Process for the synthesis of l-5-methyltetrahydrofolate and its calcium salt

Abstract

The application specifically discloses a synthesis method of L-5-methyltetrahydrofolic acid and calcium salt thereof, wherein folic acid is used as a starting material, a catalyst diiodo (p-cymene) ruthenium (II) dimer and a chiral ligand (rp, rp)-1,1-bis[bis(4-methoxy-3,5-dimethylphenyl) phosphino]-2,2-bis[(R)-alpha-(dimethylamino) benzyl] ferrocene are used for asymmetric hydrogenation reduction, and high stereoselectivity synthesis of 6S-tetrahydrofolic acid is realized. 6S-tetrahydrofolic acid is subjected to reductive amination and salt formation steps in sequence, and high-purity, stable crystal form 6S-5-methyltetrahydrofolic acid calcium can be obtained at a high yield. The reaction operation is simple, the steps are short, the efficiency is high, the cost is low, the safety factor is high, and the method is suitable for industrial production.

Description

Technical Field

[0001] This application relates to the technical field of organic synthesis, and more specifically, to a method for synthesizing L-5-methyltetrahydrofolate and its calcium salt. Background Technology

[0002] L-5-methyltetrahydrofolate (also known as 6S-5-methyltetrahydrofolate), chemically named N-[4-[[(2-amino-1,4,5,6,7,8-hexahydro-4-oxo-5-methyl-6-pteridyl)methyl]amino]benzoyl]-L-glutamic acid, is the only folic acid drug that can cross the blood-brain barrier. As a pharmaceutical, it has the following effects: First, prevention and treatment of Alzheimer's disease; second, it can be used as an antidote to enhance the compatibility of folic acid antagonists, particularly aminopterin and methotrexate in cancer treatment; third, it can enhance the therapeutic effect of fluorinated pyrimidines; fourth, it can reduce the toxicity of dideazatetrahydrofolates during chemotherapy; fifth, it can be used to treat autoimmune diseases such as psoriasis and rheumatoid arthritis; sixth, taking L-5-methyltetrahydrofolate can avoid the significant risks associated with vitamin B12 deficiency masking caused by taking folic acid alone. Meanwhile, L-5-methyltetrahydrofolate calcium is also used to prevent neural tube defects in fetuses, arteriosclerosis, and to treat megaloblastic anemia. Currently, L-5-methyltetrahydrofolate calcium has been approved by the National Health Commission as a new food fortifier, possessing advantages unmatched by other folic acid drugs, and has a very broad application and market prospect in the medical field.

[0003] Currently, methods for synthesizing L-5-methyltetrahydrofolate and its calcium salt have been reported. For example, Chinese patent CN114957257A discloses a method for preparing calcium 5-methyltetrahydrofolate. In this synthetic route, folic acid is used as a raw material and sodium borohydride is used as a reducing agent to obtain the reduced product tetrahydrofolate; tetrahydrofolate undergoes a methylation reaction to obtain 5-methyltetrahydrofolate; then, after acid leaching and purification, 5-methyltetrahydrofolate reacts with calcium salt to generate calcium 5-methyltetrahydrofolate.

[0004] The above synthetic route still has some drawbacks that cannot be ignored: First, it requires the use of excessive sodium borohydride reducing agent, and a large amount of hydrogen is generated during the post-processing, which poses a safety hazard in industrial production; Second, the product of the chemical reduction method is a mixture of two configurations (D / L)-tetrahydrofolate. Although the target configuration with higher optical purity can be obtained by chiral resolution, chiral resolution will result in at least 50% material waste, which is a serious loss. Summary of the Invention

[0005] To address the drawbacks of the aforementioned synthetic routes for L-5-methyltetrahydrofolate and its calcium salt, this application provides a method for synthesizing L-5-methyltetrahydrofolate and its calcium salt. This method results in a simplified, easy-to-operate, and safe synthetic route suitable for industrial production, and also produces a high yield and purity of the final product with stable crystal form.

