CN110790925A

CN110790925A - (R) -TAPP-BINOL-COF polymer, and preparation method and application thereof

Info

Publication number: CN110790925A
Application number: CN201911102478.4A
Authority: CN
Inventors: 董育斌; 马慧超; 陈功军
Original assignee: Shandong Normal University
Current assignee: Shandong Normal University
Priority date: 2019-11-12
Filing date: 2019-11-12
Publication date: 2020-02-14
Anticipated expiration: 2039-11-12
Also published as: CN110790925B

Abstract

The disclosure belongs to the technical field of COF catalysts, and particularly relates to a (R) -TAPP-BINOL-COF polymer, and a preparation method and application thereof. The disclosure provides a preparation method and application of a covalent organic framework (R) -TAPP-BINOL-COF, wherein the (R) -TAPP-BINOL-COF is crystallized in a C2 space group. The catalyst can effectively catalyze the synthesis reaction of a clopidogrel intermediate through photo-thermal conversion under the illumination condition, has mild reaction condition, shorter reaction time and less catalyst dosage, can be repeatedly utilized for more than five times, and has good economic significance when being applied to industrial production.

Description

(R) -TAPP-BINOL-COF polymer, and preparation method and application thereof

Technical Field

The disclosure belongs to the technical field of COF catalysts, and particularly relates to a two-dimensional chiral (R) -TAPP-BINOL-COF polymer, a preparation method thereof, and an application thereof as a chiral drug clopidogrel precursor catalyst.

Background

The information in this background section is only for enhancement of understanding of the general background of the disclosure and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.

Covalent Organic Frameworks (COFs) are crystalline porous materials, which are formed by organic building units connected into an ordered structure through covalent bonds to form a periodic porous COFs framework. COFs have the advantages of large specific surface area, light weight, stable structure and the like, and have good development prospects in the fields of catalysis, gas separation, storage, photoelectric materials and the like. Homogeneous chiral catalysis is still the mainstream of asymmetric synthesis at present, and the catalysts have the problems of difficult recycling and the like. Compared with the prior art, the heterogeneous chiral catalyst has the advantages of being capable of being repeatedly utilized and the like, and meets the requirements of sustainable development and environmental protection. The chiral COFs have high orderliness and high surface area, so that the chiral COFs become a high-efficiency heterogeneous catalyst, and the chiral COFs are convenient to separate from reactants after catalytic reaction, thereby achieving the effect of recycling. In addition, the general thermally driven asymmetric synthesis is usually carried out at low temperature, which not only increases the difficulty and cost of the reaction operation, but also tends to result in low yields of the product. Photothermal conversion materials (PTCMs) can convert light energy into thermal energy, and such materials can have high yield and stereoselectivity even at high temperatures due to the steric confinement effect.

Clopidogrel (Clopidogrel) is a platelet aggregation inhibitor researched and developed by sapofic corporation of france in 1986, can reduce thrombosis in blood vessels by irreversibly inhibiting platelet aggregation through selectively binding to ADP receptors coupled with platelet surface adenylate cyclase, and can be clinically used for preventing and treating myocardial infarction, ischemic cerebral thrombosis, obliterative vasculitis and complications caused by atherosclerosis and thromboembolism. Applied to patients with recent stroke, myocardial infarction or diagnosed peripheral artery disease. Compared with other antiplatelet drugs, clopidogrel has the advantages of strong curative effect, low cost, small side effect and the like, thereby gradually replacing aspirin and ticlopidine. At present, a plurality of synthesis routes related to clopidogrel are reported, but the problems of poor chiral selection, repeated chiral resolution, low yield and the like generally exist in the existing clopidogrel preparation process, so that the production cost and three wastes of the clopidogrel are increased. Therefore, the research and development of the preparation method of clopidogrel with high optical purity has great social and economic benefits.

Disclosure of Invention

Based on the research background, the invention provides a two-dimensional chiral (R) -TAPP-BINOL-COF type catalyst, and the polymer has good catalytic efficiency when used for catalyzing a clopidogrel intermediate, can be recycled for multiple times, and has good economic significance.

