阅读说明：本技术 杯[3]咔唑衍生物及其合成和应用 (Calix [3] carbazole derivative and synthesis and application thereof ) 是由 杨鹏 廖晓雨 于 2020-06-01 设计创作，主要内容包括：本发明涉及医药技术领域,涉及杯[3]咔唑衍生物及其合成和应用。所述杯[3]咔唑衍生物在水中能够与黄芩苷结合并改善其在水中的溶解度,展现出良好的分子载体潜力。本发明的杯[3]咔唑衍生物,其结构式如下,其中,R-(1)、R-(2)、R-(3)如权利要求书和说明书所述。(The invention relates to the technical field of medicine, in particular to a cup [3]]Carbazole derivatives and synthesis and application thereof. The cup [3]The carbazole derivative can be combined with baicalin in water and improve the solubility of the baicalin in water, and shows good molecular carrier potential. Cup [3] of the invention]The carbazole derivative has the structural formula shown in the specification, wherein R 1 、R 2 、R 3 As described in the claims and specification.)

1. A calix [3] carbazole derivative represented by formula I:

2. cup [3] according to claim 1]A carbazole derivative selected from:

3. the method for producing a calix [3] carbazole derivative according to claim 1, comprising the steps of:

(1) adding the compound A into a solvent, adding a saturated sodium hydroxide aqueous solution, stirring at room temperature, and acidifying to prepare a compound B;

(2) adding the compound B into a proper amount of ammonia water for dissolving, and freeze-drying to prepare a compound C;

(3) dissolving the compound B in a mixed solvent of tetrahydrofuran and water, adding lithium hydroxide, sodium hydroxide and potassium hydroxide, distilling under reduced pressure to remove tetrahydrofuran, and freeze-drying to obtain compounds D, E and F;

(4) adding the compound A, 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone and a small amount of water into a solvent, and stirring at room temperature to prepare a compound G;

(4) adding the compound G into a solvent, then adding a saturated sodium hydroxide aqueous solution, stirring at room temperature, and acidifying to prepare a compound H;

(5) adding a compound H into a proper amount of ammonia water for dissolving, and freeze-drying to prepare a compound I;

(6) dissolving the compound H in a mixed solvent of tetrahydrofuran and water, adding lithium hydroxide, sodium hydroxide and potassium hydroxide, distilling under reduced pressure to remove tetrahydrofuran, and freeze-drying to obtain the compounds J, K and L.

4. The preparation method according to claim 3, wherein the synthetic route is as follows:

5. the method according to claim 3, wherein the solvent used in step (1) or (4) is tetrahydrofuran, and the reaction time is 16 to 24 hours.

6. The method according to claim 3, wherein the molar ratio of the compound A to 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone in the step (3) is 1:6-10, the reaction time is 10 to 24 hours, and the reaction temperature is room temperature.

7. Use of the calix [3] carbazole derivative according to claim 1 or 2 as a molecular carrier for a drug.

8. The use of claim 7, wherein said drug is a poorly soluble drug.

9. The use of claim 7, wherein the drug is baicalin.

10. The use according to claim 9, wherein the molar ratio of poorly soluble drug to calix [3] carbazole derivative is: 1:1.

Technical Field

The invention relates to the technical field of medicines, and relates to a calix [3] carbazole derivative and synthesis and application thereof. The calix [3] carbazole derivative can be combined with baicalin in water and improve the solubility of the baicalin in water, and shows good molecular carrier potential.

Background

The traditional medicine carriers such as crown ether, cyclodextrin and the like can not meet the requirements of the modern medicine field on the functions of medicine carrying rate, sustained and controlled release and the like. The development of calixarenes in recent years has shown some unique advantages. For example: 1. the cavity is adjustable; 2. the decoration is easy; 3. the types of the package loads are various; 4. the stability is good; 5. the synthesis is simple. But also has some disadvantages: the cavity is small and cannot be tested by ultraviolet and fluorescence means. Therefore, it is necessary to develop a novel calixazole derivative with a larger cavity and easy detection.