[0006] In a first aspect, this application provides a method for synthesizing L-5-methyltetrahydrofolate, employing the following technical solution:

[0007] A method for synthesizing L-5-methyltetrahydrofolate includes the following steps:

[0008] Using folic acid as a raw material, 6S-tetrahydrofolic acid was generated by asymmetric hydrogenation reduction in the presence of diiodo(p-cymene)ruthenium(II) dimer and chiral ligand (rp,rp)-1,1-bis[bis(4-methoxy-3,5-dimethylyl)phosphino]-2,2-bis[(R)-α-(dimethylamino)benzyl]ferrocene.

[0009] Furthermore, in the asymmetric hydrogenation reduction reaction, based on folic acid, the amount of the catalyst diiodine (p-cymene)ruthenium(II) dimer is 0.2‰ to 0.4‰ equivalent.

[0010] Furthermore, in the asymmetric hydrogenation reduction reaction, based on folic acid, the amount of the catalyst, ruthenium(II) diiodide (p. cymene) dimer, is 0.2‰ equivalent.

[0011] Furthermore, in the asymmetric hydrogenation reduction reaction, the molar ratio of the catalyst diiodide (p-cymene)ruthenium(II) dimer to the chiral ligand (rp,rp)-1,1-bis[bis(4-methoxy-3,5-dimethylyl)phosphino]-2,2-bis[(R)-α-(dimethylamino)benzyl]ferrocene is 1:(1.7-2.2).

[0012] Furthermore, in the asymmetric hydrogenation reduction reaction, the molar ratio of the catalyst diiodide (p-cymene)ruthenium(II) dimer to the chiral ligand (rp,rp)-1,1-bis[bis(4-methoxy-3,5-dimethylyl)phosphino]-2,2-bis[(R)-α-(dimethylamino)benzyl]ferrocene is 1:2.

[0013] Furthermore, the solvent used in the asymmetric hydrogenation reduction reaction is a mixed solvent system of alcohol protic solvent and water (volume ratio 1:1).

[0014] Furthermore, the protic alcohol solvent satisfies at least one of the following characteristics: methanol, ethanol, isopropanol, and tert-butanol.

[0015] More preferably, the alcohol protic solvent is methanol.

[0016] Furthermore, an alkaline co-solvent is added to the solvent.

[0017] Furthermore, the alkaline co-solvent satisfies at least one of the following characteristics: sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, and sodium tert-butoxide.

[0018] More preferably, the alkaline co-solvent is a 30 wt% sodium hydroxide solution.

[0019] Furthermore, the hydrogen pressure in the asymmetric hydrogenation reduction reaction is 0.05–0.4 MPa.

[0020] Furthermore, the hydrogen pressure in the asymmetric hydrogenation reduction reaction is 0.1–0.2 MPa.

[0021] Furthermore, the reaction temperature in the asymmetric hydrogenation reduction is 20℃~40℃.

[0022] Furthermore, the asymmetric hydrogenation reduction reaction temperature is 40–45°C.

[0023] Furthermore, the reaction time in the asymmetric hydrogenation reduction is 2.0–4.0 h.

[0024] Furthermore, the reaction time in the asymmetric hydrogenation reduction is 3.0 h.

[0025] Secondly, this application provides a method for synthesizing L-5-methyltetrahydrofolate calcium, using the following technical solution:

[0026] A method for synthesizing L-5-methyltetrahydrofolate calcium includes the following steps:

[0027] Using 6S-tetrahydrofolate obtained by the aforementioned synthesis method of L-5-methyltetrahydrofolate as a raw material, calcium L-5-methyltetrahydrofolate was obtained through reductive amination and salt formation steps.