Based on the research results, the present disclosure provides the following technical solutions:

in a first aspect of the present disclosure, there is provided a polymer TAPP-BINOL-COF, wherein the structure of the polymer is represented by formula 1 below:

preferably, the polymer is a chiral space group of C2.

In a second aspect of the present disclosure, a method for preparing the polymer of the first aspect is provided, wherein the preparation method adopts Cu-TAPP and (R) -BINOL-CHO as reaction raw materials.

Preferably, the preparation method comprises the following steps: adding Cu-TAPP and (R) -BINOL-CHO into a mixed solution of diluted acetic acid, mesitylene and 1, 4-dioxane for reaction.

In a third aspect of the present disclosure, there is provided the use of a polymer as described in the first aspect as a catalyst.

Preferably, the catalyst is a clopidogrel intermediate catalyst; further, it is used as a catalyst for (S) -2- (2-chlorophenyl) -2- (6, 7-dihydrothieno [3,2-c ] pyridin-5 (4H) -yl) acetonitrile.

The research of the disclosure shows that the polymer is used as a catalyst, the structure is not changed after a plurality of catalytic cycles, and the yield is not obviously reduced after a plurality of cycles of use. The research result shows that the polymer has good stability and catalytic efficiency as a catalyst.

In a fourth aspect of the present disclosure, there is provided a process for the preparation of clopidogrel, comprising the step of using the polymer of the first aspect as a catalyst.

In a fifth aspect of the present disclosure, there is provided a process for the preparation of a clopidogrel intermediate, which employs the polymer of the first aspect as a catalyst.

In a sixth aspect of the present disclosure, there is provided a method for recovering the polymer as the catalyst, wherein the method comprises washing with ethanol, drying, and activating after centrifugally recovering the catalyst.

Compared with the prior art, the beneficial effect of this disclosure is:

(1) the disclosure provides a chiral covalent organic framework (R) -TAPP-BINOL-COF and a preparation method thereof, wherein the framework has a good effect of converting light into heat.

(2) The method utilizes (R) -TAPP-BINOL-COF as a catalyst, the catalyst can effectively catalyze the reaction of o-chlorobenzaldehyde, 4,5,6, 7-tetrahydrothieno [3,2-c ] pyridine and trimethylsilyl cyanide to generate clopidogrel intermediate (S) -2- (2-chlorophenyl) -2- (6, 7-dihydrothieno [3,2-c ] pyridine-5 (4H) -yl) acetonitrile through photothermal conversion, the yield and stereoselectivity of the catalytic reaction are high, heterogeneous catalysis is realized, the catalyst can be recycled for more than five times, the utilization rate of the catalyst is improved, and the cost is reduced.

(3) The invention provides a preparation method of a clopidogrel intermediate, which has the advantages of easily obtained raw materials, low price, high yield and purity, easy separation, no separation and racemization in a synthetic route, no use of special, toxic and harmful reagents in the experimental process, mild reaction conditions and contribution to environmental protection.

Drawings

The accompanying drawings, which are included to provide a further understanding of the disclosure, illustrate embodiments of the disclosure and together with the description serve to explain the disclosure and are not to limit the disclosure.

FIG. 1 is a solid nuclear magnetic spectrum of (R) -TAPP-BINOL-COF prepared in example 2;

FIG. 2 is a high resolution transmission electron micrograph of (R) -TAPP-BINOL-COF prepared in example 2;

FIG. 3 is a UV absorption spectrum of (R) -TAPP-BINOL-COF prepared in example 2;

FIG. 4 is a graph of light-converted thermal temperature rise for the preparation of (R) -TAPP-BINOL-COF in example 2;

FIG. 5 is a PXRD of example 2 preparation of (R) -TAPP-BINOL-COF;

FIG. 6 is N of example 2 preparation of (R) -TAPP-BINOL-COF₂Drawing;

FIG. 7 is a thermogram of (R) -TAPP-BINOL-COF prepared in example 2;

FIG. 8 is PXRD after 5 times catalysis of example 2 preparation of (R) -TAPP-BINOL-COF;

FIG. 9 is a diagram of the gas phase after catalysis for the preparation of (R) -TAPP-BINOL-COF in example 2;

FIG. 10 is a liquid phase diagram of the catalysis of example 2 for the preparation of (R) -TAPP-BINOL-COF;

FIG. 11 is a mass spectrum of the (R) -TAPP-BINOL-COF catalyst prepared in example 2.

