CN103073566B - A kind of Phenylboronic acid organic gel compound - Google Patents
A kind of Phenylboronic acid organic gel compound Download PDFInfo
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- CN103073566B CN103073566B CN201210375089.0A CN201210375089A CN103073566B CN 103073566 B CN103073566 B CN 103073566B CN 201210375089 A CN201210375089 A CN 201210375089A CN 103073566 B CN103073566 B CN 103073566B
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Abstract
The invention discloses a kind of 3-as the formula (1) (the chloro-4-ethoxycarbonyl of 3--2-butylene is amino) phenylo boric acid, and disclose described compound prepares the organogel of glucose-sensitive application as gelifying agent.
Description
(1) technical field
The present invention relates to a kind of synthesis of Phenylboronic acid organic gel compound and the preparation of gel thereof, belong to technical field of chemistry.
(2) background technology
Significant (the Zhao Y.N. of the treatment of Regular Insulin self-adjustable Co ntrolled release system to insulin-dependent diabetes mellitus, Trewyn B.G., Slowing I.I., Lin V.S.Y.J.Am.Chem.Soc., 2009,131,8398-8400.), by feeding back glucose concentration signal in body and the burst size of automatic continuous control Regular Insulin, thus the misery (Siegel R.A., Gu Y.D., the LeiM. that make diabetic subject break away from long term injections Regular Insulin to bring, Baldi A., Nuxoll E.E., Ziaie B.J.Control.Release, 2010,141,303-313; RavaineV., Ancla C., Catargi B.J.Control.Release, 2008,132,2-11.).But, the Regular Insulin glucose-sensitive that synchronization control discharges with blood sugar concentration rising can be realized and rapid response type Regular Insulin Co ntrolled release solid support material, fail to be developed well always.The present invention is based on the glucose-sensitive material that Low Molecular-Weight Gel system probe one class is novel, intend the Co ntrolled release being used for glucose molecule sensor or Regular Insulin.The present invention mainly design and synthesis one class containing the organic micromolecule gel factor of glucose-sensitive phenylo boric acid group, this gel achieves glucose-sensitive, this kind of novel glucose-sensitive material, is realizing significant in the intelligent transportation of Regular Insulin.
(3) summary of the invention
The present invention relates to a kind of synthesis of Phenylboronic acid organic gel compound and the preparation of gel thereof.
The invention provides a kind of Phenylboronic acid organic gel compound, structure is such as formula shown in (1):
The present invention also provides the described preparation method such as formula the compound shown in (1), and described method is:
(1) by 3-amino-benzene boric acid, the neopentyl glycol shown in formula (4), mix in chloroform solvent, stirred at ambient temperature reaction 1.5-5h, gained reaction solution a aftertreatment is obtained such as formula the compound (C shown in (3)
11h
16bNO
2, 3-amino-benzene boric acid DOPCP); The ratio of the amount of substance of the 3-amino-benzene boric acid shown in described formula (4), neopentyl glycol is 1.0:0.8 ~ 1.5;
(2) be dissolved in dichloromethane solvent such as formula the compound shown in (3), add 2-chloroacetyl acetacetic ester, triethylamine again, heating reflux reaction 15-30h, gained reaction solution b aftertreatment is obtained such as formula the compound (C shown in (2) after completion of the reaction
17h
23bClNO
4); The ratio of the described amount of substance such as formula the compound shown in (3), 2-chloroacetyl acetacetic ester, triethylamine is 1:1.0 ~ 1.8:0.95 ~ 1.9;
(3) such as formula the compound shown in (2) in isopropanol solvent, add diethanolamine stirring reaction 0.5-2.0h at 0-10 DEG C of temperature after, again at room temperature reaction 2.0-8.0h, suction filtration after completion of the reaction, at 0-10 DEG C, add sulfuric acid after filter cake being dissolved in ether, adjust pH is 1.0 ~ 3.0 (preferred adjust pH is 2.0), and stirring reaction is after 0.5 ~ 1 hour, leave standstill separatory, get organic phase steaming and desolventize obtained described such as formula the compound shown in (1); The ratio of the described amount of substance such as formula the compound shown in (2), diethanolamine is 1.0:0.6 ~ 1.5.
The reaction formula of described reaction is as follows:
In described step (1), described reaction solution a post-treating method is: reaction solution a washes with water, filters after getting organic phase anhydrous sodium sulfate drying, and filtrate steaming removal solvent is obtained such as formula the compound shown in (3).