[0028] Furthermore, the specific operation of the reductive amination step is as follows:

[0029] Formaldehyde solution was added to the 6S-tetrahydrofolate reaction system, and the reaction temperature was controlled at 0-30℃ for 0.5-2.0 h. Sodium borohydride was then added to the 6S-tetrahydrofolate reaction system, and the reaction temperature was controlled at 60-80℃ for 1.0-3.0 h. A stabilizer was added to adjust the pH value to 4.0-4.5, and 6S-5-methyltetrahydrofolate was obtained by crystallization.

[0030] Based on 6S-tetrahydrofolate, the dosage of formaldehyde is 1.2 to 1.5 equivalents, and the dosage of sodium borohydride is 2.0 to 4.0 equivalents.

[0031] Furthermore, the amount of formaldehyde used in the reductive amination step is 1.3 equivalents.

[0032] Furthermore, the amount of sodium borohydride used in the reductive amination step is 3.0 equivalents.

[0033] Furthermore, the stabilizer is sodium ascorbate.

[0034] Furthermore, the specific operation of the salt-forming step is as follows:

[0035] Add a soluble calcium salt to the 6S-5-methyltetrahydrofolate reaction system and adjust the system to a clear state. Control the crystallization temperature at 60℃~90℃ and add a poor solvent to crystallize and obtain L-5-methyltetrahydrofolate calcium.

[0036] Furthermore, the amount of calcium chloride used in the salt-forming step is 4 equivalents.

[0037] Furthermore, the undesirable solvent in the salt formation step satisfies at least one of the following characteristics: methanol, ethanol, isopropanol, acetonitrile, and tetrahydrofuran.

[0038] Furthermore, the unsuitable solvent in the salt formation step is a mixed solvent of ethanol and isopropanol in a ratio of 4:1.

[0039] This application has at least the following beneficial effects:

[0040] First, this application provides a new method for the efficient and convenient synthesis of 6S-tetrahydrofolate, which solves the problems of impurity introduction, material loss and low yield caused by subsequent resolution. Through a strategy of bidirectional regulation of temperature and crystallization method in the crystallization process, a new method for obtaining high-purity and stable crystal form of L-5-methyltetrahydrofolate calcium with high yield is developed.

[0041] Secondly, the raw materials used in the preparation method of this application are readily available, and the reaction conditions of this method are mild, suitable for large-scale industrial production, and have high safety and low cost.

[0042] Third, the experimental method disclosed in this application is simple, the process is advanced, the amount of waste generated during the production process is small, the environmental pressure is low, and the yield and product purity are high, making it suitable for industrial production. Attached Figure Description

[0043] Figure 1 This is the XRD pattern of L-5-methyltetrahydrofolate calcium obtained in Example 1 of this application. Detailed Implementation

[0044] Catalytic hydrogenation was an early and commonly used method for reducing folic acid to tetrahydrofolic acid. However, this method uses precious metals as catalysts, which are expensive, and the reaction requires high activation energy and harsh conditions. In addition, the product also needs to be chirally resolved, which greatly limits the application of this method.

[0045] To address the above issues, asymmetric reduction is a novel and efficient method for constructing saturated carbon-carbon and carbon-nitrogen bonds, which has emerged in recent years. Chinese patent CN113603691A discloses an asymmetric hydrogenation catalytic method for folic acid. This synthetic route uses folic acid as a starting material, reducing it to (6S)-tetrahydrofolate in the presence of an Rh pre-catalyst and a diphosphine ligand system, achieving a yield of 90.0%. Furthermore, this patent also discloses a synthetic route for 6S-5-methyltetrahydrofolate, which involves cyclization under trifluoroacetic acid catalysis to obtain (6S)-5,10-methylenetetrahydrofolate, followed by ring-opening to yield 6S-5-methyltetrahydrofolate. However, the catalytic system in this patent exhibits relatively poor stereoselectivity, with a diastereomeric excess exceeding 86%, necessitating subsequent chiral resolution to aid in the purification of the target configuration. Moreover, the overall process is complex and involves numerous steps, hindering industrial-scale production.

