CN117886819A - Synthesis method of L-5-methyltetrahydrofolate and its calcium salt - Google Patents
Synthesis method of L-5-methyltetrahydrofolate and its calcium salt Download PDFInfo
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Abstract
The application specifically discloses a synthesis method of L-5-methyltetrahydrofolate and a calcium salt thereof, wherein folic acid is used as a starting material, and catalyst diiodide (p-cymene) ruthenium (II) dimer and chiral ligand (rp, rp) -1, 1-bis [ bis (4-methoxy-3, 5-xylyl) phosphino ] -2, 2-bis [ (R) -alpha- (dimethylamino) benzyl ] ferrocene are adopted to carry out asymmetric hydrogenation reduction, so that high stereoselectivity synthesis of 6S-tetrahydrofolate is realized. The 6S-tetrahydrofolic acid is subjected to reductive amination and salification in sequence, and the 6S-5-methyltetrahydrofolic acid calcium with high purity and stable crystal form can be obtained in high yield. The method has the advantages of simple and convenient reaction operation, short steps, high efficiency, low cost and high safety coefficient, and is suitable for industrial production.
Description
Technical Field
The application relates to the technical field of organic synthesis, in particular to a synthesis method of L-5-methyltetrahydrofolate and calcium salt thereof.
Background
L-5-methyltetrahydrofolate (also known as 6S-5-methyltetrahydrofolate), chemical name N- [4- [ [ (2-amino-1, 4,5,6,7, 8-hexahydro-4-oxo-5-methyl-6-pteridinyl) methyl ] amino ] benzoyl ] -L-glutamic acid, is the only drug in folic acid drugs that can permeate the blood brain barrier. The medicine has the following effects as a medicine: first, preventing and treating Alzheimer's disease; second, they are useful as antidotes for enhancing the compatibility of folic acid antagonists, particularly for enhancing the compatibility of methotrexate and methotrexate for the treatment of cancer; third, can be used to enhance the therapeutic effect of fluorinated pyrimidines; fourth, it can be used to reduce toxicity of dideoxytetrahydrofolate (dideazatetrahydrofolates) in chemotherapy; fifth, it can be used for treating autoimmune diseases such as psoriasis and rheumatoid arthritis. Sixth, administration of L-5-methyltetrahydrofolate also avoids the significant risk of vitamin B12 deficiency masking caused by folic acid alone. Meanwhile, the L-5-methyltetrahydrofolate calcium is also used for preventing fetal neural tube defects, arteriosclerosis, treating megaloblastic anemia and the like. At present, the L-5-methyltetrahydrofolate calcium is approved by the national Wei Jian Committee to be used as a new variety of food nutrition enhancers, has incomparable superiority of other folic acid medicines, and has very wide application and market prospect in the medical field.
At present, the synthesis method of L-5-methyltetrahydrofolate and calcium salt thereof has been reported. For example, chinese patent publication No. CN114957257a discloses a method for preparing calcium 5-methyltetrahydrofolate. In the synthetic line, folic acid is used as a raw material, sodium borohydride is used as a reducing agent, and a reduced product tetrahydrofolic acid is obtained; the tetrahydrofolic acid undergoes methylation reaction to obtain 5-methyltetrahydrofolic acid; and then the 5-methyltetrahydrofolate is subjected to acid dissolution refining treatment and then is mixed with calcium salt to generate the 5-methyltetrahydrofolate calcium.
The synthesis route still has the disadvantage of not being neglected: firstly, excessive sodium borohydride reducing agent is needed to be used, a large amount of hydrogen is generated in the post-treatment process, and potential safety hazards exist in industrial production; second, the product of the chemical reduction process is a mixture of two configurations (D/L) -tetrahydrofolate, and although the target configuration with purer optical purity can be obtained by chiral resolution, chiral resolution results in at least 50% of material being wasted and serious losses.
Disclosure of Invention
In order to solve the defects of the synthetic route of the L-5-methyltetrahydrofolate and the calcium salt thereof, the application provides a synthetic method of the L-5-methyltetrahydrofolate and the calcium salt thereof, so that the synthetic route of the L-5-methyltetrahydrofolate and the calcium salt thereof is short, simple and safe to operate, suitable for industrial production, high in yield and purity of the final product and stable in crystal form of the product.