Scutellariae radix is dried root of Scutellaria baicalensis Georgi (Scutellaria baicalensis Georgi) belonging to Labiatae (Labiatae). The main component of the scutellaria baicalensis is baicalin, and the scutellaria baicalensis has wide pharmacological effects of oxidation resistance, inflammation resistance, allergy resistance, bacteria resistance, virus resistance, tumor resistance and the like. However, baicalin is almost insoluble in water, which greatly reduces the bioavailability of baicalin, and the adoption of a water-soluble molecular carrier entrapment method is one of the solutions.

The invention aims to develop a baicalin-containing high-efficiency high-fluorescence conjugated polymer with a larger cavity, ultraviolet and fluorescence properties, and the baicalin-containing high-fluorescence conjugated polymer can entrap baicalin, increase the water solubility and improve the bioavailability. The carbazole unit is subjected to cyclization reaction in one step, and the generated carbazole tricyclic is oxidized and hydrolyzed to form salt, so that the water-soluble calix [3] carbazole derivative is obtained. The carrier is easy to synthesize, has high yield, has the advantages of luminescence property and the like, has a large cavity in a molecule, can entrap baicalin, increases water solubility after entrapment, and can be used for improving the bioavailability of other insoluble drugs.

Disclosure of Invention

The invention provides a novel water-soluble calix [3] carbazole derivative, which has the following structural formula:

further, the air conditioner is provided with a fan,

the present invention is preferably a water-soluble calix [3] carbazole derivative,

the preparation synthetic route of the calix [3] carbazole derivative is as follows:

the method comprises the following specific steps:

(1) the synthesis of compound a is shown in: CN 201510309211.8.

(2) Preparation of Compounds C, D, E, F

2.1 Compound A is dissolved in THF (tetrahydrofuran), and an equal volume of saturated aqueous NaOH (sodium hydroxide) is added and reacted at room temperature for 1 day. THF was evaporated under reduced pressure and the pH was adjusted to 2-3 with hydrochloric acid. And collecting the precipitate, washing twice with water, and airing to obtain a compound B.

2.2 dissolving the compound B in ammonia water, and freeze-drying to obtain a compound C.

And 2.3, dissolving the compound B in a mixed solvent of tetrahydrofuran and water, adding three times of lithium hydroxide, sodium hydroxide and potassium hydroxide, distilling under reduced pressure to remove tetrahydrofuran, and freeze-drying to obtain compounds D, E and F.

(3) Preparation of Compounds I, J, K, L

3.1 dissolving Compound A and 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone in THF, adding a little water, reacting at room temperature for 1 day. THF was evaporated under reduced pressure, the solid was dissolved with DCM and washed three times with saturated aqueous sodium bicarbonate. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain Compound G.

3.2 Compound G was dissolved in THF (tetrahydrofuran), and an equal volume of saturated aqueous NaOH (sodium hydroxide) was added to react at room temperature for 1 day. THF was evaporated under reduced pressure and the pH was adjusted to 2-3 with hydrochloric acid. And collecting the precipitate, washing twice with water, and airing to obtain a compound H.

3.3 dissolving the compound H in ammonia water, and freeze-drying to obtain the compound I.

And 3.4, dissolving the compound H in a mixed solvent of tetrahydrofuran and water, adding three times of lithium hydroxide, sodium hydroxide and potassium hydroxide, distilling under reduced pressure to remove tetrahydrofuran, and freeze-drying to obtain the compounds J, K and L.

The calix [3] carbazole derivative can be used as a drug carrier to entrap insoluble drugs.

Taking the case that calix [3] carbazole derivative (C, I) entraps baicalin as an example:

(1) ultraviolet detection

Gradually adding baicalin into the water solution of the compound to obtain 250nm-7000nm ultraviolet absorption spectrogram.