In described step (2), described reaction solution b post-treating method is: reaction solution b steams and desolventizes methylene dichloride, residuum is extracted with ethyl acetate, get the water washing of organic layer saturated common salt, steam after organic phase drying and desolventize, must obtain such as formula the compound shown in (2) with recrystallisation from isopropanol.
In described step (1), the volumetric usage of described chloroform solvent counts 14 ~ 35mL/g with the quality of the 3-amino-benzene boric acid shown in formula (4) usually.
In described step (2), the volumetric usage of described dichloromethane solvent counts 10 ~ 15mL/g with the quality of the compound shown in formula (3) usually.
In described step (3), the volumetric usage of described isopropanol solvent counts 10 ~ 20mL/g with the quality of the compound shown in formula (2) usually.
In described step (3), the volumetric usage of said ether counts 5 ~ 10mL/g with the quality of the compound shown in formula (2) usually.
Of the present inventionly can apply such as formula the compound shown in (1) organogel preparing glucose-sensitive as gelifying agent.
Concrete, the method of described application for: will add in organic solvent such as formula the compound shown in (1), heated sealed to 60 DEG C is dissolved completely, then leave standstill and be cooled to room temperature, make the organogel of concentration 20 ~ 100mg/mL, described organic solvent is hexanaphthene, toluene, dimethylbenzene, methylene dichloride, chloroform, tetracol phenixin equal solvent.
The compound (1) that the present invention relates to prepares as gelifying agent the advantage that gel has glucose-sensitive.Compound (1) is the good gelifying agent of a class, it is in hexanaphthene, toluene, dimethylbenzene, methylene dichloride, chloroform, tetracol phenixin equal solvent, by the intermolecular non covalent bond reactive force of gelator as the reactive forces such as Van der Waals force, hydrogen bond, π-π superposition are self-assembled into three-dimensional net structure, solvent molecule is lost flowability and forms gel, as shown in Figure 1.This gel has the advantage of glucose-sensitive, because the phenylo boric acid group contained in compound (1) molecular structure is the group of a class to glucose-sensitive, when adding glucose molecule in organogel, phenylo boric acid group just generates mixture with glucose molecule, as shown in Figure 2, this mixture destroys the interaction force between gelator, destroy the three-dimensional net structure of gel further, so make the gelator dissociating be dissolved in organic solvent, gel conversion is caused to be that colloidal sol realizes responding the sensitivity of glucose molecule, as shown in Figure 3.
(4) accompanying drawing explanation
Fig. 1. compound (1) gel in toluene.
Fig. 2. phenylo boric acid group and glucose molecule form the process of mixture.
Fig. 3. with the change of the time of the increase organogel totally linearization of glucose concn.
(5) embodiment
Below in conjunction with embodiment, the invention will be further described, but protection scope of the present invention is not limited to this.
The concrete synthetic example of compound (1) is as embodiment 1-embodiment 5
Embodiment 1
30mL chloroform, 3-amino-benzene boric acid (1.37g, 10mmol) is added, neopentyl glycol (1.04g, 10mmol), stirred at ambient temperature 3h in 100mL round-bottomed flask.Reaction solution 200mL washes 2 times, isolates organic phase, filters with after anhydrous sodium sulfate drying, and organic phase is revolved and steamed to obtain compound (3) (C
11h
16bNO
2, 3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl) benzenamine), yield 99%.Get this compound (3) (7.0g, 34mmol), 2-chloroacetyl acetacetic ester (6mL, 43mmol), join in 100mL methylene dichloride, add triethylamine (7mL), heating reflux reaction 24h.Revolve steaming vibrating dichloromethane after completion of the reaction, extraction into ethyl acetate, organic phase uses saturated common salt water washing three times again, and organic phase, after revolving steaming, obtains compound (2) (C with recrystallisation from isopropanol
17h
23bClNO
4, ethyl2-chloro-3-(3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl) phenylamino) but-2-enoate), yield 51%.Compound (2) (4.0g, 12mmol) is joined in 50mL Virahol, add diethanolamine (1.26g, 12mmol) stirring reaction 1h at 0 DEG C after, more at room temperature reacts 5h.Suction filtration obtains solid after completion of the reaction, join after being dissolved in 30mL ether in round-bottomed flask, add aqueous sulfuric acid (pH=2.0) stirring reaction half an hour of 15mL at 0 DEG C after, separatory is got organic phase and is revolved and steam to obtain final product compound (1) (C
12h
15bClNO
4), yield 70%.White powder; Mp 170.7-171.6 DEG C;
1h NMR (300MHz, CDCl
3): δ 10.80 (s, 1H), 7.99 (t, J=22.8Hz, 1H), 7.874 (m, 1H), 7.496 (m, 1H), 7.231 (m, 1H), 4.252 (m, 2H), 2.40 (s, 2H), 2.20 (s, 3H), 1.357 (t, 3H);
13cNMR (75MHz, CDCl
3): δ 167.09 (s), 156.71,138.49,132.25,131.27,128.82128.64,128.306,92.42,61.04,18.06,14.14; HRMS (EI, 70eV): 284.0854 (M+H)
+, C
12h
15bClNO
4requires 283.0783; FTIR (KBr): 3456.49,2365.92,1641.61,1435.65,1374.36,1255.30,1016.27,759.77cm
-1.
