A method for preparing betulonic acid olefin dimer based on olefin metathesis reaction and application thereof

Abstract

The present application relates to a kind of betulin olefin dimers, including a synthetic route: using the cross-metathesis reaction in olefin metathesis reaction of alpha-betulin olefin derivative, obtain betulin-based olefin dimers, which can be used as the initiator of ring-opening polymerization, construct telechelic betulin-based polymer.The synthesis method of betulin-based olefin dimers involved in the present application uses the cross-metathesis in olefin metathesis reaction, which has the advantages of simple method, mild condition etc., can realize its structure control and performance adjustment by controlling derivative carbon chain length, has certain advancement, it has chain initiation structure, can prepare telechelic betulin-based polymer, to realize the high value and functionalization of natural products, the utilization of renewable biomass resources also conforms to sustainable development.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of natural product olefin modification, and particularly relates to a preparation method of a dimer based on an alpha-betulin olefin derivative. BACKGROUND

[0002] Betulin is the main component of Chinese medicine birch bark, accounting for 30wt% of its dry weight, and has the effects of antiviral, antibacterial, anti-inflammatory, etc., and is widely used in medicine engineering, food engineering, cosmetics, etc. Chemical modification of betulin molecules mainly targets three active functional groups: 3-hydroxyl, 28-hydroxyl and C20-29 double bond. Due to the difference in reactivity of the two alcohol hydroxyl groups, different betulin esterification products have betulin-like biological activity, and they can be used as initiators to further initiate polymerization to prepare betulin-based polymers, so as to realize the high value and functionalization of betulin.

[0003] Olefin metathesis is a reaction in which two olefin double bonds are broken and recombined into a new carbon-carbon double bond by the action of a catalyst. Olefin metathesis is a simple, efficient and green synthesis method for constructing new carbon skeletons using olefins as substrates. This reaction allows carbon-carbon double bonds to couple with each other, greatly enriching the spatial structure of compound skeletons and greatly simplifying reaction steps and reducing reaction difficulty. Among them, cross metathesis (CM) is an important part of olefin metathesis, which is a chemical reaction in which carbon-carbon double bonds are broken and recombined between molecules under the catalysis of metal carbene.

[0004]

[0005] Grubbs catalyst is a catalyst with ruthenium metal as the core, and the reaction is applied to cross metathesis. Grubbs first generation catalyst (such as a) has very wide functional group applicability, it is stable, easy to prepare, and even exposed to air for several weeks without decomposition. More importantly, its catalytic activity is not affected by air, water and impurities in the solvent, so it has been widely used. Grubbs second generation catalyst (such as b) also has good stability, functional group applicability and high catalytic activity. Grubbs-Hoveyda catalyst, it has higher stability than Grubbs catalyst, and has higher catalytic speed.

[0006]

[0007] Three classic olefin metathesis catalysts: a) Grubbs first generation catalyst, b) Grubbs second generation catalyst, and c) Grubbs-Hoveyda catalyst.

[0008] The present application takes monosubstituted betulafuran olefin derivatives as raw materials, designs and prepares betulafuran olefin derivative dimers through olefin metathesis reaction. Combined with the principle of olefin metathesis reaction, the betulafuran dimers constructed by the present application are expected to become chain initiators for olefin metathesis polymerization and ring-opening polymerization, generating betulafuran-based telechelic polymers.

[0009] Japanese patent application JP2008149275-A relates to the production of alpha-olefin dimers by a catalyst containing an alkali metal and an anhydrous potassium compound. The catalyst has high activity, prolongs the service life, and can produce alpha-olefin dimers with higher selectivity. Japanese patent application JP2005187698-A relates to the production of alpha-olefin dimers and anhydrous carboxylic acids by non-solvent copolymerization in the presence of a free radical initiator at a temperature of 70-250°C. WO2020176488-A1 prepared artemisinin dimers. Patent CN103079699B relates to an olefin metathesis catalyst, its preparation method and application method. Huang et al. (Biomass Chemical Engineering 2022, 02, 1673-5854.) achieved the direct application of olefin cross-metathesis in plant oil methyl esters to obtain long-chain terminal olefin compounds. George et al. (Journal of Natural Products 2014, 77, 863-872.) studied the effectiveness of betulafuran-derived amine dimers in the treatment of cancer. Karagoz et al. reported (Bioorganic & Medicinal Chemistry 2019, 27, 110-115) that betulafuran-based dimers have excellent antibacterial and antiviral advantages. However, there is no report on the method and application of preparing functional betulafuran-based olefin dimers using cross-metathesis reaction in olefin metathesis reaction, and there is no report on the preparation of natural products using betulafuran-based olefin dimers as initiators. SUMMARY