In a first aspect, the application provides a synthesis method of L-5-methyltetrahydrofolate, which adopts the following technical scheme:
A synthesis method of L-5-methyltetrahydrofolate comprises the following steps:
Folic acid is used as a raw material, and is subjected to asymmetric hydrogenation reduction under the action of a catalyst diiodide (p-cymene) ruthenium (II) dimer and chiral ligand (rp, rp) -1, 1-bis [ bis (4-methoxy-3, 5-xylyl) phosphino ] -2, 2-bis [ (R) -alpha- (dimethylamino) benzyl ] ferrocene to generate 6S-tetrahydrofolic acid.
Furthermore, in the asymmetric hydrogenation reduction reaction, based on folic acid, the dosage of the catalyst diiodide (p-cymene) ruthenium (II) dimer is 0.2 to 0.4 per mill equivalent.
Furthermore, the dosage of the catalyst diiodide (p-cymene) ruthenium (II) dimer in the asymmetric hydrogenation reduction reaction is 0.2 per mill equivalent based on folic acid.
Further, the molar ratio of the catalyst diiodium (p-cymene) ruthenium (II) dimer to chiral ligand (rp, rp) -1, 1-bis [ bis (4-methoxy-3, 5-xylyl) phosphino ] -2, 2-bis [ (R) -alpha- (dimethylamino) benzyl ] ferrocene in the asymmetric hydrogenation reduction reaction is 1 (1.7-2.2).
Further, 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-xylyl) phosphino ] -2, 2-bis [ (R) -alpha- (dimethylamino) benzyl ] ferrocene in the asymmetric hydrogenation reduction reaction is 1:2.
Further, the solvent used in the asymmetric hydrogenation reduction reaction is a mixed solvent system of an alcohol proton solvent and water (volume ratio is 1:1).
Still further, the alcoholic protic solvent satisfies at least one of the following characteristics: methanol, ethanol, isopropanol and t-butanol.
More preferably, the alcoholic protic solvent is methanol.
Further, an alkali cosolvent is added into the solvent.
Still further, the base 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.
More preferably, the base co-solvent is a 30wt% strength sodium hydroxide solution.
Further, the hydrogen pressure in the asymmetric hydrogenation reduction reaction is 0.05-0.4 MPa.
Further, the hydrogen pressure in the asymmetric hydrogenation reduction reaction is 0.1-0.2 MPa.
Further, the reaction temperature in the asymmetric hydrogenation reduction is 20-40 ℃.
Further, the asymmetric hydrogenation reduction reaction temperature is 40-45 ℃.
Further, the reaction time in the asymmetric hydrogenation reduction is 2.0-4.0 h.
Further, the reaction time in the asymmetric hydrogenation reduction was 3.0h.
In a second aspect, the application provides a method for synthesizing L-5-methyltetrahydrofolate calcium, which adopts the following technical scheme:
a synthesis method of L-5-methyltetrahydrofolate calcium comprises the following steps:
The 6S-tetrahydrofolic acid prepared by the synthesis method of the L-5-methyltetrahydrofolic acid is used as a raw material, and the L-5-methyltetrahydrofolic acid calcium is obtained through the steps of reductive amination and salification.
Further, the specific operation of the reductive amination step is as follows:
Adding formaldehyde solution into a 6S-tetrahydrofolate reaction system, controlling the reaction temperature to be 0-30 ℃, and carrying out heat preservation reaction for 0.5-2.0 h; adding sodium borohydride into a 6S-tetrahydrofolate reaction system, controlling the reaction temperature to be 60-80 ℃, carrying out heat preservation reaction for 1.0-3.0 h, adding a stabilizer, adjusting the pH value to be 4.0-4.5, and crystallizing to obtain 6S-5-methyltetrahydrofolate;
Wherein, the dosage of formaldehyde is 1.2 to 1.5 equivalents and the dosage of sodium borohydride is 2.0 to 4.0 equivalents based on 6S-tetrahydrofolate.
Further, the amount of formaldehyde used in the reductive amination step was 1.3 equivalents.
