Water-soluble large-steric-hindrance diamine ligand as well as preparation method and application thereof
By designing water-soluble large sterically hindered diamine ligands and introducing multiple carboxyl and functionalized benzyl substituent groups, the problems of existing diamine ligand instability and difficulty in catalyst recovery are solved, and the recovery of efficient catalysts is achieved and Recycling improves the selectivity of catalytic reactions and product purity, providing a green and efficient catalytic solution for the research and development of anti-cancer drugs.
Patent Information
- Application Number
- CN202311253855.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-09-27
- Publication Date
- 2024-12-10
AI Technical Summary
The existing diamine ligands have problems such as instability, difficulty in synthesis, high price and easy residue in catalytic reactions, which limit their application in organic synthesis and drug synthesis, especially in the development of anti-cancer drugs, catalyst recovery and selectivity have a greater impact.
Design a water-soluble large sterically hindered diamine ligand. By introducing multiple carboxyl groups and functionalized benzyl substituent groups, the catalytic reaction efficiency and catalyst recovery are improved. The synthesis method under mild conditions is adopted to simplify the preparation process and Suzuki reaction is performed in the aqueous phase to achieve efficient catalysis.
It realizes efficient recycling and recycling of catalysts, reduces catalyst residues in the product, improves reaction selectivity and product purity, and provides a green and efficient catalyst for the research and development of anti-cancer drugs.
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Abstract
Description
Technical Field
[0001] The invention relates to the technical field of amine ligands, and in particular to a water-soluble large sterically hindered diamine ligand and a preparation method and application thereof. Background Art
[0002] The coupling reaction catalyzed by transition metals (palladium, nickel, ruthenium, rhodium, etc.) is one of the most important methods in organic synthesis and drug synthesis. In recent years, especially in the development of new anticancer drugs, many active entities with excellent anticancer effects and prospects have been obtained through coupling reactions catalyzed by ligand transition metal complexes (Suzuki reaction, Heck reaction, Sonogashira reaction, Buchwald-Hartwig amination reaction, etc.). According to research statistics, in the 40 years from 1976 to 2015, among the drug synthesis patents reported in US patents, cross-coupling reactions such as C–C (such as Suzuki reaction, as shown in the following formula) and C–N (such as Buchwald-Hartwig amination reaction) are one of the most widely used synthesis tools.
[0003]
[0004] Suzuki reaction catalyzed by ligand-transition metal (palladium) complex
[0005] The use of transition metal-bound ligands is becoming increasingly frequent in catalytic reactions. The metal center is affected by the ligand, the catalyst activity changes, and then affects the selectivity of the reaction, making the chemical reaction more varied. Transition metal catalysts are mainly affected by the ligand's stereo effect, steric effect and electronic effect. Therefore, the design, synthesis and catalytic reaction research of ligands have become an important research field. In particular, the research on organic phosphine ligands and N-containing ligands (including diamine ligands, bipyridine ligands, oxazole ligands, NHC ligands, etc.) has also achieved fruitful results. However, these traditional ligands such as organic phosphine ligands and organic N-containing ligands have more or less defects such as unstable properties, difficult synthesis, high price and easy residue, which greatly affects the product quality and limits the promotion and application.
[0006] Although diamine ligands can serve as a good class of transition metal ligands, most of the catalytic systems are non-recyclable, and the reported diamine ligand-transition metal and catalytic reaction types are relatively small, requiring the synthesis of diamine ligand compounds with more structures.
[0007] It can be seen that the present invention develops a new diamine ligand transition metal catalyst, which can not only efficiently catalyze organic synthesis reactions but also easily separate and recycle the catalyst, and has very important scientific significance and application value in improving the selectivity and efficiency of transition metal catalysis and green chemistry. Summary of the invention
[0008] The purpose of the present invention is to provide a water-soluble large sterically hindered diamine ligand, wherein ortho-aryl diamine is substituted with tetrabenzyl groups, and multiple carboxyl groups are introduced to increase the polarity of the ligand, so as to improve the catalytic reaction efficiency, facilitate catalyst recovery, reduce catalyst residues in products and improve product quality.