[0046] Chinese patent CN1781919A discloses a method for preparing optically pure tetrahydropterin and its derivatives, particularly optically pure tetrahydrofolic acid and its derivatives, via stereoselective hydrogenation. This method discloses various metal complex catalysts such as ruthenium and rhodium, as well as various chiral ligands, and provides several examples to demonstrate that different combinations of catalysts and chiral ligands result in different final yields and purities of the products in asymmetric catalytic hydrogenation reactions. Furthermore, the synthesis of the target configuration of tetrahydrofolic acid requires first synthesizing the corresponding folic acid ester or folic acid ester salt from folic acid, followed by asymmetric catalytic hydrogenation and then hydrolysis to obtain the corresponding configuration of tetrahydrofolic acid. This increases the number of reaction steps and the risk of generating genotoxic impurities such as benzenesulfonate esters.

[0047] Based on the above, the applicant has developed a novel synthetic method for L-5-methyltetrahydrofolate and its calcium salt. Using folic acid as the starting material, the method employs asymmetric hydrogenation reduction with the catalyst diiodo(p-cymene)ruthenium(II) dimer and the chiral ligand (rp,rp)-1,1-bis[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2,2-bis[(R)-α-(dimethylamino)benzyl]ferrocene, achieving highly stereoselective synthesis of 6S-tetrahydrofolate. Furthermore, this system exhibits high catalytic efficiency, low cost, and avoids material waste caused by chiral resolution. Crystallization conditions are controlled by both crystallization temperature and crystallization mode, resulting in a product with stable crystal form and high purity. In addition, this synthetic method reduces 6S-tetrahydrofolate to 6S-5-methyltetrahydrofolate in one step, eliminating the need for prior cyclization followed by ring-opening. Furthermore, this synthetic method eliminates the need for purification of 6S-5-methyltetrahydrofolate to obtain high-purity L-5-methyltetrahydrofolate calcium. The reaction is simple, quick, efficient, low-cost, and safe, making it suitable for industrial production.

[0048] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this application will be further described below in conjunction with embodiments.

[0049] Example

[0050] Example 1

[0051] A method for synthesizing L-5-methyltetrahydrofolate and its calcium salt, comprising the following steps:

[0052] Asymmetric catalytic hydrogenation: Add 2L of purified water and 1kg of folic acid to a 5L hydrogenation reactor, stir, and add 182g of a 30% aqueous solution of sodium hydroxide to the reactor until the system is clear; seal the reactor, replace the air in the reactor with nitrogen three times, continue to purge nitrogen until the pressure inside the reactor reaches 0.3MPa, maintain the pressure and heat the liquid to 45℃, stir for 10min; weigh 0.96g of (rp,rp)-1,1-bis[bis(4-methoxy-3,5-dimethyl)phosphino]-2,2-bis[(R)-α-(dimethylamino)benzyl]ferrocene and diiodine (p-cymene)ruthenium ( II) Dissolve 0.44 g of the dimer in an appropriate amount of anhydrous ethanol to prepare a catalyst mixture; add the prepared catalyst mixture to the hydrogenation reactor, purge with nitrogen three times, and purge with hydrogen three times; introduce hydrogen into the hydrogenation reactor, control the temperature inside the reactor at 45℃, maintain the pressure at 0.2 MPa, and hydrogenate for 3 hours until the reaction is complete; depressurize the reactor, purge with nitrogen three times, open the reactor, pour out the reaction solution, add 4.0 g of vitamin C, adjust the pH of the solution to 2.0-3.0 with 2M hydrochloric acid, centrifuge, and collect the solid, which is 6S-tetrahydrofolic acid. No drying is required; proceed directly to the next reaction.