[0010] The technical problem to be solved by the present application is to provide a method for preparing betulafuran olefin dimers based on olefin metathesis reaction, which can be used as chain initiators for olefin metathesis polymerization and ring-opening polymerization to generate betulafuran-based polymers with betulafuran groups embedded in the macromolecular structure.

[0011] To solve the above technical problems, the present application obtains a betulafuran-based olefin dimer based on alpha-betulafuran olefin, which has the following structure:

[0012]

[0013] Another object of the present application is to provide a method for preparing the above-mentioned betulafuran olefin dimers based on olefin metathesis reaction:

[0014] The steps include the following steps:

[0015] (1) First, in a round bottom flask, sequentially add the olefinic acid reagent, betulinol, 4-dimethylaminopyridine, dichloromethane, and stir. Then slowly drop the mixed solution of dicyclohexyl carbodiimide and dichloromethane under the condition of an ice water bath, and stir the mixture at room temperature overnight. Wash the obtained mixture with a 5% hydrochloric acid solution, dry the organic phase with anhydrous magnesium sulfate, filter, and evaporate the solvent to obtain the crude product. The crude product is separated by column chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain an alpha-betulinol olefin;

[0016] (2) Add the alpha-betulinol olefin prepared in step (1) to a reaction tube, repeat vacuum-argon five times, then add the re-distilled solvent under the condition of argon, stir and disperse uniformly, and then add the prepared catalyst solution. The above mixture is reacted at room temperature for 4-12 h, and the reaction temperature is kept at 25-75°C and the constant rotation speed during the reaction. After the reaction is cooled to room temperature, a quenching agent is added, and stirring is continued for 2 h to obtain the crude product. The crude product is filtered through basic aluminum oxide to remove the catalyst and evaporate the solvent. The obtained crude product is separated by column chromatography (petroleum ether / ethyl acetate = 5 / 1), and the product is vacuum dried at 40°C for 8 h to obtain the final product.

[0017] The olefinic acid reagent in step (1) is 4-pentenoic acid or undecenoic acid.

[0018] The catalyst in step (1) is one of Grubbs second-generation metal carbene catalyst or Hoveyda-Grubbs second-generation metal carbene catalyst.

[0019] The quenching agent in step (1) is vinyl ether.

[0020] The solution in step (1) is one of toluene, tetrahydrofuran, and dichloromethane.

[0021] The present application selects alpha-betulinol olefin derivatives as raw materials, and prepares betulinol-based dimers by olefin metathesis polymerization method, which can be blended with other polymers to prepare functional polymer products.

[0022] An object of the present application is to provide a betulinol olefin dimer-based initiator for preparing a telechelic betulinol-based polymer by ring-opening polymerization.

[0023]

[0024] The present application uses cross-metathesis reaction in olefin metathesis reaction to prepare functional olefin monomers, and uses 1 HNMR, 13C NMR, HRMS and so on to characterize its structure; then, through Grubbs II catalyst polymerization to prepare betulafuran-based olefin dimers, through 1 HNMR to characterize it.

[0025] Compared with the prior art, the present application has the beneficial effects that:

[0026] (1) The present application can effectively control the influence of catalyst on the catalytic process in the field of preparing natural product olefin derivatives, has mild reaction conditions, fast reaction rate and high isotacticity.

[0027] (2) The present application can prepare betulafuran-based telechelic polymers using olefin dimers as initiators, achieve the high value and functionalization of natural products, achieve the purpose of sustainable development using renewable biomass resources, has simple process steps and convenient synthesis, and lays a foundation for the mass synthesis and industrialization of betulafuran-based telechelic polymers. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figure 1 The HNMR spectrum of the prepared compound betulafuran olefin derivative UBet is shown in Figure 1. 1 The HNMR spectrum of the prepared compound betulafuran olefin derivative UBet is shown in Figure 1.