Still further, the amount of sodium borohydride used in the reductive amination step was 3.0 equivalents.
Further, the stabilizer is sodium ascorbate.
Further, the specific operation of the salifying step is as follows:
Adding soluble calcium salt into a 6S-5-methyltetrahydrofolate reaction system and adjusting the system to be dissolved, controlling the crystallization temperature to be 60-90 ℃, adding a poor solvent, and crystallizing to obtain the L-5-methyltetrahydrofolate calcium.
Further, the amount of calcium chloride used in the salification step was 4 equivalents.
Further, the poor solvent in the salifying step satisfies at least one of the following characteristics: methanol, ethanol, isopropanol, acetonitrile and tetrahydrofuran.
Further, the poor solvent in the salifying step is ethanol: isopropanol=4: 1.
The application has at least the following beneficial effects:
Firstly, the application provides a novel method for synthesizing 6S-tetrahydrofolate efficiently and conveniently, solves the problems of impurity introduction, material loss and low yield caused by subsequent resolution, and develops a novel method for obtaining high-purity and stable crystal form L-5-methyltetrahydrofolate calcium with high yield by a strategy of temperature control and bidirectional regulation of a crystallization mode in a crystallization process.
Secondly, the raw materials used in the preparation method are easy to obtain, and meanwhile, the method is mild in reaction condition, suitable for large-scale industrial production, high in safety and low in cost.
Thirdly, the disclosed experimental method is simple, the process is advanced, the three wastes generated in the production process are less, the environment-friendly pressure is low, the yield is high, the product purity is high, and the method is suitable for industrial production.
Drawings
FIG. 1 shows the XRD pattern of calcium L-5-methyltetrahydrofolate obtained in example 1 of the present application.
Detailed Description
Catalytic hydrogenation is a common method used early to reduce folic acid to tetrahydrofolate. However, the method uses noble metal as a catalyst, has high price, high reaction activation energy and harsh reaction conditions, and meanwhile, the product also needs chiral resolution, so that the application of the method is greatly limited.
In view of the above, the asymmetric reduction method has been developed in recent years as a new method for efficiently constructing chemical bonds such as saturated carbon-carbon bonds and carbon-nitrogen bonds. The chinese patent with publication No. CN113603691a discloses an asymmetric hydrogenation catalytic mode of folic acid, and this synthetic route uses folic acid as raw material, and reduces to generate (6S) -tetrahydrofolic acid under the action of Rh procatalyst and diphosphine ligand system, and the yield of (6S) -tetrahydrofolic acid is 90.0%. Also, this patent discloses a synthetic route for 6S-5-methyltetrahydrofolate, in which (6S) -5, 10-methyltetrahydrofolate is first cyclized under the catalysis of trifluoroacetic acid and then ring-opened to give 6S-5-methyltetrahydrofolate. The catalytic system of the patent has relatively poor stereoselectivity, the diastereoisomer excess value is more than 86 percent, and the chiral resolution is still needed to assist in purifying the target configuration. Meanwhile, the method has complex whole process and multiple steps, and is not beneficial to industrial production.
Chinese patent publication No. CN1781919a discloses a process for preparing optically pure tetrahydropterin and its derivatives, especially optically pure tetrahydrofolate and its derivatives, by stereospecific hydrogenation, in which various ruthenium, rhodium etc. metal complex catalysts and various chiral ligands are disclosed, and examples are given to demonstrate that different catalysts and chiral ligand combinations differ in final yields and purities of the products in asymmetric catalytic hydrogenation reactions. In addition, for the synthesis of the tetrahydrofolic acid with the target configuration, corresponding folic acid ester or folic acid ester salt is synthesized from folic acid, and then the tetrahydrofolic acid with the corresponding configuration is obtained by hydrolysis after asymmetric catalytic hydrogenation, so that the reaction steps are increased, and the risk of generating benzenesulfonate gene toxic impurities is increased.