[0009] To achieve the above object, the present invention provides a water-soluble large sterically hindered diamine ligand, the structural formula of which is selected from any one of I-III:
[0010]
[0011] Among them, R 1 Selected from one of H, Alkyl, OMe, and CO2H.
[0012] The second object of the present invention is to provide a preparation method of the above structural formula I, which specifically comprises the following steps:
[0013] S1, after reactant A, reactant B, diisopropylethylamine and tetrabutylammonium iodide are mixed, heating and stirring in an oil bath for reaction;
[0014] S2. After the reaction is completed, the reaction solution is cooled to room temperature, ethyl acetate and water are added, the organic layer is separated, the aqueous layer is extracted with ethyl acetate, the organic layers are combined, and the mixture is dried over anhydrous sodium sulfate, concentrated by rotary evaporation, chromatographed, and evaporated to dryness using a rotary evaporator to obtain product A;
[0015] S3, mixing product A with sodium hydroxide, adding water and tetrahydrofuran, stirring and rotary evaporating to remove tetrahydrofuran, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH until the reaction is completed, filtering, washing, and drying to obtain a product of structural formula I;
[0016] Among them, the structural formula of reactant A is:
[0017] The structural formula of product A is: Among them, R 1 is selected from one of H, Alkyl, OMe, CO2H, R 2 For Alkyl.
[0018] The third object of the present invention is to provide a preparation method of structural formula II, which specifically comprises the following steps:
[0019] S1, after reactant A, reactant B, diisopropylethylamine and tetrabutylammonium iodide are mixed, heating and stirring in an oil bath to react;
[0020] S2. After the reaction is completed, the reaction solution is cooled to room temperature, ethyl acetate and water are added, the organic layer is separated, the aqueous layer is extracted with ethyl acetate, the organic layers are combined, and the mixture is dried over anhydrous sodium sulfate, concentrated by rotary evaporation, chromatographed, and evaporated to dryness using a rotary evaporator to obtain product A;
[0021] S3, mixing product A with sodium hydroxide, adding water and tetrahydrofuran, stirring and rotary evaporating to remove tetrahydrofuran, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH until the reaction is completed, filtering, washing, and drying to obtain a product of structural formula II;
[0022] Among them, the structural formula of reactant A is:
[0023] The structural formula of product A is:
[0024] Among them, R 1 is selected from one of H, Alkyl, OMe, CO2H, R 2 For Alkyl.
[0025] The fourth object of the present invention is to provide a preparation method of structural formula III, which specifically comprises the following steps:
[0026] S1, after reactant A, reactant B, diisopropylethylamine and tetrabutylammonium iodide are mixed, heating and stirring in an oil bath to react;
[0027] S2. After the reaction is completed, the reaction solution is cooled to room temperature, ethyl acetate and water are added, the organic layer is separated, the aqueous layer is extracted with ethyl acetate, the organic layers are combined, and the mixture is dried over anhydrous sodium sulfate, concentrated by rotary evaporation, chromatographed, and evaporated to dryness using a rotary evaporator to obtain product A;
[0028] S3, mixing product A with sodium hydroxide, adding water and tetrahydrofuran, stirring and rotary evaporating to remove tetrahydrofuran, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH until the reaction is completed, filtering, washing, and drying to obtain a product of structural formula III;
[0029] Among them, the structural formula of reactant A is:
[0030] The structural formula of product A is:
[0031] Among them, R 1 is selected from one of H, Alkyl, OMe, CO2H, R 2 For Alkyl.
[0032] Preferably, in step S1, reactant B is selected from one of (1) to (13),
[0033]
[0034] and X is Cl or Br, and the molar ratio of reactant A to reactant B is 1:(4-6).