Detailed Description

It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present disclosure. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.

As introduced by the background art, aiming at the defects in the prior art, the disclosure provides an (R) -TAPP-BINOL-COF covalent organic framework polymer, a preparation method thereof and application thereof as a clopidogrel intermediate (S) -2- (2-chlorphenyl) -2- (6, 7-dihydrothieno [3,2-c ] pyridine-5 (4H) -group) acetonitrile.

preferably, the polymer is a chiral space group of C2.

The present disclosure carried out structural simulation of powder data of (R) -TAPP-BINOL-COF by Materials Studio (ver.8.0) software, simulation result COF being chiral space group of C2, refinement unit cell parameter beingα -90.0 deg., β -104.46 deg., γ -90.0 deg., and refinement factors Rwp and Rp of 2.15% and 3.03%, respectively, the unit cell parameters and atomic coordinates of which are shown in table 1.

TABLE 1 unit cell parameters and atomic coordinates of (R) -TAPP-BINOL-COF

In a second aspect of the present disclosure, a method for preparing the polymer of the first aspect is provided, wherein the preparation method adopts Cu-TAPP and (R) -BINOL-CHO as reaction raw materials;

wherein, the structure of Cu-TAPP is shown as the following formula 2, and the structure of (R) -BINOL-CHO is shown as the following formula 3:

Preferably, the reaction temperature is 110-130 ℃.

Preferably, the reaction time is 2.5-3.5 d.

Preferably, the molar mass ratio of the Cu-TAPP to the (R) -BINOL-CHO is 0.8-1.2: 1.8 to 2.2.

Preferably, the volume ratio of the dilute acetic acid to the mesitylene to the 1, 4-dioxane is 2-4: 4-6: 14-17.

Preferably, the preparation method further comprises: and after the reaction is finished, collecting a solid part, and washing the solid part by using ethanol to obtain purple black powder, namely the polymer (R) -TAPP-BINOL-COF.

Preferably, the clopidogrel intermediate is prepared by reacting o-chlorobenzaldehyde, 4,5,6, 7-tetrahydrothieno [3,2-c ] pyridine and trimethylsilyl cyanide under irradiation conditions,

the reaction equation of the clopidogrel intermediate is as follows:

In order to make the technical solutions of the present disclosure more clearly understood by those skilled in the art, the technical solutions of the present disclosure will be described in detail below with reference to specific examples and comparative examples.

Example 1: synthesis of (R) -BINOL-CHO

R-1, 1' -bi-2-naphthol (10.0mmol,2.86g) is placed in a 100ml three-neck flask, dichloromethane (20ml) is added, liquid bromine (25.2mmol,4.00 g) is slowly added dropwise with stirring after cooling to 0 ℃, and after the addition is completed, the reaction solution is light orange. After further reaction at 0 ℃ for 24h, Na is added₂S₂O₃(7.4 mmol,1.20g) of the aqueous solution, stirring was continued for 2 h. After the reaction, the color of the reaction solution changed from orange to light yellow. Filtering the reaction solution, transferring the filtrate to a separating funnel, washing the organic phase with saturated NaCl solution for three times, combining the organic phases, adding a proper amount of Na₂SO₄Drying and rotary evaporation are carried out to remove the solvent, thus obtaining the light yellow solid product (R) -6,6 '-dibromo-1, 1' -bi-2-naphthol.

(R) -6,6 '-dibromo-1, 1' -bi-2-naphthol (10.0mmol,4.44g) was weighed in a 100ml flask, acetone (40ml) was added, stirring was performed until the solid was completely dissolved, and anhydrous K was added₂CO₃(40.0mmol,5.50g), bromoethane (60.0mmol,7.00g), the reaction was heated to reflux and reacted for 48 h. After the reaction is finished, the reaction product is cooled to room temperature, filtered, and the filtrate is decompressed and rotary evaporated to obtain yellow solid (R) -6,6 ' -dibromo-2, 2 ' -diethoxy-1, 1 ' -binaphthyl.