[0029] Figure 2 The HNMR spectrum of the prepared compound betulafuran olefin derivative UBet is shown in Figure 1. 1 The HNMR spectrum of the prepared compound betulafuran olefin derivative UBet is shown in Figure 1.

[0030] Figure 3 The HNMR spectrum of the prepared compound betulafuran olefin derivative UBet is shown in Figure 1. 1 The HNMR spectrum of the prepared compound betulafuran olefin derivative UBet is shown in Figure 1.

[0031] Figure 4 The GPC spectrum of the prepared betulafuran-based telechelic polymer is shown in Figure 4. DETAILED DESCRIPTION

[0032] The present application will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not used to limit the scope of the present application. In addition, it should be understood that those skilled in the art can make various modifications or changes to the present application after reading the content taught by the present application, and these equivalent forms also fall within the scope of the appended claims.

[0033] Example 1:

[0034] Preparation of a betulafuran-based olefin dimer PBet:

[0035]

[0036] (1) First, 4-pentenoic acid (11.4 mmol, 1.16 mL), betulin (11.3 mmol, 5 g), 4-dimethylaminopyridine (150 mg), dichloromethane (200 mL) were added in sequence into a 500 mL round bottom flask, and stirred. A mixture solution of dicyclohexyl carbodiimide (17.1 mmol, 3.30 g) and dichloromethane (20 mL) was slowly added dropwise using a constant pressure dropping funnel under the condition of ice water bath, and the flow rate was adjusted so that the mixture was added dropwise within one hour. The mixture was stirred at room temperature overnight. The obtained mixture was washed with 5% hydrochloric acid solution, and the organic phase was dried with anhydrous magnesium sulfate, filtered and the solvent was evaporated. The obtained crude product was separated by column chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain PBet monomer.

[0037] (2) 1 g of PBet was added into a reaction tube, and dissolved in 20 ml of heavy toluene, and freeze-dried three times; 1.7 mg of Grubbs second generation metal carbene catalyst was weighed in a glove box, dissolved in 1 mL of toluene, transferred into a 1 mL syringe, and quickly injected into the above reaction tube. The above mixture was reacted on a 75°C heating table for 4 h, and the reaction temperature and constant rotation speed were maintained during the reaction. After the reaction was cooled to room temperature, 1 mL of vinyl ether was added, and stirring was continued for 2 h to obtain the crude product.

[0038] (3) The final crude product treatment step, the crude product was filtered to remove the catalyst through basic aluminum oxide and the solvent was evaporated. The obtained crude product was separated by column chromatography (petroleum ether / ethyl acetate = 5 / 1), and the product was vacuum dried at 40°C for 8 hours to obtain the final product. The final conversion rate of the reaction was 31%.

[0039] wherein the NMR of the above PBet monomer is as follows:

[0040] 1 H NMR (600 MHz, Chloroform-d) δ 5.80 (tdd, J = 10.5, 8.3, 5.1 Hz, 1H), 5.03 (dd, J = 17.4, 5.5 Hz, 1H), 4.97 (dd, J = 10.6, 5.8 Hz, 1H), 4.66 (q, J = 2.4 Hz, 1H), 4.56 (d, J = 5.2 Hz, 1H), 4.24 (dd, J = 11.1, 4.7 Hz, 1H), 3.83 (dd, J = 11.2, 5.2 Hz, 1H), 3.14 (ddd, J = 11.5, 7.0, 4.6 Hz, 1H), 2.38 (dq, J = 26.8, 6.7 Hz, 6H).

[0041] wherein, as shown in Figure 2 the NMR of the above PBet dimer is as follows:

[0042] 1 H NMR (600 MHz, Chloroform-d) δ 5.49 - 5.35 (m, 2H), 4.71 (d, J = 2.2 Hz, 1H), 4.63 - 4.59 (m, 1H), 4.28 (d, J = 11.1 Hz, 1H), 3.87 (d, J = 11.0 Hz, 1H), 3.21 (dd, J = 11.5, 4.6 Hz, 1H), 2.46 (td, J = 11.0, 5.7 Hz, 1H), 2.40 (dd, J = 8.8, 5.6 Hz, 2H), Birchwood Strips and alkane protons are observed Figure 2 .