Based on the above circumstances, the present inventors developed a novel synthesis method of L-5-methyltetrahydrofolate and its calcium salt, using folic acid as a starting material, and adopting catalyst diiodium (p-cymene) ruthenium (II) dimer and chiral ligand (rp, rp) -1, 1-bis [ bis (4-methoxy-3, 5-xylyl) phosphino ] -2, 2-bis [ (R) -alpha- (dimethylamino) benzyl ] ferrocene to perform asymmetric hydrogenation reduction, thereby realizing high stereoselective synthesis of 6S-tetrahydrofolate. In addition, the system has high catalytic efficiency and low cost, and avoids material waste caused by chiral resolution. The crystallization conditions are controlled from two dimensions of crystallization temperature and crystallization mode, and the obtained product has stable crystal form and high purity. In addition, in the synthesis method, the 6S-tetrahydrofolate is reduced into the 6S-5-methyltetrahydrofolate in one step, and cyclization and ring opening are not needed. Meanwhile, the high-purity L-5-methyltetrahydrofolate calcium can be obtained without refining the 6S-5-methyltetrahydrofolate in the synthesis method. The method has the advantages of simple and convenient reaction operation, short steps, high efficiency, low cost and high safety coefficient, and is suitable for industrial production.
In order to make the objects, technical solutions and advantages of the present application more apparent, the technical solutions of the present application will be further described below with reference to examples.
Examples
Example 1
The synthesis method of the L-5-methyltetrahydrofolate and the calcium salt thereof comprises the following steps:
Asymmetric catalytic hydrogenation: adding 2L of purified water and 1kg of folic acid into a 5L hydrogenation kettle, stirring, and adding 182g of 30% aqueous solution of sodium hydroxide into the reaction kettle to dissolve the system; sealing the kettle, replacing air in the reaction kettle with nitrogen for three times, continuously introducing nitrogen until the pressure in the kettle reaches 0.3MPa, maintaining the pressure, heating the feed liquid to 45 ℃, and stirring for 10min; weighing 0.96g of (rp, rp) -1, 1-bis [ bis (4-methoxy-3, 5-xylyl) phosphino ] -2, 2-bis [ (R) -alpha- (dimethylamino) benzyl ] ferrocene and 0.44g of diiodo (p-cymene) ruthenium (II) dimer, and dissolving the mixture with a proper amount of absolute ethyl alcohol to prepare a catalyst mixed solution; adding the prepared catalyst mixed solution into a hydrogenation kettle, carrying out nitrogen substitution for 3 times, and carrying out hydrogen substitution for 3 times; introducing hydrogen into the hydrogenation kettle, controlling the temperature in the kettle to be 45 ℃, maintaining the pressure to be 0.2MPa, and carrying out hydrogenation reaction for 3 hours until the reaction is complete; the reaction kettle is depressurized, the kettle is opened after 3 times of replacement by nitrogen, the reaction liquid is poured out, 4.0g of vitamin C is added, 2M hydrochloric acid is used for adjusting the pH value of the feed liquid to be 2.0-3.0, the mixture is centrifuged, and the solid is collected to be the 6S-tetrahydrofolate, and the next reaction is directly carried out without drying.
Reductive amination: adding 3L of purified water and the wet solid obtained in the first embodiment into a 5L three-port bottle, cooling to 10 ℃, dropwise adding 30% sodium hydroxide aqueous solution to dissolve the system, adding 1.3 equivalent of 37wt% formaldehyde aqueous solution, and after adding, keeping the temperature at 10 ℃ and stirring for reaction for 1h; slowly adding 3 equivalents of sodium borohydride into the system, heating to 60 ℃ after adding, and preserving heat for 2.0h; after the reaction is finished, 4.0g of vitamin C is added into the system, the pH=4.0-4.5 is regulated by using 2M hydrochloric acid, the temperature is kept for crystallization for 2 hours, the pressure is reduced, the suction filtration is carried out, the solid is collected, the vacuum drying is carried out, the yellowish green powdery solid is obtained, the weight is 890.0g, and the yield is: 85.50% (overall two-step yield).
1H 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;2.936-2.948,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;13C 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.