N₂Under the protection of(R) -6,6 ' -dibromo-2, 2 ' -diethoxy-1, 1 ' -binaphthyl (10.0mmol,4.97 g), cuprous chloride (22.0mmol,2.20g), and DMF (15ml) were placed in a 100ml three-necked flask, and stirred at a constant temperature of 110 ℃ for 48 hours. After the reaction, the mixture was filtered while it was hot, and the filtrate was poured into secondary water (300 ml) with stirring to precipitate a pale yellow solid. Filtering, drying the solid, dissolving with dichloromethane, and performing column chromatography (eluent: dichloromethane) to obtain a yellow solid product, namely 6,6 ' -dichloro-2, 2 ' -diethoxy-1, 1 ' -binaphthyl.

6,6 ' -dichloro-2, 2 ' -diethoxy-1, 1 ' -binaphthyl (1.0mmol,0.41g) was weighed into a 100ml three-neck flask, and dichloromethane (30ml) was added and stirred until dissolved, and liquid bromine (24.0 mmol,1.25ml) was slowly added dropwise at-78 ℃ for about 1 hour. After the dropwise addition, the reaction system was slowly warmed to room temperature and continued for 24 hours. Then cooling to 0 ℃, slowly dropping sodium bisulfite solution into a constant pressure dropping funnel to quench the reaction, and changing the orange color of the reaction solution into light yellow color after the dropping is finished. Separating with separating funnel, washing organic phase with saturated NaCl solution for three times, combining organic phases, adding appropriate amount of Na₂SO₄Drying and rotary evaporation to obtain yellow solid (R) -4,4 '-dibromo-6, 6' -dichloro-2, 2 '-diethoxy-1, 1' -binaphthyl.

N₂Under protection, (R) -4,4 '-dibromo-6, 6' -dichloro-2, 2 '-diethoxy-1, 1' -binaphthyl (1.0mmol, 0.57g), 4-methoxycarbonylphenylboronic acid (2.0mmol,0.36g), tetrakis (triphenylphosphine) palladium (0.06 mmol,0.08g), anhydrous potassium carbonate (6.0mmol,0.82g), tetrahydrofuran (30ml) and water (10ml) were placed in a 100ml three-necked flask, and stirred at a constant temperature of 75 to 80 ℃ for 36 hours. After the reaction was completed, liquid was separated while hot, the upper organic layer was taken, the aqueous layer was extracted three times with dichloromethane (20ml), the organic layers were combined, dried over sodium sulfate, and rotary-evaporated to give an orange oil. Dissolving with a small amount of dichloromethane, and performing column chromatography (eluent: dichloromethane: petroleum ether ═ 1:1) to obtain (R) -4,4 '-dimethoxycarbonyl-6, 6' -dichloro-2, 2 '-diethoxy-1, 1' -binaphthyl ((R) -BINOL-CHO) as a yellow solid.

Example 2: synthesis of (R) -TAPP-BINOL-COF

Cu-TAPP (0.05mmol,36.60mg), (R) -BINOL-CHO (0.10mmol,61.60 mg), dilute acetic acid (6M,0.30ml) and a solution of 1, 4-dioxane/mesitylene (2ml, volume ratio 3:1) were added to a pressure tube. Freezing with liquid nitrogen, vacuumizing, thawing, repeating the above steps for three times, and reacting in a constant temperature oven at 120 deg.C for 3 days. After cooling to room temperature, collected by centrifugation and washed repeatedly with ethanol, vacuum dried to give violet black Cu-COF powder in 82% yield.

This example is by solid Nuclear magnetism, PXRD, N₂This compound was characterized by adsorption, TGA and the results are shown in figures 1, 5,6 and 7, respectively. The polymer can be seen to have a hollow structure. The UV absorption of (R) -TAPP-BINOL-COF prepared by the above method in acetonitrile solution (FIG. 3) shows that the absorption is maximum at 420nm, and the temperature rise of the light conversion heat of COF is found under the light of 420nm (FIG. 4). XRD (FIG. 5), BET (FIG. 6) and TGA (FIG. 7) of catalyst (R) -TAPP-BINOL-COF demonstrate that this COF is a crystalline porous material with high thermal stability.