[0043] Example 2

[0044] Preparation of a birch alcohol based olefin dimer PBet:

[0045]

[0046] (1) First, 4-pentenoic acid (11.4 mmol, 1.16 mL), birch alcohol (11.3 mmol, 5 g), 4-dimethylaminopyridine (150 mg), dichloromethane (200 mL) were added in sequence into a 500 mL round bottom flask, and stirred. A mixture solution of dicyclohexyl carbodiimide (17.1 mmol, 3.30 g) and dichloromethane (20 mL) was slowly added dropwise using a constant pressure dropping funnel under the condition of ice water bath, and the flow rate was adjusted so that the mixture was added dropwise within one hour. The mixture was stirred at room temperature overnight. The obtained mixture was washed with 5% hydrochloric acid solution, and the organic phase was dried with anhydrous magnesium sulfate, filtered and the solvent was evaporated. The obtained crude product was separated by column chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain PBet monomer.

[0047] (2) 1 g of PBet was added into a reaction tube, dissolved in 20 ml of freshly distilled tetrahydrofuran, and freeze-dried three times; 1.2 mg of Hoveyda-Grubbs second generation metal carbene catalyst was weighed in a glove box, dissolved in 1 mL of tetrahydrofuran, transferred into a 1 mL syringe, and quickly injected into the above reaction tube. The above mixture was reacted on a 50°C heating table for 12 h, and the reaction temperature and constant rotation speed were maintained during the reaction. After the reaction was cooled to room temperature, 1 mL of vinyl ether was added, and stirring was continued for 2 h to obtain the crude product.

[0048] (3) The final crude product treatment step, the crude product was filtered to remove the catalyst through basic aluminum oxide and the solvent was evaporated. The obtained crude product was separated by column chromatography (petroleum ether / ethyl acetate = 5 / 1), and the product was vacuum dried at 40°C for 8 hours to obtain the final product. The final conversion rate of the reaction was 51%.

[0049] Example 3

[0050] Preparation of a betulin-based olefin dimer, UBet dimer:

[0051]

[0052] (1) First, in a 500 mL round bottom flask, undecapentenoic acid (11.4 mmol, 1.91 mL), betulin (11.3 mmol, 5 g), 4-dimethylaminopyridine (150 mg), dichloromethane (200 mL) were added in order and stirred. A mixed solution of dicyclohexyl carbodiimide (17.1 mmol, 3.30 g) and dichloromethane (20 mL) was slowly added dropwise using a constant pressure dropping funnel under an ice water bath, and the flow rate was adjusted so that the mixture was added dropwise within one hour. The mixture was stirred at room temperature overnight. The resulting mixture was washed with 5% hydrochloric acid solution, the organic phase was dried with anhydrous magnesium sulfate, filtered and the solvent was evaporated. The resulting crude product was separated by column chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain UBet monomer.

[0053] (2) 1.16 g of UBet was added to a reaction tube, dissolved in 20 mL of heavy toluene, and freeze-dried three times; Grubbs second-generation metal carbene catalyst 42.2 mg was weighed in a glove box, dissolved in 1 mL of toluene, transferred to a 2 mL syringe, and quickly injected into the above reaction tube. The mixture was heated on a 50°C heating table for 12 h, and the reaction temperature and constant rotation speed were maintained throughout the reaction. After the reaction was cooled to room temperature, 1 mL of vinyl ether was added, and stirring was continued for 2 h to obtain the crude product.

[0054] (3) The final crude product treatment step, the crude product was filtered to remove the catalyst through basic alumina and the solvent was evaporated. The resulting crude product was separated by column chromatography (petroleum ether / ethyl acetate = 5 / 1), and the product was vacuum dried at 40°C for 8 hours to obtain the final product. The final conversion rate of the reaction was 96%.

[0055] wherein, as shown in Figure 1 the NMR of UBet monomer is as follows:

[0056] 1H NMR (600 MHz, Chloroform-d) δ 5.83 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), 5.01 (dq, J = 17.1, 1.7 Hz, 1H), 4.95 (ddt, J = 10.2, 2.3, 1.2 Hz, 1H), 4.71 (d, J = 2.3 Hz, 1H), 4.63 - 4.59 (m, 1H), 4.28 (dd, J = 11.1, 1.9 Hz, 1H), 3.86 (d, J = 11.1 Hz, 1H), 3.81 - 3.73 (m, 6H), 3.21 (d, J = 10.3 Hz, 1H), 2.47 (td, J = 11.1, 5.7 Hz, 1H), 2.34 (t, J = 7.5 Hz, 2H), Betulol skeleton and alkane protons see Figure 1 .