[0035] In the first step of the synthesis of the sterically hindered water-soluble thiourea ligand of the present invention, when preparing the functionalized benzyl-substituted o-phenylenediamine intermediate, we use functionalized benzyl bromide / benzyl chloride, because there are more substituent sites on the benzyl group, which can not only adjust the type and number of functional groups to adjust the water solubility and polarity of the diamine ligand, but also create huge steric hindrance through multiple transformable sites of the functionalized benzyl / benzyl chloride, which are all conducive to the improvement of the recyclability and catalytic activity of the diamine ligand. At the same time, since the reaction activity of benzyl bromide / benzyl chloride is higher than that of bromohydrocarbon, the first step of the reaction conditions of the synthesis of the diamine ligand is more mild, which is conducive to reducing the generation of side reactions and improving the purity of the product.
[0036] Preferably, in step S1, the molar ratio of reactant A to diisopropylethylamine is 1:(4-6), and the molar ratio of reactant A to tetrabutylammonium iodide is 1:(0.01-0.06)
[0037] Preferably, in step S1, the heating and stirring temperature is 80-180° C., and the heating and stirring time is 0.5-2 h.
[0038] Preferably, in step S3, the molar ratio of product A to sodium hydroxide is 1:(8-12), and the pH is adjusted to 1 after hydrochloric acid is added dropwise.
[0039] The fifth object of the present invention is to provide an application of a water-soluble bulky hindered diamine ligand, which comprises applying the water-soluble bulky hindered diamine ligand to a Suzuki reaction catalyzed by aqueous recyclable palladium.
[0040] Preferably, the application specifically comprises the following steps: at room temperature and in air, a water-soluble large sterically hindered diamine ligand, Na2PdCl4, arylboronic acid, potassium hydroxide, TBAB, bromoaryl hydrocarbon, and water are added to a round-bottom flask containing a stirring bar, the mixture is stirred in the round-bottom flask at 25°C or 100°C until the reaction is completed, the obtained reaction mixture is extracted with ether, the organic layers are combined, and the cross-coupling product is obtained after rotary evaporation and concentration by silica gel flash column chromatography.
[0041] The catalytic Suzuki reaction involving a large sterically hindered water-soluble diamine is carried out in water. After the reaction is completed, only an organic solvent needs to be added to extract the product into an organic layer. The new water-soluble diamine catalyst containing a hydrophilic structure in the water layer can be reused, and the diamine catalyst solid containing multiple carboxyl functional group structures can be precipitated by acidification of the water layer. The advantages of the present invention are that the large sterically hindered water-soluble diamine catalyst solid can be recovered by simple acidification and filtration, which not only conveniently realizes the recycling and reuse of the ligand and reduces the synthesis cost, but also utilizes the polarity and water solubility difference between the ligand (large polarity) and the reaction raw materials and products (small polarity) to simply and efficiently realize the separation from the reaction raw materials and products, reduce the residual ligand as an impurity in the product, and directly improve the purity of the product. More importantly, the large sterically hindered water-soluble diamine recovered from the previous round of catalytic reaction can be conveniently used for the next round of catalytic Suzuki reaction after adding reaction raw materials and solvent, thereby laying a good foundation for realizing highly selective, easy to recover, low-toxic and efficient catalytic Suzuki reaction, and providing a green and efficient excellent catalyst for the pharmaceutical industry.
[0042] Compared with the prior art, the present invention has the following advantages:
[0043] 1. The present invention achieves better water solubility control (large polarity is conducive to improving ligand catalyst recovery rate) and steric hindrance control (large steric hindrance is conducive to improving catalytic activity) of the hydrophilic group by designing the hydrophilic functionalization of the diamine ligand and introducing carboxyl functionalized benzyl groups on the two nitrogen atoms.
[0044] 2. Due to the use of functionalized benzyl side chains, the synthesis of the water-soluble diamine ligand of the present invention is efficient and simple, and the conditions are mild. The aromatic amine only needs to react with the halogenated functionalized benzyl side chain and finally hydrolyze to obtain the target product, the sterically hindered water-soluble diamine with functionalized benzyl carboxylic acid side chain. Benzyl halogenated hydrocarbons are highly active and the reaction conditions are mild. Strict anhydrous and oxygen-free operation is not required, and no additional reduction operation and cumbersome and dangerous post-treatment process are required. The entire synthesis and post-treatment are simple, safe and environmentally friendly. The sterically hindered water-soluble diamine ligand can be easily recovered and recycled after acid adjustment. DETAILED DESCRIPTION
[0045] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, specific embodiments of the present invention are described in detail below.