[0053] Reductive amination: Add 3L of purified water and the wet solid obtained in Example 1 to a 5L three-necked flask, cool to 10°C, add 30% sodium hydroxide aqueous solution dropwise to dissolve the system, add 1.3 equivalents of 37wt% formaldehyde aqueous solution, and after the addition is complete, keep the temperature at 10°C and stir for 1h; slowly add 3 equivalents of sodium borohydride to the system, and after the addition is complete, raise the temperature to 60°C and keep the temperature for 2.0h; after the reaction is complete, add 4.0g of vitamin C to the system, adjust the pH to 4.0-4.5 with 2M hydrochloric acid, keep the temperature for 2h to crystallize, filter under reduced pressure, collect the solid, and dry under vacuum to obtain a yellow-green powdery solid weighing 890.0g, yield: 85.50% (overall yield of two steps).

[0054] 1 H NMR (DMSO-d6, 300MHz): δ2.040-2.055, m, 1H; 2.072-2.098, m, 1H; 2.320-2.350 ,m,2H;2.504-2.513,s,3H;2.787-2.825,m,1H;2.862-2.900,m,1H;2.936-2.9 48,m,1H; 3.150-3.216,m,2H; 4.333-4.377,m,1H; 5.936,s,2H; 6.067,s,1H; 6. 500,s,1H;7.656-7.673,d,2H;8.108-8.123,d,2H;9.965,s,1H;12.389,s,1H; 13 C NMR(DMSO-d6,100MHz)δ26.055,30.483,35.476,42.681,43.469,51.763,55.185,99.508,110.753 ,120.459,129.027,151.190,151.388,153.041,158.789,166.455,173.869,173.985; MS(m / z,M+H + = 460.19.

[0055] Salt formation: Add 300.0g of dried 6S-5-methyltetrahydrofolate, 3L of purified water, and 1.15g of vitamin C to a 10L three-necked flask. Add 30% sodium hydroxide solution dropwise at room temperature until the system is completely dissolved. 362.3g 725 mL of CaCl2 aqueous solution was added dropwise to the above reaction solution. After the addition was complete, the temperature was raised to 60 °C, and the system was dissolved. 3 L of ethanol-isopropanol (volume ratio = 4:1) was slowly added dropwise to obtain a mixed solvent. After the addition was complete, the mixture was stirred to induce crystallization for 2 h. The solid was collected by vacuum filtration and dried under vacuum to obtain a white powdery solid, which is the target product L-5-methyltetrahydrofolate calcium, weighing 243.7 g, with a yield of 75.0%.

[0056] 1 H NMR (D2O, 300MHz): δ2.027-2.057,m,1H; 2.126-2.195,m,1H; 2.273-2.342,m,2H; 2.529,s,3H; 2.941-2.982,m,1H; 3.0 52-3.131,m,1H; 3.222-3.251,m,1H; 3.451-3.483,m,1H; 4.303-4.330,m,1H; 6.795-6.812,d,2H; 7.685-7.703,d,2H; 13 C NMR(DMSO-d6,100MHz)δ28.607,34.377,35.742,42.648,43.417,55.025,55.916,102.469,112.89 7,121.588,129.090,152.015,153.731,159.259,169.908,170.708,179.350,182.449; MS(m / z,MH - =458.18.

[0057] See Figure 1 The XRD pattern of L-5-methyltetrahydrofolate calcium shows that it has a stable crystal form.

[0058] Example 2

[0059] A method for synthesizing L-5-methyltetrahydrofolate and its calcium salt, comprising the following steps:

[0060] Asymmetric catalytic hydrogenation: Add 2L of purified water and 1kg of folic acid to a 5L hydrogenation reactor, stir, and add 182g of a 30% aqueous solution of sodium hydroxide to the reactor until the system is clear; seal the reactor, replace the air in the reactor with nitrogen three times, continue to purge nitrogen until the pressure inside the reactor reaches 0.2MPa, maintain the pressure and heat the liquid to 40℃, stir for 5min; weigh 1.44g of (rp,rp)-1,1-bis[bis(4-methoxy-3,5-dimethyl)phosphino]-2,2-bis[(R)-α-(dimethylamino)benzyl]ferrocene and diiodo(p-cymene)ruthenium(II) 0.4 g of the dimer was dissolved in an appropriate amount of anhydrous ethanol to prepare a catalyst mixture. The prepared catalyst mixture was added to the hydrogenation reactor, and nitrogen was purged three times, followed by hydrogen purging three times. Hydrogen was introduced into the hydrogenation reactor, and the temperature inside the reactor was controlled at 40°C. The pressure was maintained at 0.2 MPa, and the hydrogenation reaction was carried out for 2.5 h until the reaction was complete. The reactor was depressurized and purged with nitrogen three times before being opened. The reaction solution was poured out, 4.0 g of vitamin C was added, and the pH of the solution was adjusted to 2.0-3.0 with 2M hydrochloric acid. The solution was centrifuged, and the solid was collected, which is 6S-tetrahydrofolic acid. No drying is required, and it can be directly used for the next reaction.

[0061] Reductive amination: Add 3L of purified water and the wet solid obtained in Example 1 to a 5L three-necked flask, cool to 5°C, add 30% sodium hydroxide aqueous solution dropwise to dissolve the system, add 1.2 equivalents of 37% formaldehyde aqueous solution, and after the addition is complete, keep the temperature at 5°C and stir for 1 hour; slowly add 2 equivalents of sodium borohydride to the system, and after the addition is complete, raise the temperature to 70°C and keep the temperature for 3.0 hours; after the reaction is complete, add 4.0g of vitamin C to the system, adjust the pH to 4.0-4.5 with 2M hydrochloric acid, keep the temperature for 2 hours to crystallize, filter under reduced pressure, collect the solid, and dry under vacuum to obtain a yellow-green powdery solid weighing 873.2g, yield: 83.89% (total yield of two steps).

[0062] Salt formation: Add 300.0g of dried 6S-5-methyltetrahydrofolate, 3L of purified water, and 1.15g of vitamin C to a 10L three-necked flask. Add 30% sodium hydroxide solution dropwise at room temperature until the system is completely dissolved. 362.3g 725 mL of CaCl2 aqueous solution was added dropwise to the above reaction solution. After the addition was complete, the temperature was raised to 75 °C, and the system was dissolved. 3 L of ethanol-isopropanol (volume ratio = 4:1) was slowly added dropwise to obtain a mixed solvent. After the addition was complete, the mixture was stirred to induce crystallization for 2 h. The solid was collected by vacuum filtration and dried under vacuum to obtain a white powdery solid, which was the target product L-5-methyltetrahydrofolate calcium, weighing 221.4 g, with a yield of 68.13%.

[0063] Example 3

[0064] A method for synthesizing L-5-methyltetrahydrofolate and its calcium salt, comprising the following steps:

[0065] Asymmetric catalytic hydrogenation: Add 2L of purified water and 1kg of folic acid to a 5L hydrogenation reactor, stir, and add 182g of a 30% aqueous solution of sodium hydroxide to the reactor until the system is clear; seal the reactor, replace the air in the reactor with nitrogen three times, continue to purge nitrogen until the pressure inside the reactor reaches 0.4MPa, maintain the pressure and heat the liquid to 45℃, stir for 10min; weigh 1.92g of (rp,rp)-1,1-bis[bis(4-methoxy-3,5-dimethyl)phosphino]-2,2-bis[(R)-α-(dimethylamino)benzyl]ferrocene and diiodine (p-cymene)ruthenium ( II) Dissolve 0.52 g of the dimer in an appropriate amount of anhydrous ethanol to prepare a catalyst mixture; add the prepared catalyst mixture to the hydrogenation reactor, purge with nitrogen three times, and purge with hydrogen three times; introduce hydrogen into the hydrogenation reactor, control the temperature inside the reactor at 45℃, maintain the pressure at 0.2 MPa, and hydrogenate for 3 hours until the reaction is complete; depressurize the reactor, purge with nitrogen three times, open the reactor, pour out the reaction solution, add 4.0 g of vitamin C, adjust the pH of the solution to 2.0-3.0 with 2M hydrochloric acid, centrifuge, and collect the solid, which is 6S-tetrahydrofolic acid. No drying is required; proceed directly to the next reaction.