[0057] wherein, as shown in Figure 3 , the NMR of the UBet dimer is as follows:

[0058] 1 H NMR (600 MHz, Chloroform-d) δ 5.42 - 5.35 (m, 2H), 4.71 (d, J = 2.3 Hz, 1H), 4.61 (dt, J = 2.4, 1.4 Hz, 1H), 4.28 (dd, J = 11.1, 1.9 Hz, 1H), 3.86 (d, J = 11.1 Hz, 1H), 3.20 (dt, J = 11.0, 5.2 Hz, 1H), 2.51 - 2.40 (m, 2H), 2.34 (t, J = 7.5 Hz, 2H), Betulol skeleton and alkane protons see Figure 3 .

[0059] Example 4

[0060] A betulol-based telechelic polymer was prepared using the betulol-based olefin dimer as an initiator:

[0061]

[0062] (1) First, in a 50 mL reaction tube, the betulol dimer obtained in Example 2 (0.2 g), tetrahydrofuran (25 mL), cyclooctene (1.0 mL), were freeze degassed three times. In the glove box, Grubbs second generation metal carbene catalyst 6.0 mg was weighed, dissolved in 0.5 mL tetrahydrofuran and transferred into a 1 mL syringe, and quickly injected into the above reaction tube. The mixture was stirred at 45 °C for 24 h. After the reaction was cooled to room temperature, 1 mL of vinyl ether was added, and stirring was continued for 2 h to obtain the crude product.

[0063] (2) The final crude product treatment step, the crude product was filtered through basic alumina to remove the catalyst and the solvent was evaporated. The crude product was reprecipitated in methanol and dried under vacuum at room temperature for 8 hours to obtain the final betulin-based telechelic polymer with a conversion of 89%. The GPC of the obtained product is shown in Figure 4 Figure 6, with a number average molecular weight Mn= 30000 g / mol and a PDI = 1.68.

Claims

1. Betulafuran-based olefin dimer, having the following structure: or 。 2. The method of preparing betulin-based olefin dimer according to claim 1, characterized in that, The betulafuran-based olefin dimer comprises the following steps: S1: In a round-bottom flask, 4-pentenoic acid or 10-undecenoic acid, betulafuran, 4-dimethylaminopyridine, dichloromethane are sequentially added, a mixed solution of dicyclohexyl carbodiimide and dichloromethane is slowly added dropwise under the condition of ice water bath, the mixture is stirred at room temperature overnight, the obtained mixture is washed with 5% hydrochloric acid solution, the organic phase is dried with anhydrous magnesium sulfate, filtered and the solvent is evaporated, the obtained crude product is separated by column chromatography to obtain a reaction substrate, and the chromatography solvent of the column chromatography is petroleum ether / ethyl acetate=6 / 1; S2: In a glove box, the catalyst is dissolved in a solvent to obtain a catalyst solution, the reaction substrate is added to a reaction tube, vacuum-argon is repeated five times, then re-distilled solvent is added under the condition of argon, the mixture is stirred and dispersed uniformly, then the prepared catalyst solution is added, the above mixture is reacted at room temperature for 6-48 h, the reaction temperature is kept at 25-75°C and the constant rotation speed during the reaction, after the reaction is cooled to room temperature, a quenching agent is added, and the stirring is continued for 2 h to obtain a crude product, the crude product is filtered through basic aluminum oxide to remove the catalyst and the solvent is evaporated, the obtained crude product is separated by column chromatography to obtain a product, and the product is vacuum dried at 40°C for 8 h to obtain a final product, and the chromatography solvent of the column chromatography is petroleum ether / ethyl acetate=5 / 1.

3. The method of preparing betulin-based olefin dimer according to claim 2, characterized in that, The quenching agent is vinyl ethyl ether.

4. The method for preparing betulinol-based olefin dimers according to claim 2, characterized in that, The solvent is one of toluene, tetrahydrofuran and dichloromethane.

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