Preparation method and application of calcium L-5-methyltetrahydrofolate based on metal organic framework (MOFs) catalyst

Abstract

The invention discloses a preparation method of L-5 methyltetrahydrofolic acid based on an MOFs catalyst, and high-selectivity hydrogenation and methylation of folic acid are realized under mild conditions by designing MOFs material loaded noble metal nanoparticles with a chiral confinement effect. The method does not need an optical resolution step, and the ee value of the product is gt; and the catalyst can be recycled, so that the method is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis and catalytic materials, and specifically relates to a process for preparing L-5-methyltetrahydrofolate from folic acid through stereoselective hydrogenation and methylation reactions using metal organic frameworks (MOFs) as catalysts. Background Art

[0002] 1. Problems with existing technologies

[0003] L-5-Methyltetrahydrofolate is a key drug for treating folic acid deficiency, neurological diseases, cardiovascular and cerebrovascular diseases, and preventing birth defects. Its synthesis requires precise control of the 6S stereoconfiguration at the C6 site. Traditional processes rely on homogeneous palladium / platinum catalysts combined with chiral ligands, which have the following drawbacks:

[0004] (1) Catalyst recovery is difficult and costly;

[0005] (2) The steps for optical isomer resolution are complex and the product yield is low (usually <70%);

[0006] (3) Insufficient stereoselectivity in homogeneous systems (ee value is about 80-90%).

[0007] It can be seen from this that the hydrogenation process using precious metals as catalysts has the problems of unstable reaction condition control, complex operation, and easy poisoning and failure of the catalyst, which makes its production cost high and does not meet the conditions for industrial mass production. In recent years, porous materials (such as molecular sieves) have been tried for heterogeneous catalysis, but their pore size and chemical environment are difficult to adapt to the requirements of folic acid macromolecules and chirality control. This method attempts to explore the field of heterogeneous asymmetric catalytic production of L-5 methyltetrahydrofolate. Introducing chiral molecules into the framework of the MOFs stereotopological structure to construct a chiral reaction microenvironment enables asymmetric catalysis to obtain L-type optical isomers, improves the optical isomer selectivity of the catalytic reaction, and aims to achieve a green production model with low process cost and reusable catalyst materials.

[0008] 2. Current status of MOFs technology

[0009] MOFs have been used in catalysis due to their tunable pore size, high specific surface area, and functional potential (e.g., CN112299927A discloses Zr-MOFs for CO2 reduction). However, their application in the stereoselective synthesis of folic acid derivatives by combining chiral confinement has not been reported. This invention utilizes Zn and Pt bimetallic ion clusters linked to organic matter to form MOFs and introduces chiral molecules for modification, thereby enhancing the material's strength and stability and creating a chirally asymmetric catalytic microenvironment at the metal catalytic site. Summary of the Invention

[0010] Purpose of the Invention

[0011] This paper provides a method for preparing L-5-methyltetrahydrofolate with high efficiency and without the need for optical resolution. By designing a MOFs catalyst with both stereoselectivity and stability, the paper solves the problems of low yield and complex resolution steps in the existing process.

[0012] Technical Solution

[0013] 1. Catalyst design

[0014] The MOF framework consists of zinc clusters (Zn(NO₃)₂) as metal nodes, connected to chiral biphenol organic ligands (BINOL) containing nitrogen / carboxylic acid groups, forming a three-dimensional porous structure with pore sizes of 1.5-3.0 nm. Solution A was prepared by dissolving 5g of Zn(NO₃)₂.6H₂O in 150ml of DMF, and solution B was prepared by dissolving 12g of BINOL in 150ml of DMF. Solution A was then added dropwise to solution B under ultrasonic conditions with constant stirring. After the reaction lasts for 30-60 minutes, the mixture is centrifuged and allowed to stand for 20 minutes. The separated solid material is then re-dissolved in 150 ml of DMF solution. 5 g of Zn(NO3)2.6H2O and 12 g of BINOL are simultaneously added to a 200 ml reactor. The mixture is heated at 120°C for 2-3 hours, cooled to room temperature, centrifuged, washed several times with methanol, and vacuum dried to obtain a MOF [Pt Zn(BINOL)(DMF)2(NO3)2.2MeOH] skeleton composite material of zinc ion clusters bound to BINOL.

[0015] Precious Metal Loading: Pt nanoparticles (2-5 nm in diameter) were loaded into the MOF pores via an in situ reduction method, with a metal loading of 0.5-5 wt%. The resulting zinc ion cluster-complexed BINOL complex was assembled with PtCl2 using a hot solvent method to form a Pt-Zn-MOF bimetallic material chiral control unit.

[0016] The enantioselectivity of the composite material was improved by assembling MOF with functional chiral ligands and metal centers. The chiral group L-aspartic acid was introduced into the organic ligand and assembled with Pt-Zn-MOFs material using a hot solvent method.

[0017] Alternatively, modifying β-cyclodextrin or chiral ionic liquids (such as [BMIM][L-Pro]) within the pores of MOFs can also produce the same modification effect.