[0046] The specific embodiment of the present invention provides a water-soluble large sterically hindered diamine ligand, the structural formula of which is selected from any one of I-III:
[0047]
[0048] Among them, R 1 Selected from one of H, Alkyl, OMe, and CO2H.
[0049] The second object of the specific embodiment of the present invention is to provide a preparation method of the above structural formula I, which specifically comprises the following steps:
[0050] S1. After reactant A, reactant B, diisopropylethylamine and tetrabutylammonium iodide are mixed, the mixture is heated and stirred in an oil bath for reaction. The molar ratio of reactant A to diisopropylethylamine is 1:(4-6), the molar ratio of reactant A to tetrabutylammonium iodide is 1:(0.01-0.06), the heating and stirring temperature is 80-180°C, and the heating and stirring time is 0.5-2h;
[0051] S2. After the reaction is completed, the reaction solution is cooled to room temperature, ethyl acetate and water are added, the organic layer is separated, the aqueous layer is extracted with ethyl acetate, the organic layers are combined, and the mixture is dried over anhydrous sodium sulfate, concentrated by rotary evaporation, chromatographed, and evaporated to dryness using a rotary evaporator to obtain product A;
[0052] S3, after mixing product A with sodium hydroxide, add water and tetrahydrofuran, stir and evaporate to remove tetrahydrofuran, add hydrochloric acid dropwise under ice bath stirring to adjust pH to 1 until the reaction is completed, filter, wash and dry to obtain product structural formula I, wherein the molar ratio of product A to sodium hydroxide is 1:(8-12);
[0053] Among them, the structural formula of reactant A is:
[0054] The structural formula of product A is: Among them, R 1 is selected from one of H, Alkyl, OMe, CO2H, R 2 For Alkyl.
[0055] The third object of the specific embodiment of the present invention is to provide a preparation method of structural formula II, which specifically comprises the following steps:
[0056] S1. After reactant A, reactant B, diisopropylethylamine and tetrabutylammonium iodide are mixed, the mixture is heated and stirred in an oil bath for reaction. The molar ratio of reactant A to diisopropylethylamine is 1:(4-6), the molar ratio of reactant A to tetrabutylammonium iodide is 1:(0.01-0.06), the heating and stirring temperature is 80-180°C, and the heating and stirring time is 0.5-2h;
[0057] S2. After the reaction is completed, the reaction solution is cooled to room temperature, ethyl acetate and water are added, the organic layer is separated, the aqueous layer is extracted with ethyl acetate, the organic layers are combined, and the mixture is dried over anhydrous sodium sulfate, concentrated by rotary evaporation, chromatographed, and evaporated to dryness using a rotary evaporator to obtain product A;
[0058] S3, after mixing product A with sodium hydroxide, add water and tetrahydrofuran, stir and evaporate to remove tetrahydrofuran, add hydrochloric acid dropwise under ice bath stirring to adjust pH until the reaction is completed, filter, wash and dry to obtain product structural formula II, the molar ratio of product A to sodium hydroxide is 1:(8-12);
[0059] Among them, the structural formula of reactant A is:
[0060] The structural formula of product A is:
[0061] Among them, R 1 is selected from one of H, Alkyl, OMe, CO2H, R 2 For Alkyl.