Salt formation: adding 300.0g of dried 6S-5-methyltetrahydrofolate, 3L of purified water and 1.15g of vitamin C into a 10L three-mouth bottle, dropwise adding 30% sodium hydroxide solution at room temperature until the system is dissolved, dropwise adding 725mL of water solution of 362.3gCaCl 2 into the reaction liquid, heating to 60 ℃ after the addition, slowly dropwise adding 3L of ethanol-isopropanol (volume ratio=4:1) to obtain a mixed solvent, stirring and crystallizing for 2h after the addition, decompressing and filtering, collecting solid, and vacuum drying to obtain white powdery solid, namely the target product L-5-methyltetrahydrofolate calcium, and weighing 243.7g, wherein the yield: 75.0%.
1H 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;3.052-3.131,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;13C NMR(DMSO-d6,100MHz)δ28.607,34.377,35.742,42.648,43.417,55.025,55.916,102.469,112.897,121.588,129.090,152.015,153.731,159.259,169.908,170.708,179.350,182.449;MS(m/z,M-H-)＝458.18.
Referring to FIG. 1, the XRD pattern of calcium L-5-methyltetrahydrofolate can be seen to be in a stable crystalline form.
Example 2
The synthesis method of the L-5-methyltetrahydrofolate and the calcium salt thereof comprises the following steps:
asymmetric catalytic hydrogenation: adding 2L of purified water and 1kg of folic acid into a 5L hydrogenation kettle, stirring, and adding 182g of 30% aqueous solution of sodium hydroxide into the reaction kettle to dissolve the system; sealing the kettle, replacing air in the reaction kettle with nitrogen for three times, continuously introducing nitrogen until the pressure in the kettle reaches 0.2MPa, maintaining the pressure, heating the feed liquid to 40 ℃, and stirring for 5min; weighing 1.44g of (rp, rp) -1, 1-bis [ bis (4-methoxy-3, 5-xylyl) phosphino ] -2, 2-bis [ (R) -alpha- (dimethylamino) benzyl ] ferrocene and 0.4g of diiodide (p-cymene) ruthenium (II) dimer, and dissolving the mixture with a proper amount of absolute ethyl alcohol to prepare a catalyst mixed solution; adding the prepared catalyst mixed solution into a hydrogenation kettle, carrying out nitrogen substitution for 3 times, and carrying out hydrogen substitution for 3 times; introducing hydrogen into the hydrogenation kettle, controlling the temperature in the kettle to be 40 ℃, maintaining the pressure to be 0.2MPa, and carrying out hydrogenation reaction for 2.5 hours until the reaction is complete; the reaction kettle is depressurized, the kettle is opened after 3 times of replacement by nitrogen, the reaction liquid is poured out, 4.0g of vitamin C is added, 2M hydrochloric acid is used for adjusting the pH value of the feed liquid to be 2.0-3.0, the mixture is centrifuged, and the solid is collected to be the 6S-tetrahydrofolate, and the next reaction is directly carried out without drying.
Reductive amination: adding 3L of purified water and the wet solid obtained in the first embodiment into a 5L three-port bottle, cooling to 5 ℃, dropwise adding 30% sodium hydroxide aqueous solution to dissolve the system, adding 1.2 equivalent of 37% formaldehyde aqueous solution, and after adding, keeping the temperature at 5 ℃ and stirring for reaction for 1h; slowly adding 2 equivalents of sodium borohydride into the system, heating to 70 ℃ after adding, and preserving heat for reaction for 3.0h; after the reaction is finished, 4.0g of vitamin C is added into the system, the pH=4.0-4.5 is regulated by 2M hydrochloric acid, the temperature is kept for crystallization for 2 hours, the pressure is reduced, the suction filtration is carried out, the solid is collected, the vacuum drying is carried out, the yellowish green powdery solid is obtained, the weight is 873.2g, and the yield is: 83.89% (overall two-step yield).
Salt formation: adding 300.0g of dried 6S-5-methyltetrahydrofolate, 3L of purified water and 1.15g of vitamin C into a 10L three-mouth bottle, dropwise adding 30% sodium hydroxide solution at room temperature until the system is dissolved, dropwise adding 725mL of water solution of 362.3gCaCl 2 into the reaction liquid, heating to 75 ℃ after the addition, slowly dropwise adding 3L of ethanol-isopropanol (volume ratio=4:1) to obtain a mixed solvent, stirring and crystallizing for 2h after the addition, decompressing and filtering, collecting solid, and vacuum drying to obtain white powdery solid, namely the target product L-5-methyltetrahydrofolate calcium, weighing 221.4g, and obtaining the yield: 68.13%.