(2) Fluorescence detection

Setting the spectrum range at 350-650nm and the excitation wavelength at 340nm, and gradually adding baicalin solution into the water solution dissolved in the compound to obtain the fluorescence absorption spectrum. By [ C ]_Baicalin]On the abscissa, with (F-F)_o)/(F_max-F_o) And (5) drawing for the ordinate, and fitting a curve by using an equation to obtain the binding constant K.

Fluorescence detection shows that the compound I can entrap baicalin in water at a ratio of 1: 1.

Drawings

FIG. 1 is a fluorescence titration spectrum of compound C and baicalin, wherein the fluorescence of compound C is quenched when baicalin is gradually added from 0.6 times to 15 times.

FIG. 2 shows the result R of fitting the compound C with baicalin according to the 1:1 combination formula²＝0.98，K＝1.0*10⁴M^-1。

FIG. 3 is a fluorescence titration spectrum of compound I and baicalin, which is gradually dropped from 0.2 times to 5 times. The fluorescence of compound I was quenched.

FIG. 4 shows the result R of fitting the compound I with baicalin according to the 1:1 combination formula²＝0.99，K＝1.8*10⁵M^-1。

Detailed Description

Example 1

Synthesis of Compound A

Adding 50g (0.3mol) of carbazole into a 1L three-necked flask, adding 400mL of DMSO, adding 57g of sodium hydroxide, stirring at 85 ℃ for 4 days, dissolving 50g of bromoacetic acid with 30mL of DMSO, adding into the three-necked flask, continuously heating and stirring for 3 days, and finishing the reaction. Pouring the reaction solution into a large amount of water, and filtering to obtain filtrate. The pH of the filtrate is adjusted to 3-5, and a large amount of precipitate is separated out to obtain 40.5g of the product with the yield of 60.1%.

A250 mL round bottom flask is weighed with 8.0g (35.5mmol) of 2- (9H-carbazole-9-yl) acetic acid and added into the flask, 120mL ethanol is added, 6 drops of concentrated sulfuric acid are slowly dripped, heating reflux is carried out, after 12 hours of reaction, the reaction is finished and solid is separated out. Solid was obtained by suction filtration to obtain (compound 4)5.3g, yield 66%.

A1L round-bottom flask was weighed to 1g (3.9mmol) of the monomer, charged into the flask, 1L of dichloromethane was added, 120mg (4.0mmol) of paraformaldehyde was added, stirred, 266mg (0.97mmol) of Lewis acid-ferric trichloride was slowly added in portions, stirred at room temperature for 15 hours, and after completion of the reaction, ammonia was added to quench the reaction. After silica gel chromatography column, 300mg of compound a was obtained in 29% yield.¹H-NMR(600MHz,CDCl₃),δ(ppm):7.90(s,6H),7.39(d,6H),7.23(d,6H),4.94(s,6H), 4.29(s,6H),4.20(q,6H),1.22(t,9H).

Example 2

Synthesis of Compounds B, C, D, E, F

A25 mL round-bottomed flask was weighed to 150mg (0.19mmol) of Compound A, and 4mL of THF was added to dissolve the compound A, 4mL of a saturated aqueous solution of sodium hydroxide was added thereto, and the mixture was stirred at room temperature for 1 day, after the reaction was completed, THF was distilled off under reduced pressure, and the pH was adjusted to 2 to 3 with dilute hydrochloric acid. Centrifugation gave a white powder, compound B. After air-drying, 107mg were weighed, and the yield was 80%.¹H NMR(600MHz,DMSO-d₆) δ12.88(s,3H),8.21(s,6H),7.39(s,6H),7.36(s,6H),5.08(s,6H),4.21(s,6H).

Taking a 10mL beaker, adding 107mg of the compound B, adding 5mL of ammonia water, stirring and dissolving, and freeze-drying in a freeze dryer to obtain white powder C109mg with the yield: 95 percent.

Dissolving 107mg of compound B in 5mL of mixed solvent of tetrahydrofuran and water, adding three times of lithium hydroxide, sodium hydroxide and potassium hydroxide, fully dissolving, distilling under reduced pressure to remove tetrahydrofuran, and freeze-drying to obtain compounds D, E and F.