[0062] The fourth object of the specific embodiment of the present invention is to provide a preparation method of structural formula III, which specifically comprises the following steps:
[0063] S1. After reactant A, reactant B, diisopropylethylamine and tetrabutylammonium iodide are mixed, the mixture is heated and stirred in an oil bath for reaction. The molar ratio of reactant A to diisopropylethylamine is 1:(4-6), the molar ratio of reactant A to tetrabutylammonium iodide is 1:(0.01-0.06), the heating and stirring temperature is 80-180°C, and the heating and stirring time is 0.5-2h;
[0064] S2. After the reaction is completed, the reaction solution is cooled to room temperature, ethyl acetate and water are added, the organic layer is separated, the aqueous layer is extracted with ethyl acetate, the organic layers are combined, and the mixture is dried over anhydrous sodium sulfate, concentrated by rotary evaporation, chromatographed, and evaporated to dryness using a rotary evaporator to obtain product A;
[0065] S3, after mixing product A with sodium hydroxide, add water and tetrahydrofuran, stir and evaporate to remove tetrahydrofuran, add hydrochloric acid dropwise under ice bath stirring to adjust pH until the reaction is completed, filter, wash and dry to obtain product structural formula III, the molar ratio of product A to sodium hydroxide is 1:(8-12);
[0066] Among them, the structural formula of reactant A is:
[0067] The structural formula of product A is:
[0068] Among them, R 1 is selected from one of H, Alkyl, OMe, CO2H, R 2 For Alkyl.
[0069] In a specific implementation case, in step S1, reactant B is selected from one of (1)-(13):
[0070] and X is Cl or Br, and the molar ratio of reactant A to reactant B is 1:(4-6).
[0071] In the first step of the synthesis of the sterically hindered water-soluble thiourea ligand of the present invention, when preparing the functionalized benzyl-substituted o-phenylenediamine intermediate, we use functionalized benzyl bromide / benzyl chloride, because there are more substituent sites on the benzyl group, which can not only adjust the type and number of functional groups to adjust the water solubility and polarity of the diamine ligand, but also create huge steric hindrance through multiple transformable sites of the functionalized benzyl / benzyl chloride, which are all conducive to the improvement of the recyclability and catalytic activity of the diamine ligand. At the same time, since the reaction activity of benzyl bromide / benzyl chloride is higher than that of bromohydrocarbon, the first step of the reaction conditions of the synthesis of the diamine ligand is more mild, which is conducive to reducing the generation of side reactions and improving the purity of the product.
[0072] The fifth object of the specific embodiment of the present invention is to provide an application of a water-soluble bulky hindered diamine ligand, wherein the application includes applying the water-soluble bulky hindered diamine ligand to a water-phase recyclable palladium-catalyzed Suzuki reaction.
[0073] In a specific case, the above application may include the following steps: at room temperature and in air, a water-soluble large sterically hindered diamine ligand, Na2PdCl4, arylboronic acid, potassium hydroxide, TBAB, bromoaryl hydrocarbon, and water are added to a round-bottom flask containing a stirring bar, the mixture is stirred in the round-bottom flask at 25°C or 100°C until the reaction is completed, the obtained reaction mixture is extracted with ether, the organic layers are combined, and the cross-coupling product is obtained after rotary evaporation and concentration by silica gel flash column chromatography.
[0074] The following is a full description with reference to specific embodiments.
