Heterogeneous catalyst support, process for its preparation and use thereof

Abstract

The application provides a heterogeneous catalyst carrier and a preparation method and application thereof. The heterogeneous catalyst carrier is successfully prepared through three-step reactions of 6-bromohexylation, chiral ligand amination and phosphination, Rh(I) is loaded by using a coordination chelation method to obtain a high-molecular-load chiral Rh-based catalyst, and the actual loading amount of Rh is 0.9 mmol / g. The catalyst has a conversion rate of 100% and an ee value of 98.78% in an acetoamide methyl acrylate hydrogenation reaction, and the performance is superior to that of a Rh-DPAMPP homogeneous catalyst.

Description

Technical Field

[0001] This invention relates to heterogeneous chiral catalysts, specifically to heterogeneous chiral catalyst supports, their preparation methods, and applications. Background Technology

[0002] Chirality is a fundamental characteristic of nature and living organisms, closely related to daily human life. Proteins, nucleic acids, and most drug molecules are composed of chiral structural units, and differences in chiral configuration often directly affect their physiological activity and function. Asymmetric catalytic hydrogenation, as one of the most direct and efficient methods for obtaining chiral compounds, relies on the rational design and precise preparation of chiral catalysts. Rhodium (Rh), as a representative element among transition metals catalyzing asymmetric hydrogenation reactions, has been successfully applied to the industrial synthesis of various chiral drug intermediates, such as L-DOPA and paclitaxel side chains, using homogeneous catalysts formed with chiral diphosphine ligands (e.g., BINAP, DuPhos, Josiphos). However, the practical application of Rh homogeneous catalysts is often a single-use process, resulting in significant resource waste, and residual metal ions can easily affect the purity of drug products, limiting their further application in the pharmaceutical field.

[0003] Polymer-supported catalysis technology effectively integrates the high selectivity of homogeneous catalysis with the easy separation characteristics of heterogeneous catalysis by immobilizing homogeneous catalysts on the surface of polymer supports. Compared with inorganic supports such as silica gel and molecular sieves, polymer supports have significant advantages. Therefore, the development of high-performance polymer-supported chiral Rh catalysts is of great theoretical and practical significance for reducing the consumption of precious metals, simplifying the process flow, and promoting the industrialization of asymmetric catalysis technology. The choice of support is the foundation of polymer-supported catalysis technology. Currently, a variety of functional polymer materials such as cross-linked polystyrene (PS), polyethylene glycol (PEG), polyamide-amine dendrimer (PAMAM), and covalent organic frameworks (COFs) have been developed. Although some breakthroughs have been made, there are still many problems to be solved in polymer-supported chiral Rh catalysts: (1) The enantioselectivity of the catalyst after loading is generally lower than that of the homogeneous catalyst; (2) The Rh active centers are not uniformly dispersed, and Rh nanoparticles are easily formed during the reaction, resulting in a significant decrease in catalytic activity; (3) The cycle stability is insufficient, and ligands are detached or Rh is lost during long-term reactions. Therefore, how to achieve a synergistic improvement in catalytic activity, enantioselectivity, and cycle stability through support structure optimization and ligand molecule modification is the core challenge in the current research field of polymer-supported chiral Rh catalysts. Summary of the Invention

[0004] To address the problems in the prior art, this invention provides a heterogeneous chiral catalyst support, its preparation method, and its application.

[0005] The present invention adopts the following technical solution: A heterogeneous chiral catalyst support has the structural formula shown in Formula I:

[0006] Formula I in, x is an integer from 1 to 6; Where n is 5-50; m is 3-20; R1 is H or a C1-C6 alkyl group; R2 is H or a C1-C6 alkyl group; R3 is H or a C1-C6 alkyl group; R4 is H or a C1-C6 alkyl group; R5 is H or a C1-C6 alkyl group; R6 is H or a C1-C6 alkyl group; R7 is H or a C1-C6 alkyl group.

[0007] According to one embodiment of the present invention, the term "C1C6 alkyl" as used herein refers to a saturated straight-chain or branched hydrocarbon alkyl group having 16 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, etc.

[0008] According to one embodiment of the present invention, x is an integer from 3 to 6.

[0009] According to one embodiment of the present invention, x is 6; and R 1、 R 2、 R 3、 R 4、 R 5、 R 6、 R7 is all H.

[0010] According to one embodiment of the present invention, the compound of formula I is used as a rhodium-based heterogeneous chiral catalyst support.

[0011] In a second aspect, the present invention provides a compound of formula II. The compound of formula II is used as a starting material or intermediate to prepare the compound of formula I. The structural formula of the compound of formula II is as follows:

[0012] Formula II in, x is an integer from 1 to 6; Where n is 5-50; m is 3-20; R1 is H or a C1-C6 alkyl group; R2 is H or a C1-C6 alkyl group; R3 is H or a C1-C6 alkyl group.

[0013] According to one embodiment of the present invention, x is 6; and R 1、 R 2、 R3 is all H.

[0014] According to one embodiment of the present invention, the use of compound II as a raw material or intermediate in the preparation of compound I.

