K
2CO
3Perhaps NaHCO
3
7. but the synthetic method of the azobenzene derivatives carrier of a kind of program release according to claim 2, it is characterized in that, the described halogenated hydrocarbon solvent of step (3) comprises dichloromethane, chloroform, tetrachloromethane or 1, the 2-dichloroethanes, described benzene kind solvent comprises chlorobenzene or toluene.
8. but the synthetic method of the azobenzene derivatives carrier of a kind of program release according to claim 2, it is characterized in that, the described alcohols solvent of step (4) comprises methanol, ethanol, propanol or butanols, and described ether solvent comprises oxolane or methyltetrahydrofuran; The mol ratio of described chemical compound 3, nitrogen-containing heterocycle compound and KI is 1: 2-5: 0.001-0.05.
9. but according to claim 2 or the synthetic method of the azobenzene derivatives carrier of 8 described a kind of program releases, it is characterized in that described nitrogen-containing heterocycle compound is that five-membered ring, hexatomic ring or the multi-ring and upper hydrogen of ring are by the alkyl substituent.
10. but the application of the azobenzene derivatives carrier of a program release as claimed in claim 1, it is characterized in that, this azobenzene derivatives carrier can be used for the stimulating responsive material aspect of procedural drug release carrier and other photaesthesia or temp. sensitive, and described azobenzene derivatives all has good response performance to light and temperature.
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| CN2012105296224A CN103028115A (en) | 2012-12-10 | 2012-12-10 | Programmed-drug-release azobenzene derivative carrier, and preparation method and application thereof |
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| CN2012105296224A CN103028115A (en) | 2012-12-10 | 2012-12-10 | Programmed-drug-release azobenzene derivative carrier, and preparation method and application thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001233893A (en) * | 2000-02-21 | 2001-08-28 | Natl Inst Of Advanced Industrial Science & Technology Meti | Liquid crystal compound bearing a photosensitive site, liquid crystal additive and optical recording medium |
| JP2005314261A (en) * | 2004-04-28 | 2005-11-10 | National Institute Of Advanced Industrial & Technology | Azobenzene compound and gelatinizer comprising the same and method for producing the gelatinizer |
| CN1850844A (en) * | 2006-05-12 | 2006-10-25 | 中国科学院上海有机化学研究所 | Cholesterol derivative containing azobenzene group, and its synthesizing method and use |
-
2012
- 2012-12-10 CN CN2012105296224A patent/CN103028115A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001233893A (en) * | 2000-02-21 | 2001-08-28 | Natl Inst Of Advanced Industrial Science & Technology Meti | Liquid crystal compound bearing a photosensitive site, liquid crystal additive and optical recording medium |
| JP2005314261A (en) * | 2004-04-28 | 2005-11-10 | National Institute Of Advanced Industrial & Technology | Azobenzene compound and gelatinizer comprising the same and method for producing the gelatinizer |
| CN1850844A (en) * | 2006-05-12 | 2006-10-25 | 中国科学院上海有机化学研究所 | Cholesterol derivative containing azobenzene group, and its synthesizing method and use |
Non-Patent Citations (3)
| Title |
|---|
| XIN-MING LIU ET AL.: "Photoisomerisable cholesterol derivatives as photo-trigger of liposomes: Effect of lipid polarity, temperature, incorporation ratio, and cholesterol", 《BIOCHIMICA ET BIOPHYSICA ACTA》, 6 December 2005 (2005-12-06), pages 29 * |
| YAN-QUN DAI ET AL.: "Photo-responsive release of ascorbic acid and catalase in CDBA-liposome for commercial application as a sunscreen cosmetic", 《RSC ADVANCES》, vol. 2, 24 February 2012 (2012-02-24), pages 3341 * |
| 武清粉 等: "光感应化合物在光控治疗中的应用", 《生物物理学报》, vol. 27, no. 2, 28 February 2011 (2011-02-28), pages 108 - 120 * |
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Application publication date: 20130410 |