Example 3: (R) -TAPP-BINOL-COF catalyzes the reaction of clopidogrel intermediates.

The reaction equation in this example is as follows:

catalyst (R) -TAPP-BINOL-COF (2.1 mol% Cu,10.0mg), o-chlorobenzaldehyde (0.5mmol, 56. mu.l), (0.5mmol, 59. mu.l), trimethylsilyl chloride (0.55mmol, 70. mu.l) and acetonitrile (1.5ml) were placed in a glass vial under a 300W xenon lamp (. lamda. gtoreq.420 nm, intensity 2.5Wcm^-230cm from the reaction vessel) was stirred for reaction under irradiation. The reaction yield was determined by GC analysis and the ee value of the product was determined by HPLC analysis, the results of which are shown in FIGS. 9, 10 and 11, respectively.

Experimental example 4: (R) -TAPP-BINOL-COF catalyzes the cycle number of the reaction of clopidogrel intermediate.

Tracking the reaction by gas chromatography, after the reaction is finished, centrifugally recovering the catalyst, directly putting the catalyst into the next cycle for reaction, using the catalyst for 5 cycles according to the conditions, calculating the yield of the reaction liquid by gas chromatography (o-chlorobenzaldehyde is used as an internal standard), and analyzing and determining the ee value of the reaction product by liquid chromatography. The catalytic effect is shown in table 2.

TABLE 2 yield and stereoselectivity of 5 cycles of (R) -TAPP-BINOL-COF catalyzed reactions

Yield determination by gas chromatography b ee values determined by liquid chromatography analysis

The recovered catalyst was characterized by PXRD, as shown in FIG. 9, with (R) -TAPP-BINOL-COF still retaining the original framework.

After the reaction is finished, centrifuging the solution, washing the obtained catalyst for 3 times by using ethanol, and drying at 90 ℃ to be reused.

The above description is only a preferred embodiment of the present disclosure and is not intended to limit the present disclosure, and various modifications and changes may be made to the present disclosure by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present disclosure should be included in the protection scope of the present disclosure.

Claims

1. A polymer TAPP-BINOL-COF, wherein the structure of the polymer is shown as the following formula 1:

2. the method for preparing the polymer according to claim 1, wherein Cu-TAPP and (R) -BINOL-CHO are used as reaction raw materials;

3. the method of preparing the polymer of claim 2, wherein the method comprises: adding Cu-TAPP and (R) -BINOL-CHO into a mixed solution of diluted acetic acid, mesitylene and 1, 4-dioxane for reaction.

4. The method for preparing the polymer according to claim 2, wherein the reaction temperature is 110 to 130 ℃; or the reaction time is 2.5-3.5 d.

5. The method for preparing the polymer according to claim 2, wherein the molar mass ratio of the Cu-TAPP to the (R) -BINOL-CHO is 0.8-1.2: 1.8-2.2 or the volume ratio of the dilute acetic acid to the mesitylene to the 1, 4-dioxane is 2-4: 4-6: 14-17;

or the preparation method further comprises the following steps: and after the reaction is finished, collecting a solid part, and washing the solid part by using ethanol to obtain purple black powder, namely the polymer (R) -TAPP-BINOL-COF.

6. Use of the polymer of claim 1 as a catalyst.

7. Use of the polymer of claim 6 as a catalyst, wherein said catalyst is a clopidogrel intermediate catalyst; preferably, it is used as a catalyst for (S) -2- (2-chlorophenyl) -2- (6, 7-dihydrothieno [3,2-c ] pyridin-5 (4H) -yl) acetonitrile;

the reaction equation of the clopidogrel intermediate is as follows:

8. a process for the preparation of clopidogrel, characterized by comprising the step of using the polymer of claim 1 as a catalyst.

9. A process for producing a clopidogrel intermediate, characterized by using the polymer of claim 1 as a catalyst.

10. A method for recovering the polymer of claim 1 as a catalyst, which comprises recovering the catalyst by centrifugation, washing with ethanol, drying, and activating.