Example 3
The synthesis method of the L-5-methyltetrahydrofolate and the calcium salt thereof comprises the following steps:
Asymmetric catalytic hydrogenation: adding 2L of purified water and 1kg of folic acid into a 5L hydrogenation kettle, stirring, and adding 182g of 30% aqueous solution of sodium hydroxide into the reaction kettle to dissolve the system; sealing the kettle, replacing air in the reaction kettle with nitrogen for three times, continuously introducing nitrogen until the pressure in the kettle reaches 0.4MPa, maintaining the pressure, heating the feed liquid to 45 ℃, and stirring for 10min; 1.92g of (rp, rp) -1, 1-bis [ bis (4-methoxy-3, 5-xylyl) phosphino ] -2, 2-bis [ (R) -alpha- (dimethylamino) benzyl ] ferrocene and 0.52g of diiodo (p-cymene) ruthenium (II) dimer are weighed, and dissolved in a proper amount of absolute ethyl alcohol to prepare a catalyst mixed solution; adding the prepared catalyst mixed solution into a hydrogenation kettle, carrying out nitrogen substitution for 3 times, and carrying out hydrogen substitution for 3 times; introducing hydrogen into the hydrogenation kettle, controlling the temperature in the kettle to be 45 ℃, maintaining the pressure to be 0.2MPa, and carrying out hydrogenation reaction for 3 hours until the reaction is complete; the reaction kettle is depressurized, the kettle is opened after 3 times of replacement by nitrogen, the reaction liquid is poured out, 4.0g of vitamin C is added, 2M hydrochloric acid is used for adjusting the pH value of the feed liquid to be 2.0-3.0, the mixture is centrifuged, and the solid is collected to be the 6S-tetrahydrofolate, and the next reaction is directly carried out without drying.
Reductive amination: adding 3L of purified water and the wet solid obtained in the first embodiment into a 5L three-port bottle, cooling to 0 ℃, dropwise adding 30% sodium hydroxide aqueous solution to dissolve the system, adding 1.5 equivalent of 37% formaldehyde aqueous solution, and after adding, keeping the temperature at 0 ℃ and stirring for reaction for 3 hours; slowly adding 4 equivalents of sodium borohydride into the system, heating to 80 ℃ after adding, and preserving heat for reaction for 3.0h; after the reaction is finished, 4.0g of vitamin C is added into the system, the pH=4.0-4.5 is regulated by 2M hydrochloric acid, the temperature is kept for crystallization for 2 hours, the pressure is reduced, the suction filtration is carried out, the solid is collected, the vacuum drying is carried out, the yellowish green powdery solid is obtained, the weight is 894.7g, and the yield is: 85.95% (overall two-step yield).
Salt formation: adding 300.0g of dried 6S-5-methyltetrahydrofolate, 3L of purified water and 1.15g of vitamin C into a 10L three-mouth bottle, dropwise adding 30% sodium hydroxide solution at room temperature until the system is dissolved, dropwise adding 725mL of water solution of 362.3gCaCl 2 into the reaction liquid, heating to 80 ℃ after the addition, slowly dropwise adding 3L of ethanol-isopropanol (volume ratio=4:1) to obtain a mixed solvent, stirring and crystallizing for 2h after the addition, decompressing and filtering, collecting solid, and vacuum drying to obtain white powdery solid, namely the target product L-5-methyltetrahydrofolate calcium, weighing 237.5g, and obtaining the yield: 73.10%.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
Moreover, the foregoing examples are illustrative of only a few embodiments of the invention, and are not intended to limit the scope of the invention in any way. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (10)
1. The synthesis method of the L-5-methyltetrahydrofolate is characterized by comprising the following steps of: folic acid is used as a raw material, and is subjected to asymmetric hydrogenation reduction under the action of a catalyst diiodide (p-cymene) ruthenium (II) dimer and chiral ligand (rp, rp) -1, 1-bis [ bis (4-methoxy-3, 5-xylyl) phosphino ] -2, 2-bis [ (R) -alpha- (dimethylamino) benzyl ] ferrocene to generate 6S-tetrahydrofolic acid.
