A method for chiral resolution and scale-up of racemic nickel organophosphonic acid polymers

Abstract

This invention relates to the chiral resolution and scale-up of molecular materials. The invention utilizes the reaction of racemic 1-(4-bromophenylethylaminomethylphosphonic acid) (Rac-BrpempH2) with transition metal Ni2+ ions. Through a solvothermal reaction, the spontaneous resolution of racemic organophosphonic acid molecules is achieved via the molecular isomerism effect of the co-solvent butanol and the coordination-driven synergistic effect of the metal ions. Furthermore, the introduction of chiral amino acid molecules successfully induces the resolution and chiral scale-up of single chiral organophosphonic acid molecules. The advantages of this invention are that by controlling reaction conditions and introducing chiral inducers, a single macroscopic helical structure material can be successfully synthesized from racemic ligands, providing a new strategy for chiral resolution and opening new avenues for designing and constructing chiral coordination polymers with helical morphology.

Description

Technical Field

[0001] This invention belongs to the field of chiral molecular material preparation. For the first time, a chiral resolution and scale-up strategy was achieved through solvent isomerization and metal ion coordination, providing a method for chiral resolution through chiral scale-up. In particular, in coordination polymer systems, this provides a new approach for the design and self-assembly of chiral materials with controllable chiral orientation. Background Technology

[0002] Chirality has long been considered a defining characteristic of life, pervasive at every level of matter in nature, from the smallest neutrinos and chiral amino acid molecules to DNA, plant vines, sea snails, and even the spiral arms of galaxies in outer space. Stereochemistry plays a crucial role in chemistry and materials science, agrochemical manufacturing, and even medicine due to its high sensitivity. Typically, only one conformation of an enantiomer produces beneficial pharmacodynamic effects in physiological processes, while the other conformation is medically ineffective or may even produce harmful side effects or toxicity, as seen in drugs like ofloxacin, amlodipine, and propranolol. Unfortunately, most chiral substances exist in racemic forms in nature or as synthetic products. Therefore, how to synthesize or obtain enantiomerically pure compounds is a critical and important issue. Chiral resolution and asymmetric synthesis are important research directions for preparing pure enantiomers. Chiral resolution is one of the important techniques for preparing single enantiomers. Compared with asymmetric synthesis, chiral separation has major advantages such as low cost, simple separation, and rapid scaling. To date, most chiral resolution processes primarily utilize chiral acids / bases or solvents as resolving agents to form diastereomer salts, co-crystallize, or preferentially crystallize to separate racemic mixtures. In recent years, Wan's team has designed and constructed a series of novel, custom-designed additives that can modulate the crystallization process of racemic mixtures, while simultaneously imparting color, fluorescence, or magnetism to one enantiomer, further enhancing the visual and functional differences between the two chiral crystals through varying physical properties. In this latest advancement, they achieved mechanical resolution of racemic mixture crystals without using any form of crystallization additive, simply by heating the chiral crystals and causing them to jump in opposite directions. However, chiral resolution remains a significant challenge. A major limitation of classical chiral resolution is the need to crystallize the target product into easily separable conglomerates through crystallization engineering, but the crystallization rates of all compounds are statistically low. Therefore, novel chiral resolution methods and the exploration of more forms of chiral resolution are of significant research importance. Summary of the Invention

[0003] Based on the above technical analysis, the purpose of this invention is to provide a new preparation method for resolving and chiral amplifying racemic organophosphonic acid molecules. Using Ni2+ as a transition metal ion and racemic 1-(4-bromo)phenylethylaminomethylphosphonic acid (Rac-Br-pempH2) as a ligand, and by selecting butanol with different configurations as co-solvents, helical products with different morphologies, Ni(Brpemp)(H2O)·(H2O), were obtained. The specific synthesis steps are as follows.

[0004] Add to a 20 mL glass reaction flask Rac -BrpempH2 (0.1 mmol, 0.0294 g), 5 mL H2O and 100 μL imidazole (4M) were stirred at room temperature for 30 min, and the solution changed from turbid to clear.

[0005] Then add 1 mL of NiSO4·7H2O solution (0.1 mmol / mL, 0.0282 g), and D-phenylalanine (0.1 mmol / mL, 0.0165 g) or L-phenylalanine, and stir for 30 min.

[0006] Add 4 mL of sec-butanol (SBA), n-butanol (NBA), isobutanol (IBA), or tert-butanol (TBA), and stir for 30 min to ensure thorough mixing.

[0007] Finally, the reaction flask was placed in a 100 ℃ oven for 2 days to obtain a light blue gel-like product.

[0008] The gel-like product was centrifuged and washed three times with water and ethanol, and the product was collected.

[0009] The products in different solvents were characterized using SEM, IR, PXRD, and CD.

[0010] For the first time, spontaneous chiral resolution was achieved through butanol isomerization and metal ion coordination. After introducing a chiral amino acid resolving agent, the resolution and amplification of a single chiral helix were successfully realized, providing a method for chiral resolution through chiral amplification.