[0075] Example 1
[0076] The present invention provides a water-soluble sterically hindered diamine ligand, the structural formula of which is as follows:
[0077]
[0078] Prepared by the following preparation method:
[0079] S1. Mix 4,5-dimethyl-o-phenylenediamine (0.681 g, 5 mmol), 5-bromomethyl-dimethyl isophthalate (7.177 g, 25 mmol), diisopropylethylamine (3.23 g, 25 mmol) and tetrabutylammonium iodide (92 mg, 0.25 mmol) in a round-bottom flask, heat and stir at 130°C in an oil bath for 1 hour to stop the reaction. After the reaction solution is cooled to room temperature, 25 ml of ethyl acetate and 25 ml of water are added and stirred, the organic layer is separated, the aqueous layer is extracted with ethyl acetate (20 ml x 2), the organic layers are combined, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and subjected to silica gel flash column chromatography (eluent: petroleum ether: ethyl acetate = 3:1), and evaporated to dryness on a rotary evaporator to obtain a reddish brown oil N 1 ,N 1 ,N 2 ,N 2 -Tetrakis[(3,5-dicarboxylic acid methyl ester) benzyl]-4,5-dimethyl o-phenylenediamine crude product 3.892g, yield 81%, the crude product was used directly in the next step without further purification, the reaction formula is as follows:
[0080]
[0081] S2, in a fume hood, stir at room temperature in a mixture containing N 1 ,N 1 ,N 2 ,N 2 -Tetra[(3,5-dicarboxylic acid methyl ester) benzyl]-4,5-dimethyl o-phenylenediamine crude product (3.844g, 4mmol) and sodium hydroxide (1.6g, 40mmol) were mixed in a round-bottom flask, and water (30mL) and tetrahydrofuran (30mL) were added. Stir at room temperature for 24 hours, and tetrahydrofuran was removed by rotary evaporation. Under ice bath cooling and stirring, hydrochloric acid was carefully added dropwise to adjust the pH to 1. A large amount of white solid precipitated in the solution, and stirring was continued in the ice bath for 30 minutes. The white solid obtained by suction filtration was washed with water (15ml x 3) and dried to obtain 3.157g of white solid, with a yield of 93%. The reaction formula is as follows:
[0082]
[0083] The performance of the product A and the final product obtained in Example 1 was tested, and the test results are as follows:
[0084] Product A:
[0085]
[0086] White solid; melting point: 173-174℃
[0087] 1H NMR (400MHz, CDCl3) δ8.46(t,J=1.6Hz,4H),7.93(d,J=1.6Hz,8H),6.62(s,2H),4.36(s,8H),3.78(s,24H),2.09(s,6H).
[0088] 13 C NMR (100MHz, CDCl3) δ165.6,134.00,137.9,134.6,130.4,129.5,128.1,124.5,56.0,52.3,19.3.
[0089] Final product:
[0090]
[0091] White solid; melting point: 326-328℃
[0092] 1 H NMR (400MHz, DMSO) δ12.95(s,8H),8.27(t,J=1.5Hz,4H),7.92(d,J=1.4Hz,8H),6.70(s,2H),4.45(s,8H),2.00(s,6H).
[0093] 13 C NMR (100MHz, DMSO) δ166.3,139.9,138.9,133.9,130.9,130.2,128.8,124.0,55.1,19.1.
[0094] Example 2
[0095] The only difference from Example 1 is that the molar ratio of reactant A to reactant B in this example is 1:4, and the rest is the same as Example 1 and will not be repeated here.
[0096] Example 3
[0097] The only difference from Example 1 is that the molar ratio of reactant A to reactant B in this example is 1:6, and the rest is the same as that in the example, which will not be repeated here.
[0098] Example 4
[0099]
[0100] Example 5
[0101]
[0102] Example 6
[0103]
[0104] The water-soluble bulky hindered diamine ligand-palladium complex prepared in Example 1 can be recycled in the aqueous phase to catalyze the Suzuki reaction.
[0105]
[0106] At room temperature, in air, water-soluble bulky hindered diamine ligand (0.1 mol%, 2.9 mg), Na2PdCl4 (0.1 mol%, 1.5 mg), arylbenzene boronic acid (7.5 mmol), potassium hydroxide (561 mg, 10.0 mmol), TBAB (5 mmol, 1.61 g), bromoaryl hydrocarbon (5.0 mmol) and water (5 mL) were added to a round-bottom flask containing a stirring bar. The mixture was stirred in a round-bottom flask at 25°C or 100°C until the reaction was completed. The resulting reaction mixture was extracted with ether (3×10 mL). The organic layers were combined, concentrated by rotary evaporation, and then subjected to silica gel flash column chromatography to obtain the cross-coupling product. The coupling product was then 1 H NMR and 13 C NMR detection, the data obtained are consistent with the nuclear magnetic data reported in the literature. The same reaction starting materials arylphenylboronic acid (7.5mmol) and bromoaryl hydrocarbon (5.0mmol) were added to the water layer again, and potassium hydroxide (561mg, 10.0mmol) was added to start the next round of catalytic reaction. After six cycles of catalysis, the activity of the new water-soluble self-assembled thiourea ligand palladium catalyst did not decrease significantly.