Embodiment 2
35mL chloroform, 3-amino-benzene boric acid (1.37g, 10mmol), neopentyl glycol (1.25g, 12mmol) is added, stirred at ambient temperature 4h in 100mL round-bottomed flask.Reaction solution 200mL washes 2 times, isolates organic phase, filters with after anhydrous sodium sulfate drying, and organic phase is revolved and steamed to obtain compound (3), yield 99%.Get this compound (3) (7.0g, 34mmol), 2-chloroacetyl acetacetic ester (4.7mL, 34mmol), join in 75mL methylene dichloride, then add triethylamine (4.5mL), heating reflux reaction 15h.Revolve steaming vibrating dichloromethane after completion of the reaction, extraction into ethyl acetate, organic phase uses saturated common salt water washing three times again, and organic phase, after revolving steaming, obtains compound (2) with recrystallisation from isopropanol, yield 47%.Compound (2) (4.0g, 12mmol) is joined in 40mL Virahol, add diethanolamine (7.2mmol) stirring reaction 1.5h at 5 DEG C after, more at room temperature reacts 6.0h.Suction filtration obtains solid after completion of the reaction, suction filtration obtains solid after completion of the reaction, join after being dissolved in 20mL ether in round-bottomed flask, add aqueous sulfuric acid (pH=2.0) stirring reaction half an hour of 15mL at 0 DEG C after, separatory is got organic phase and is revolved and steam to obtain final product compound (1), yield 58%.
Embodiment 3
40mL chloroform, 3-amino-benzene boric acid (1.37g, 10mmol), neopentyl glycol (1.56g, 15mmol) is added, stirred at ambient temperature 2h in 100mL round-bottomed flask.Reaction solution 220mL washes 2 times, isolates organic phase, filters with after anhydrous sodium sulfate drying, and organic phase is revolved and steamed to obtain compound (3), yield 98%.Get this compound (3) (7.0g, 34mmol), 2-chloroacetyl acetacetic ester (62mmol), joins in 100mL methylene dichloride, then adds triethylamine (9mL), heating reflux reaction 30h.Revolve steaming vibrating dichloromethane after completion of the reaction, extraction into ethyl acetate, organic phase uses saturated common salt water washing three times again, and organic phase, after revolving steaming, obtains compound (2) with recrystallisation from isopropanol, yield 60%.Compound (2) (4.0g, 12mmol) is joined in 60mL Virahol, add diethanolamine (18mmol) stirring reaction 2.0h at 0 DEG C after, more at room temperature reacts 8.0h.Suction filtration obtains solid after completion of the reaction, join after being dissolved in 40mL ether in round-bottomed flask, add aqueous sulfuric acid (pH=2.0) stirring reaction half an hour of 15mL at 0 DEG C after, separatory is got organic phase and is revolved and steam to obtain final product compound (1), yield 75%.