[0011] By controlling reaction conditions and introducing chiral inducing agents, we successfully synthesized a single macroscopic helical structure material from racemic ligands, opening up new avenues for designing and constructing single-chiral coordination polymers with helical morphology.

[0012] The synthesis conditions of the complexes are convenient and simple, with low cost, high yield, and high purity; the preparation and functional transformation processes are in line with environmentally friendly chemistry. Attached Figure Description

[0013] Figure 1 is a schematic diagram showing the chiral resolution and magnification of racemic nickel organophosphonic acid polymers.

[0014] Figure 2 shows scanning electron micrographs of the effects of different conformations and amounts of butanol on the formation of the spirochete Ni(Brpemp)(H2O)·(H2O).

[0015] Figure 3 is a scanning electron micrograph of a single helix formed by adding different amino acids (D / L-Phe and D / L-Pca) to the helix Ni(Brpemp)(H2O)·(H2O).

[0016] Figure 4 shows the infrared, PXRD, and CD spectra of the single helix formed by adding different amino acids (D / L-Phe and D / L-Pca) to the helix Ni(Brpemp)(H2O)·(H2O).

[0017] Figure 5 shows scanning electron micrographs of the helical Ni(Brpemp)·(H2O)(H2O) using 5%, 20%, 50%, and 80% L-Phe (mole percentage relative to the ligand).

[0018] Figure 6 is a scanning electron micrograph of the spirochete Ni(Brpemp)(H2O)·(H2O) with equivalent amounts of alanine (Ala), glutamic acid (Glu), and serine (Ser) instead of phenylalanine (Phe). Detailed Implementation

[0019] Rac-BrpempH2 (0.1 mmol, 0.0294 g), 5 mL H2O, and 100 μL imidazole (4 M) were added to a 20 mL glass reaction flask. The mixture was stirred at room temperature for 30 min, and the solution changed from turbid to clear. Then, 0.5 mL of NiSO4·7H2O solution (0.2 mmol / mL, 0.0282 g) was added, and the mixture was stirred for 30 min. Next, 4 mL of sec-butanol (SBA) was added, and the mixture was stirred for 30 min. The reaction flask was then placed in a 100°C oven for 2 days to obtain a pale blue gel-like product with a yield of 59.5%.

[0020] Elemental analysis experimental values ​​(%): C, 27.44; H, 4.03; N, 3.78%; Theoretical values: C, 27.95; H, 3.91; N, 3.62%.

[0021] Infrared spectrum (KBr, cm-1): 3445(w), 3261(m), 3115(w), 2981(w), 2901(w), 1650(w), 1589(w), 1487(m), 1460(w), 1433(w), 1403(w), 1344(m), 1296(w), 1271(w), 1225(w), 1130(w), 1107(s), 1076(s), 1029(w), 983(s), 891(w), 864(m), 820(m), 787(m), 596(m).

[0022] The Rac-BrpempH2 / Ni system was explored using different types and amounts of amino acids. The products in different solvents were characterized using SEM, IR, PXRD, and CD.

Claims

1. A method for resolving and chiralizing racemic organophosphonic acid molecules, characterized in that... Includes the following steps: (1) pH adjuster: Imidazole, an organic base, was selected as the pH adjuster for dissolving ligands and adjusting the reaction solution; (2) Ingredients: Racemic organic ligand 1-(4-bromo)phenylethylaminomethylphosphonic acid (Rac-BrpempH2) and NiSO4·6H2O were selected and reacted in a molar ratio of 1:

1. (3) Solvent: The reaction is carried out in a mixed solvent of butanol solvent selected from straight-chain butanol or branched-chain butanol and water; (4) Synthesis and preparation: The reaction solution was stirred at room temperature for a certain time, then placed in a reaction flask and placed in a set drying oven for a certain time to obtain a light blue gel-like product; (5) Chiral resolution: Add different amounts of chiral amino acids as chiral inducers to the above reaction, and then carry out the above reaction.

2. The method according to claim 1, characterized in that, In step (1), the pH adjuster is an organic base imidazole, and the imidazole solid is prepared into a 4M imidazole aqueous solution.

3. The method according to claim 1, characterized in that, Step (2) includes: adding 100 μL of 4M imidazole solution to an aqueous solution containing the organophosphonic acid ligand and stirring for 30 minutes; then adding an equimolar amount of NiSO4·6H2O.

4. The method according to claim 1, characterized in that, Step (3) includes: stirring for 1 hour, then adding a mixed solvent of butanol and water, the total volume of which is 10 mL, and then stirring for another 30 minutes.

5. The method according to claim 1, characterized in that, In step (4), the reaction is carried out in an oven at 100°C for 2 days.

6. The method according to claim 1, characterized in that, In step (5), the chiral amino acids added are D / L-phenylalanine (Phe), D / L-piperidine (Pac), L-alanine (Ala), L-glutamic acid (Glu) and L-serine (Ser).

7. The method according to claim 1, characterized in that, In step (5), when the chiral amino acid is L-phenylalanine (L-Phe), its amount is 5%, 20%, 50% or 80% relative to the molar amount of the ligand.

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