[0107] Recovery and catalytic reaction of water-soluble large steric hindered diamine ligand: The water layer retained after post-treatment was stirred under ice bath cooling, and hydrochloric acid was carefully added to adjust the pH to 1. A large amount of white solid precipitated in the solution, and stirring was continued in the ice bath for 30 minutes. The white solid obtained by filtration was washed with water (10ml x 3), and dried to obtain 2.9mg of white solid (water-soluble large steric hindered diamine ligand). The reaction starting materials Na2PdCl4 (0.1mol%, 1.5mg), arylphenylboronic acid (7.5mmol), potassium hydroxide (561mg, 10.0mmol), TBAB (5mmol, 1.61g), bromoaryl hydrocarbon (5.0mmol) and water (5mL) were added again to start the next round of catalytic reaction. After six cycles of catalysis, the recovery and catalytic activity of the new water-soluble self-assembled thiourea ligand palladium catalyst did not decrease significantly.
[0108] It can be seen from the above results that the catalytic Suzuki reaction involving the large sterically hindered water-soluble diamine of the present invention is carried out in water. After the reaction is completed, it is only necessary to add an organic solvent to extract the product into the organic layer. The new water-soluble diamine catalyst containing a hydrophilic structure in the water layer can be reused, and the diamine catalyst solid containing multiple carboxyl functional group structures can be precipitated by acidification of the water layer. The advantage of the present invention is that the large sterically hindered water-soluble diamine catalyst solid can be recovered by simple acidification and filtration, which not only conveniently realizes the recycling and reuse of the ligand and reduces the synthesis cost, but also utilizes the polarity and water solubility difference between the ligand (large polarity) and the reaction raw materials and products (small polarity) to simply and efficiently realize the separation from the reaction raw materials and products, reduce the residual ligand as an impurity in the product, and directly improve the purity of the product. More importantly, the large sterically hindered water-soluble diamine recovered from the previous round of catalytic reaction can be conveniently used for the next round of catalytic Suzuki reaction after adding reaction raw materials and solvent, thereby laying a good foundation for realizing highly selective, easy to recover, low-toxic and efficient catalytic Suzuki reaction, and providing green and efficient excellent catalysts for the pharmaceutical industry.
[0109] Although the disclosure is disclosed as above, the protection scope of the disclosure is not limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the disclosure, and these changes and modifications will fall within the protection scope of the present invention.
Claims
1. A water-soluble, bulky hindered diamine ligand, It is characterized in that The structural formula is selected from any one of I-III: Among them, R 1 Selected from H, Alkyl, OMe, CO 2 One of H.
2. A method for preparing a water-soluble bulky hindered diamine ligand as claimed in claim 1, It is characterized in that The preparation method of the structural formula I specifically comprises the following steps: S1, after reactant A, reactant B, diisopropylethylamine and tetrabutylammonium iodide are mixed, heating and stirring in an oil bath for reaction; S2. After the reaction is completed, the reaction solution is cooled to room temperature, ethyl acetate and water are added, the organic layer is separated, the aqueous layer is extracted with ethyl acetate, the organic layers are combined, and the mixture is dried over anhydrous sodium sulfate, concentrated by rotary evaporation, chromatographed, and evaporated to dryness using a rotary evaporator to obtain product A; S3, mixing product A with sodium hydroxide, adding water and tetrahydrofuran, stirring and rotary evaporating to remove tetrahydrofuran, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH until the reaction is completed, filtering, washing, and drying to obtain a product of structural formula I; Among them, the structural formula of reactant A is: The structural formula of product A is: Among them, R 1 Selected from H, Alkyl, OMe, CO 2 One of H, R 2 For Alkyl.