[0015] In a third aspect, the present invention provides a compound of formula III. The compound of formula III is used as a starting material or intermediate to prepare the compound of formula II. The structural formula of the compound of formula III is as follows:

[0016] Formula III in, x is an integer from 1 to 6; Where n is 5-50; m is 3-20; R3 is H or a C1-C6 alkyl group; R8 is a halogen.

[0017] According to one embodiment of the invention, the term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.

[0018] According to one embodiment of the present invention, x is 6; and R3 is H.

[0019] According to one embodiment of the present invention, the use of compound III as a raw material or intermediate in the preparation of compound II.

[0020] The compound of formula III of this invention is obtained by conversion of the compound of formula IV.

[0021]

[0022] Formula IV Where n, m, and R3 are the same as above.

[0023] Beneficial effects This invention provides a heterogeneous chiral catalyst support, its preparation method, and its application. The synergistic chelation between the heterogeneous chiral catalyst support and Rh, the hydrogen bonding between the support and the substrate, the constraint effect on the catalytic unit, and the steric hindrance effect of the chiral ligands collectively ensure high catalytic performance.

[0024] This invention successfully prepared a heterogeneous chiral catalyst support through a three-step reaction involving 6-bromohexylation, chiral amination, and phosphineation. Rh(I) was then supported using a coordination chelation method to obtain a polymer-supported chiral Rh-based catalyst with an actual Rh loading of 0.9 mmol / g. This catalyst achieved 100% conversion and an ee value of 98.78 in the hydrogenation of acetamide methyl acrylate, demonstrating superior performance compared to the Rh-DPAMPP homogeneous catalyst. After six cycles, the conversion and ee value remained consistent, with only a slight increase in reaction time, exhibiting excellent cycling stability. This indicates that the strong coordination between the heterogeneous chiral catalyst support and Rh(I) effectively suppressed Rh loss, resulting in good cycling stability. Attached Figure Description

[0025] Figure 1 The infrared spectrum of the product of Example 1; Figure 2 The infrared spectrum of the product of Example 2; Figure 3 The infrared spectrum of the product of Example 3; Figure 4 The infrared spectrum of the product of Example 4 is shown below. Detailed Implementation

[0026] In the following embodiments, the invention has only been described exemplarily; however, those skilled in the art can make various modifications to the invention without departing from its spirit and scope after reading this patent application. In the embodiments of the invention, n and m are determined by the technical specifications of the poly(styrene-co-propylene alcohol) used (average Mn ~ 1500, allyl alcohol 30 mol%, hydroxyl number 210, SAA-100). It is usually expressed by measuring the amount of hydroxyl groups, converted to the amount of potassium hydroxide, for example, 210 mg / g means that 1g of polymer requires 210 mg of potassium hydroxide for the hydroxyl groups. Once the number of hydroxyl groups is determined, m is defined, and then the value of n can be obtained from the molecular weight.

[0027] Example 1 The preparation of compound III, 6-bromohexylated poly(styrene-co-propenol-O-(CH2)6-Br) (CM1-14), follows the reaction route below:

[0028] Procedure: Poly(styrene-co-propenol) (30 mmol, 8.0 g, 1 g / 3.75 mmol) was placed in a 250 mL double-necked flask. 150 mL of DMF and NaH (36 mol, 1.4 g, 60%) were added. The mixture was stirred at 60 °C for 1 h under a nitrogen atmosphere. 1,6-Dibromohexane (72 mol, 17.6 g) was added, and stirring continued for 24 h. The reaction mixture was cooled to room temperature, and 600 mL of water was added. The mixture was filtered to obtain a white solid. The white solid was washed successively with petroleum ether, ethanol, and deionized water until the filtrate was neutral. The filtrate was dried under vacuum at 60 °C for 12 h to obtain 6-bromohexylated poly(styrene-co-propenol-O-(CH2)6-Br) (CM1-14, 11.7 g). The bromine content was determined by elemental analysis, and the degree of 6-bromohexylation was calculated to be 91%. The infrared spectrum is shown below. Figure 1 As shown.

[0029] Example 2 The preparation of the chiral ligand-modified support of compound II, poly(styrene-co-propenol-O-(CH2)6-NH(Ph)CHCH(Ph)-OH) (CM2-15), follows the reaction route as follows:

[0030] Procedure: CM1-14 (24 mmol, 10.0 g) prepared in Example 1, (1R,2S)-2-amino-1,2-diphenylethanol (48 mmol, 10.2 g), anhydrous potassium carbonate (96 mmol, 13.2 g), and 150 mL of DMF were placed in a 250 mL double-necked flask and stirred at 80 °C for 48 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, 600 mL of water was added, and the mixture was filtered to obtain a white solid. The white solid was washed successively with ethanol and deionized water, and dried under vacuum at 60 °C for 12 h to obtain the chiral ligand modified support (styrene-co-propenol-O-(CH2)6-NH(Ph)CHCH(Ph)-OH) (CM2-15, 11.5 g). The nitrogen content was determined by elemental analysis, and the degree of chiral liganding was calculated to be 88%. The infrared spectrum is shown below. Figure 2 As shown.