[0066] Reductive amination: Add 3L of purified water and the wet solid obtained in Example 1 to a 5L three-necked flask, cool to 0°C, add 30% sodium hydroxide aqueous solution dropwise to dissolve the system, add 1.5 equivalents of 37% formaldehyde aqueous solution, and after the addition is complete, keep the temperature at 0°C and stir for 3 hours; slowly add 4 equivalents of sodium borohydride to the system, and after the addition is complete, raise the temperature to 80°C and keep the temperature for 3.0 hours; after the reaction is complete, add 4.0g of vitamin C to the system, adjust the pH to 4.0-4.5 with 2M hydrochloric acid, keep the temperature for 2 hours to crystallize, filter under reduced pressure, collect the solid, and dry under vacuum to obtain a yellow-green powdery solid weighing 894.7g, yield: 85.95% (overall yield of two steps).

[0067] Salt formation: Add 300.0g of dried 6S-5-methyltetrahydrofolate, 3L of purified water, and 1.15g of vitamin C to a 10L three-necked flask. Add 30% sodium hydroxide solution dropwise at room temperature until the system is completely dissolved. 362.3g 725 mL of CaCl2 aqueous solution was added dropwise to the above reaction solution. After the addition was complete, the temperature was raised to 80 °C, and the system was dissolved. 3 L of ethanol-isopropanol (volume ratio = 4:1) was slowly added dropwise to obtain a mixed solvent. After the addition was complete, the mixture was stirred to induce crystallization for 2 h. The solid was collected by vacuum filtration and dried under vacuum to obtain a white powdery solid, which is the target product L-5-methyltetrahydrofolate calcium, weighing 237.5 g, with a yield of 73.10%.

[0068] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0069] Furthermore, the above-described embodiments merely illustrate several implementation methods of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A method for synthesizing L-5-methyltetrahydrofolate, characterized in that, The process includes the following steps: using folic acid as a raw material, 6S-tetrahydrofolic acid is generated by asymmetric hydrogenation reduction in the presence of a catalyst, diiodo(p-cymene)ruthenium(II) dimer, and a chiral ligand (rp,rp)-1,1-bis[bis(4-methoxy-3,5-dimethylphosphino]-2,2-bis[(R)-α-(dimethylamino)benzyl]ferrocene. In the asymmetric hydrogenation reduction reaction, folic acid is used as the reference, and the amount of the catalyst, ruthenium(II) diiodide (p. cymene) dimer, is 0.2‰ to 0.4‰ equivalent. In the asymmetric hydrogenation reduction reaction, the molar ratio of the catalyst diiodide (p-cymene)ruthenium(II) dimer to the chiral ligand (rp,rp)-1,1-bis[bis(4-methoxy-3,5-dimethylyl)phosphino]-2,2-bis[(R)-α-(dimethylamino)benzyl]ferrocene is 1:(1.7-2.2).

2. The method for synthesizing L-5-methyltetrahydrofolate as described in claim 1, characterized in that: In the asymmetric hydrogenation reduction reaction, the molar ratio of the catalyst diiodide (p-cymene)ruthenium(II) dimer to the chiral ligand (rp,rp)-1,1-bis[bis(4-methoxy-3,5-dimethylyl)phosphino]-2,2-bis[(R)-α-(dimethylamino)benzyl]ferrocene is 1:

2.

3. The method for synthesizing L-5-methyltetrahydrofolate as described in claim 1, characterized in that: The reaction time in the asymmetric hydrogenation reduction is 2.0–4.0 h.

4. The method for synthesizing L-5-methyltetrahydrofolate as described in claim 1, characterized in that: The hydrogen pressure in the asymmetric hydrogenation reduction reaction is 0.05–0.4 MPa.

Images