Embodiment 4
20mL chloroform, 3-amino-benzene boric acid (1.37g, 10mmol), neopentyl glycol (0.83g, 8mmol) is added, stirred at ambient temperature 5h in 100mL round-bottomed flask.Reaction solution 150mL washes 2 times, isolates organic phase, filters with after anhydrous sodium sulfate drying, and organic phase is revolved and steamed to obtain compound (3), yield 95%.Get this compound (3) (7.0g, 34mmol), 2-chloroacetyl acetacetic ester (50mmol), joins in 100mL methylene dichloride, then adds triethylamine (7mL), heating reflux reaction 25h.Revolve steaming vibrating dichloromethane after completion of the reaction, extraction into ethyl acetate, organic phase uses saturated common salt water washing three times again, and organic phase, after revolving steaming, obtains compound (2) with recrystallisation from isopropanol, yield 57%.Compound (2) (4.0g, 12mmol) is joined in 50mL Virahol, add diethanolamine (1.26g, 12mmol) stirring reaction 1h at 10 DEG C after, then at room temperature reaction 5h.Suction filtration obtains solid after completion of the reaction, join after being dissolved in 30mL ether in round-bottomed flask, add aqueous sulfuric acid (pH=2.0) stirring reaction half an hour of 15mL at 0 DEG C after, separatory is got organic phase and is revolved and steam to obtain final product compound (1), yield 65%.
Embodiment 5
45mL chloroform, 3-amino-benzene boric acid (1.37g, 10mmol), neopentyl glycol (1.35g, 13mmol) is added, stirred at ambient temperature 1.5h in 100mL round-bottomed flask.Reaction solution 200mL washes 2 times, isolates organic phase, filters with after anhydrous sodium sulfate drying, and organic phase is revolved and steamed to obtain compound (3), yield 98%.Get this compound (3) (7.0g, 34mmol), 2-chloroacetyl acetacetic ester (35mmol), join in 70mL methylene dichloride, then add triethylamine (5mL), heating reflux reaction 15h.Revolve steaming vibrating dichloromethane after completion of the reaction, extraction into ethyl acetate, organic phase uses saturated common salt water washing three times again, and organic phase, after revolving steaming, obtains compound (2) with recrystallisation from isopropanol, yield 50%.Compound (2) (4.0g, 12mmol) is joined in 50mL Virahol, add diethanolamine (1.26g, 12mmol) stirring reaction 1h at 0 DEG C after, more at room temperature reacts 5h.Suction filtration obtains solid after completion of the reaction, join after being dissolved in 30mL ether in round-bottomed flask, add aqueous sulfuric acid (pH=2.0) stirring reaction half an hour of 15mL at 0 DEG C after, separatory is got organic phase and is revolved and steam to obtain final product compound (1), yield 70%.
The specific solution of compound (1) gel is as embodiment 6-embodiment 11
Embodiment 6
The gelifying agent that 25mg is prepared by embodiment 1 method is joined in 1.0mL hexanaphthene, is sealed in ampoule and is heated to 60 DEG C, gelator is dissolved completely, then leave standstill and be cooled to room temperature, the organogel that concentration is 25mg/mL can be obtained.
Embodiment 7
The gelifying agent that 20mg is prepared by embodiment 2 method is joined in 1.0mL tetracol phenixin, is sealed in ampoule and is heated to 60 DEG C, gelator is dissolved completely, then leave standstill and be cooled to room temperature, the organogel that concentration is 20mg/mL can be obtained.
Embodiment 8
30mg is joined in 1.0mL toluene by gelifying agent prepared by embodiment 3 method, be sealed in ampoule and be heated to 35 DEG C, gelator is dissolved completely, then leave standstill and be cooled to room temperature, can obtain the organogel that concentration is 30mg/mL, gained gel photograph as shown in Figure 1.
Embodiment 9
The gelifying agent that 50mg is prepared by embodiment 4 method is joined in 1.0mL dimethylbenzene, is sealed in ampoule and is heated to 60 DEG C, gelator is dissolved completely, then leave standstill and be cooled to room temperature, the organogel that concentration is 50mg/mL can be obtained.
Embodiment 10
The gelifying agent that 100mg is prepared by embodiment 5 method is joined in 1.0mL methylene dichloride, is sealed in ampoule and is heated to 60 DEG C, gelator is dissolved completely, then leave standstill and be cooled to room temperature, the organogel that concentration is 100mg/mL can be obtained.
Embodiment 11
The gelifying agent that 100mg is prepared by embodiment 1 method is joined in 1.0mL chloroform, is sealed in ampoule and is heated to 60 DEG C, gelator is dissolved completely, then leave standstill and be cooled to room temperature, the organogel that concentration is 100mg/mL can be obtained.