[0031] Example 3 The preparation of compound I, P-functionalized support (styrene-co-propenol-O-(CH2)6-N(Ph)(PPh2)CHCH(Ph)-O-PPh2) (CM3-16), follows the reaction route as follows:

[0032] Procedure: CM2-15 (18 mmol, 10.0 g) prepared in Example 2 and 100 mL of toluene were added to a 200 mL two-necked flask. Under a nitrogen atmosphere at 0 °C, diphenylphosphine chloride (54 mmol, 11.9 g) and anhydrous triethylamine (40 mL) were added, and the reaction was stirred for 12 h at room temperature. The reaction mixture was cooled to room temperature, 600 mL of water was added, and the mixture was filtered to obtain a white solid. The white solid was washed successively with ethanol and deionized water, freeze-dried, and then vacuum-dried at 25 °C for 48 h to obtain the P-functionalized support (styrene-co-propenol-O-(CH2)6-N(Ph)(PPh2)CHCH(Ph)-O-PPh2) (CM3-16, 151.8 g). The phosphine content was determined by elemental analysis, and the degree of P-functionalization was calculated to be 96%. Infrared spectra are shown below. Figure 3 As shown.

[0033] Example 4 Preparation of supported chiral Rh catalyst (CM4-19) CM3-16 (1 mmol, 0.92 g) and [Rh(COD)Cl]2 (0.5 mmol, 0.25 g) were added to a 10 mL two-necked flask containing methanol (5.5 mL) and water (0.5 mL). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 4 h, followed by the addition of a 2.5 mL solution of NaBF4 (4 mmol, 0.4 g) in water. The reaction mixture was stirred at room temperature for another 2 h, and then filtered to obtain an orange-yellow solid. The solid was washed successively with deionized water (3 times) and ethanol (2 times), and then dried under vacuum at 25 °C for 48 h to obtain a polymer-supported chiral Rh catalyst (CM4-19, 1.01 g). The Rh content was determined by XRD and elemental analysis, and the Rh loading was calculated to be 90%. The infrared spectrum is shown below. Figure 4 As shown.

[0034] Example 5 Application of supported chiral Rh catalyst (CM4-19) in the catalytic hydrogenation of acetamidoacrylate 1 2 Compound 1 (0.5 mmol), catalyst (CM4-19, 0.05 mmol, 56 mg), and 10 mL of methanol were added to a reaction flask, and hydrogenation was carried out at room temperature under a hydrogen atmosphere. After 1 h, TLC showed that the reaction was complete. The mixture was filtered, and the filter cake (catalyst, CM4-19) was recovered. The solvent in the filtrate was evaporated to give product 2, with configuration S, in 100% yield, ee value 98.78%, and Ms (M+1, 220.11).

[0036] The results showed that the catalyst formed by the heterogeneous chiral support and Rh in this invention exhibited excellent catalytic activity and enantioselectivity for both methyl acetamipridate derivative substrates. Compared with the homogeneous Rh(I)-DPAMPP catalyst, the CM4-19 catalyst had a higher ee value while maintaining a similar catalytic activity (TOF value). After six cycles, the conversion and ee value remained unchanged, with only a slight increase in reaction time, demonstrating excellent cycle stability.

Claims

1. A heterogeneous chiral catalyst support having the structural formula shown in Formula I: ， in, x is an integer from 1 to 6; Where n is 5-50; m is 3-20; R1 is H or a C1-C6 alkyl group; R2 is H or a C1-C6 alkyl group; R3 is H or a C1-C6 alkyl group; R4 is H or a C1-C6 alkyl group; R5 is H or a C1-C6 alkyl group; R6 is H or a C1-C6 alkyl group; R7 is H or a C1-C6 alkyl group.

2. The compound according to claim 1, characterized in that, x is an integer between 3 and 6.

3. The compound according to claim 1, characterized in that, x is 6; R 1、 R 2、 R 3、 R 4、 R 5、 R 6、 R7 is all H.

4. The use of the compound of formula I according to any one of claims 1-3 as a rhodium-based heterogeneous chiral catalyst support.

5. Compound of formula II, with the following structural formula: ， in, x is an integer from 1 to 6; Where n is 5-50; m is 3-20; R1 is H or a C1-C6 alkyl group; R2 is H or a C1-C6 alkyl group; R3 is H or a C1-C6 alkyl group.

6. The compound according to claim 1, characterized in that, x is 6; at the same time R 1、 R 2、 R3 is all H.

7. The use of the compound of formula II as described in claim 5 or 6 in the preparation of compound of formula I as a raw material or intermediate.

8. Compound of formula III, with the following structural formula: ， in, x is an integer from 1 to 6; Where n is 5-50; m is 3-20; R3 is H or a C1-C6 alkyl group; R8 is a halogen.

9. The compound according to claim 1, characterized in that, x is 6; and R3 is H.

10. The use of the compound of formula III as described in claim 8 or 9 in the preparation of compound of formula II as a raw material or intermediate.

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