3. A method for preparing a water-soluble bulky hindered diamine ligand as claimed in claim 1, It is characterized in that The preparation method of the structural formula II specifically comprises the following steps: S1, after reactant A, reactant B, diisopropylethylamine and tetrabutylammonium iodide are mixed, heating and stirring in an oil bath for reaction; S2. After the reaction is completed, the reaction solution is cooled to room temperature, ethyl acetate and water are added, the organic layer is separated, the aqueous layer is extracted with ethyl acetate, the organic layers are combined, and the mixture is dried over anhydrous sodium sulfate, concentrated by rotary evaporation, chromatographed, and evaporated to dryness using a rotary evaporator to obtain product A; S3, mixing product A with sodium hydroxide, adding water and tetrahydrofuran, stirring and rotary evaporating to remove tetrahydrofuran, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH until the reaction is completed, filtering, washing, and drying to obtain a product of structural formula II; Among them, the structural formula of reactant A is: The structural formula of product A is: Among them, R 1 Selected from H, Alkyl, OMe, CO 2 One of H, R 2 For Alkyl.
4. A method for preparing a water-soluble bulky hindered diamine ligand as claimed in claim 1, It is characterized in that The preparation method of the structural formula III specifically comprises the following steps: S1, after reactant A, reactant B, diisopropylethylamine and tetrabutylammonium iodide are mixed, heating and stirring in an oil bath for reaction; S2. After the reaction is completed, the reaction solution is cooled to room temperature, ethyl acetate and water are added, the organic layer is separated, the aqueous layer is extracted with ethyl acetate, the organic layers are combined, and the mixture is dried over anhydrous sodium sulfate, concentrated by rotary evaporation, chromatographed, and evaporated to dryness using a rotary evaporator to obtain product A; S3, mixing product A with sodium hydroxide, adding water and tetrahydrofuran, stirring and rotary evaporating to remove tetrahydrofuran, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH until the reaction is completed, filtering, washing, and drying to obtain a product of structural formula III; Among them, the structural formula of reactant A is: The structural formula of product A is: Among them, R 1 Selected from H, Alkyl, OMe, CO 2 One of H, R 2 For Alkyl.
5. A method for preparing a water-soluble bulky hindered diamine ligand according to any one of claims 2 to 4, It is characterized in that In step S1, reactant B is selected from one of (1) to (13), and X is Cl or Br, and the molar ratio of reactant A to reactant B is 1:(4-6).
6. A method for preparing a water-soluble bulky hindered diamine ligand according to any one of claims 2 to 4, It is characterized in that In the step S1, the molar ratio of reactant A to diisopropylethylamine is 1:(4-6), and the molar ratio of reactant A to tetrabutylammonium iodide is 1:(0.01-0.06).
7. A method for preparing a water-soluble bulky hindered diamine ligand according to any one of claims 2 to 4, It is characterized in that In the step S1, the temperature of heating and stirring is 80-180° C., and the time of heating and stirring is 0.5-2 h.
8. A method for preparing a water-soluble bulky hindered diamine ligand according to any one of claims 2 to 4, It is characterized in that In step S3, the molar ratio of product A to sodium hydroxide is 1:(8-12), and the pH is adjusted to 1 after hydrochloric acid is added dropwise.
9. Application of a water-soluble large sterically hindered diamine ligand, Features: The application comprises applying the water-soluble bulky hindered diamine ligand according to claim 1 to a cyclic palladium-catalyzed Suzuki reaction.
10. Use of the water-soluble bulky hindered diamine ligand according to claim 9, It is characterized in that The application specifically comprises the following steps: at room temperature, in air, a water-soluble large sterically hindered diamine ligand, Na 2 PdCl 4 , arylboronic acid, potassium hydroxide, TBAB, bromoaryl hydrocarbon, and water are added to a round-bottom flask containing a stirring bar, and the mixture is stirred in the round-bottom flask at 25°C or 100°C until the reaction is completed. The obtained reaction mixture is extracted with ether and the organic layers are combined, concentrated by rotary evaporation, and subjected to silica gel flash column chromatography to obtain the cross-coupling product.