Embodiment 12
Join in 1.0mL toluene by 50mg by gelifying agent prepared by embodiment 3 method, being prepared into concentration according to the method for embodiment 8 is 50mg/mL organogel, prepares 9 organogel samples altogether, then adding 1.0mL concentration is respectively 0,1,3,5,10,20,30,40, the D/W of 50mg/mL, record gel conversion is the time of colloidal sol be the time of response.As shown in Figure 3, when adding water blanks, gel conversion is the time of colloidal sol is 48h.And along with the increase of D/W concentration, the gel time of response shortens gradually, and when the D/W concentration added is increased to 50mg/mL, the time of response shortens to 8h, and above result shows that this gel has glucose-sensitive.
Claims (6)
1. one kind such as formula the compound shown in (1):
2., as claimed in claim 1 such as formula the preparation method of the compound shown in (1), it is characterized in that described method is:
(1) by 3-amino-benzene boric acid, the neopentyl glycol shown in formula (4), mix in chloroform solvent, stirred at ambient temperature reaction 1.5-5h, gained reaction solution a aftertreatment is obtained such as formula the compound shown in (3); The ratio of the amount of substance of the 3-amino-benzene boric acid shown in described formula (4), neopentyl glycol is 1.0:0.8 ~ 1.5;
(2) be dissolved in dichloromethane solvent such as formula the compound shown in (3), add 2-chloroacetyl acetacetic ester, triethylamine again, heating reflux reaction 15-30h, gained reaction solution b aftertreatment is obtained such as formula the compound shown in (2) after completion of the reaction; The ratio of the described amount of substance such as formula the compound shown in (3), 2-chloroacetyl acetacetic ester, triethylamine is 1:1.0 ~ 1.8:0.95 ~ 1.9;
(3) such as formula the compound shown in (2) in isopropanol solvent, add diethanolamine stirring reaction 0.5-2.0h at 0-10 DEG C of temperature after, again at room temperature reaction 2.0-8.0h, suction filtration after completion of the reaction, at 0-10 DEG C, add sulfuric acid after filter cake being dissolved in ether, adjust pH is 1.0 ~ 3.0, and stirring reaction is after 0.5 ~ 1 hour, leave standstill separatory, get organic phase steaming and desolventize obtained described such as formula the compound shown in (1); The ratio of the described amount of substance such as formula the compound shown in (2), diethanolamine is 1.0:0.6 ~ 1.5.
3. method as claimed in claim 2, it is characterized in that in described step (1), described reaction solution a post-treating method is: reaction solution a washes with water, filters after getting organic phase anhydrous sodium sulfate drying, and filtrate steaming removal solvent is obtained such as formula the compound shown in (3).
4. method as claimed in claim 2, it is characterized in that in described step (2), described reaction solution b post-treating method is: reaction solution b steams and desolventizes methylene dichloride, residuum is extracted with ethyl acetate, get the water washing of organic layer saturated common salt, steam after dry and desolventize, must obtain such as formula the compound shown in (2) with recrystallisation from isopropanol.
5. the application preparing the organogel of glucose-sensitive such as formula the compound shown in (1) as gelifying agent according to claim 1.
6. apply as claimed in claim 5, it is characterized in that the method for described application for: will add in organic solvent such as formula the compound shown in (1), heated sealed to 60 DEG C is dissolved completely, then leaves standstill and is cooled to room temperature, make the organogel of concentration 20 ~ 100mg/mL.
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| CN103467502B (en) * | 2013-08-19 | 2015-12-02 | 温州大学 | One class Phenylboronic acid organic gel compound |
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| CN101273961A (en) * | 2007-03-30 | 2008-10-01 | 中国人民解放军总医院 | Glucose-sensitive hydrogels |
| US20090191642A1 (en) * | 2008-01-29 | 2009-07-30 | University Of South Carolina | Compositions, Systems, and Methods for Continuous Glucose Monitoring |
| WO2010041037A2 (en) * | 2008-10-10 | 2010-04-15 | The University Of Bath | Materials and methods for resolving polyhydric species by electrophoresis |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101273961A (en) * | 2007-03-30 | 2008-10-01 | 中国人民解放军总医院 | Glucose-sensitive hydrogels |
| US20090191642A1 (en) * | 2008-01-29 | 2009-07-30 | University Of South Carolina | Compositions, Systems, and Methods for Continuous Glucose Monitoring |
| WO2010041037A2 (en) * | 2008-10-10 | 2010-04-15 | The University Of Bath | Materials and methods for resolving polyhydric species by electrophoresis |
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| Boronic acid functionalized superparamagnetic iron oxide nanoparticle as a novel tool for adsorption of sugar;S. Mohapatra et al;《Materials Science and Engineering C》;20090606;第29卷;第2254-2260页 * |
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