Example 3

Synthesis of Compound G

Weighing 150mg (0.19mmoL) of compound A in a 25mL round-bottom flask, adding 10mL THF to dissolve, adding 260 mg (1.14mmoL L) of 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone, and stirring at room temperatureFor 1 day. After completion of the TLC detection, THF was distilled off under reduced pressure, the solid was dissolved in DCM and washed three times with saturated aqueous sodium hydrogen carbonate solution. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give compound G120mg in 77% yield.¹H NMR(600MHz, Chloroform-d)δ8.65(s,2H),8.57(s,2H),8.42(s,2H),8.16(s,2H),8.15(s,2H),7.61(s,2H), 7.41(s,4H),7.18(s,2H),5.22(s,2H),4.95(s,4H),4.34(q,J＝7.1Hz,2H),4.17(q,J＝7.1Hz, 4H),1.36(t,J＝7.1Hz,3H),1.21(t,J＝7.1Hz,6H).

Example 4

Synthesis of Compounds H, I, J, K, L

120mg (0.15mmol) of compound H is weighed out from a 25mL round-bottom flask, 4mL of THF is added to dissolve the compound H, 4mL of saturated aqueous sodium hydroxide solution is added, the mixture is stirred at room temperature for 1 day, after the reaction is finished, THF is evaporated under reduced pressure, and the pH is adjusted to 2-3 with dilute hydrochloric acid. Centrifuging to obtain the compound H. After air-drying, 80mg was weighed, and the yield was 74%.¹H NMR(600MHz,DMSO-d₆)δ13.05 (s,3H),8.92(s,2H),8.75(s,2H),8.51(s,2H),8.22(s,2H),8.00(s,2H),7.90(s,2H),7.73(s,2H), 7.48(s,2H),7.42(s,2H),5.50(s,2H),5.23(s,4H),4.13(d,2H).

Taking a 10mL beaker, adding 80mg of compound H, adding 5mL of ammonia water, stirring and dissolving, and freeze-drying in a freeze dryer to obtain 82mg of compound I, wherein the yield is as follows: 96 percent.

Dissolving 80mg of compound H in 5mL of mixed solvent of tetrahydrofuran and water, adding three times of lithium hydroxide, sodium hydroxide and potassium hydroxide, fully dissolving, distilling under reduced pressure to remove tetrahydrofuran, and freeze-drying to obtain compounds J, K and L.

Example 5

Ultraviolet detection

Ultraviolet detection shows that the ultraviolet absorption curve of the compound is highly coincident with baicalin, so that the ultraviolet detection technology is not applicable.

Example 6

Fluorescence detection

The invention can analyze the entrapment condition of the compound to the baicalin and the binding energy K after entrapment by adopting fluorescence detection.

Taking compound C, I as an example:

setting the spectrum range at 345-600nm and the excitation wavelength at 314nm, adding 2000. mu.L of aqueous solution into the cuvette, adding the compound C to make the final concentration reach 10. mu.M, and obtaining the fluorescence titration spectrogram with the increase of the addition of baicalin (figure 1).

Setting the spectrum range at 350-650nm and the excitation wavelength at 340nm, adding 2000. mu.L of aqueous solution into the cuvette, adding the compound F to make the final concentration reach 10. mu.M, and obtaining the fluorescence titration spectrogram with the increase of the addition of baicalin (shown in figure 3).

By [ C ]_Baicalin]On the abscissa, with (F-F)_o)/(F_max-F_o) For ordinate plots, 500nm was selected for fluorescence quenching range and fitted using a 1:1 model with a binding energy K of 1.0 x 10⁴. (FIG. 2).

By [ C ]_Baicalin]On the abscissa, with (F-F)_o)/(F_max-F_o) For ordinate plots, 500nm was selected for fluorescence quenching range and fitted using a 1:1 model with a binding energy K of 1.8 x 10⁵. (FIG. 4).

The above tests show that: the calixazole derivative can be combined with baicalin molecules in a 1:1 mode, and has high combination energy and firm entrapment.