[0018] 2. Preparation process

[0019] Step 1: Asymmetric hydrogenation of folic acid

[0020] Under hydrogen pressure of 0.05-0.4 MPa and temperature of 25-40°C, Pd-Zn-MOF is used as a catalyst in a water / DMF mixed solvent (volume ratio of 1:1-1:3) for 2-4 hours, and an appropriate amount of folic acid is added to react to generate 6S-tetrahydrofolate (ee value ≥99%).

[0021] Step 2: Methylation and salt formation

[0022] Add formaldehyde (molar ratio 1:1.2) and sodium borohydride (0.1-0.5 mol / L) to the reaction system, adjust the pH to 8-10, react for 1-2 hours, add CaCl2 solution, and crystallize and separate L-5-methyltetrahydrofolate calcium.

[0023] The advantages of this technology are as follows:

[0024] a High stereoselectivity: The confinement effect of MOFs pores and the chiral microenvironment work synergistically, and the ee value of the hydrogenation reaction is >99%, without the need for subsequent splitting.

[0025] b Catalyst recyclability: MOFs support protects the noble metal active sites, and the activity remains >90% after 20 cycles.

[0026] c. Green and efficient: The aqueous reaction system reduces the use of organic solvents, and the product yield is ≥95% (an increase of more than 25% compared to traditional processes). DETAILED DESCRIPTION

[0027] Example 1: Preparation and catalytic performance testing of Pd-Zn-MOF

[0028] 1. Catalyst Synthesis

[0029] ZnCl2 (1.2 mmol) and L-aspartic acid-modified chiral biphenol ligand (1.0 mmol) were dissolved in DMF (20 mL), reacted at 120 °C for 24 h, and centrifuged to obtain chiral Zn-MOF;

[0030] Zn-MOF was immersed in 0.1 M PdCl2 solution (pH = 3) for 12 h and then reduced with H2 (200 ° C, 2 h) to obtain Pd-Zn-MOF (Pd loading 2.3 wt%).

[0031] 2. Hydrogenation reaction

[0032] Folic acid (1.0 g) and Pd-Zn-MOF (50 mg) were added to DMF / H2O (20 mL, 1:1 v / v), H2 (0.2 MPa) was introduced, and the mixture was stirred at 35°C for 3 hours. HPLC analysis showed that the yield of 6S-tetrahydrofolate was 97.2% (ee value 99.5%).

[0033] 3. Methylation and Purification

[0034] 37% formaldehyde (0.8 mL) and NaBH4 (0.3 g) were added to the reaction solution, and the mixture was reacted at pH = 9 for 1.5 hours. After adding CaCl2 (0.5 g), white crystals were precipitated, which were filtered and dried to obtain L-5-methyltetrahydrofolate calcium (purity 99.8%).

[0035] Example 2: Catalyst cycle performance test

[0036] The Pd-Zn-MOF in Example 1 was recovered and reused 20 times, and the product yield dropped from 97.2% to 93.1%. XRD characterization showed that the MOFs structure did not collapse.

[0037] Description of the drawings

[0038] Figure 1 : Schematic diagram of the structure of MOFs catalyst (marking the metal nodes, chiral ligands and Pd nanoparticle distribution);

[0039] Figure 2 : Folic acid hydrogenation-methylation reaction pathway diagram;

[0040] Figure 3 : Product HPLC collection of illustrative plates among the embodiment 1.

Claims

1. A method for preparing L-5-methyltetrahydrofolate, characterized in that: Using chiral MOFs loaded with noble metal nanoparticles as catalysts, a 6S configuration product is directly obtained through asymmetric hydrogenation and methylation of folic acid, including the following steps: a) In a hydrogen atmosphere, folic acid reacts with the MOFs catalyst in a solvent to produce 6S-tetrahydrofolate; b) adding a methylating agent and an alkali metal borohydride to the product of step a, and reacting to form a salt crystal.

2. The method according to claim 1, wherein: The MOFs catalyst is a CMOFs material combining a bimetallic cluster with an organic ligand, wherein the metal node is Zr, Zn or Fe, the noble metal is Pd, Pt or Rh, and the loading amount is 0.5-5 wt%.

3. The method according to claim 1, wherein: MOFs nano-skeleton materials are formed by assembling o-phenol derivatives (BINOL) as ligands with metal ions.

4. The method according to claim 1, wherein: The chiral MOFs are introduced with chiral units through ligand modification or pore functionalization, including β-cyclodextrin, L-proline derivatives, BINOL phosphate or L-aspartic acid derivatives.

5. The method according to claim 2, wherein: The molar ratio of the metal Zr, Zn or Fe in the material to the noble metal Pd, Pt or Rh in the assembly reaction is 1:

100.

6. The method according to claim 4, characterized in that: In the MOFs material assembly reaction, the molar ratio of L-aspartic acid, Zn, and Pt is 1:1:100.

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