2. The method for synthesizing L-5-methyltetrahydrofolate according to claim 1, wherein: in the asymmetric hydrogenation reduction reaction, folic acid is used as a reference, and the dosage of the catalyst diiodide (p-cymene) ruthenium (II) dimer is 0.2-0.4 per mill equivalent.
3. The method for synthesizing L-5-methyltetrahydrofolate according to claim 1, wherein: the molar ratio of the catalyst diiodium (p-cymene) ruthenium (II) dimer to chiral ligand (rp, rp) -1, 1-bis [ bis (4-methoxy-3, 5-xylyl) phosphino ] -2, 2-bis [ (R) -alpha- (dimethylamino) benzyl ] ferrocene in the asymmetric hydrogenation reduction reaction is 1 (1.7-2.2).
4. A process for the synthesis of L-5-methyltetrahydrofolate according to claim 3, wherein: the molar ratio of the catalyst diiodium (p-cymene) ruthenium (II) dimer to the chiral ligand (rp, rp) -1, 1-bis [ bis (4-methoxy-3, 5-xylyl) phosphino ] -2, 2-bis [ (R) -alpha- (dimethylamino) benzyl ] ferrocene in the asymmetric hydrogenation reduction reaction is 1:2.
5. The method for synthesizing L-5-methyltetrahydrofolate according to claim 1, wherein: the reaction time in the asymmetric hydrogenation reduction is 2.0-4.0 h.
6. The method for synthesizing L-5-methyltetrahydrofolate according to claim 1, wherein: the hydrogen pressure in the asymmetric hydrogenation reduction reaction is 0.05-0.4 MPa.
7. A synthesis method of L-5-methyltetrahydrofolate calcium is characterized by comprising the following steps: the method comprises the following steps:
The method for synthesizing L-5-methyltetrahydrofolate according to any one of claims 1-6, wherein the L-5-methyltetrahydrofolate calcium is obtained by taking 6S-tetrahydrofolate as a raw material and performing reductive amination and salification steps.
8. The method for synthesizing the L-5-methyltetrahydrofolate calcium according to claim 7, wherein the method comprises the following steps: the specific operation of the reductive amination step is as follows:
Adding formaldehyde solution into a 6S-tetrahydrofolate reaction system, controlling the reaction temperature to be 0-30 ℃, and carrying out heat preservation reaction for 0.5-2.0 h; adding sodium borohydride into a 6S-tetrahydrofolate reaction system, controlling the reaction temperature to be 60-80 ℃, carrying out heat preservation reaction for 1.0-3.0 h, adding a stabilizer, adjusting the pH value to be 4.0-4.5, and crystallizing to obtain 6S-5-methyltetrahydrofolate;
Wherein, the dosage of formaldehyde is 1.2 to 1.5 equivalents and the dosage of sodium borohydride is 2.0 to 4.0 equivalents based on 6S-tetrahydrofolate.
9. The method for synthesizing the L-5-methyltetrahydrofolate calcium according to claim 7, wherein the method comprises the following steps: the specific operation of the salifying step is as follows:
adding a stabilizer into a 6S-5-methyltetrahydrofolate reaction system, regulating the system to dissolve, adding soluble calcium salt, controlling the crystallization temperature to be 60-90 ℃, adding a poor solvent, and crystallizing to obtain the L-5-methyltetrahydrofolate calcium.
10. The method for synthesizing the L-5-methyltetrahydrofolate calcium according to claim 7, wherein the method comprises the following steps: further, the poor solvent in the salifying step satisfies at least one of the following characteristics: methanol, ethanol, isopropanol, acetonitrile and tetrahydrofuran.
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| CN115974725A (en) * | 2022-12-15 | 2023-04-18 | 深圳市祥根生物医药有限公司 | Method for preparing pharmaceutical intermediate |
| CN116514815A (en) * | 2023-03-28 | 2023-08-01 | 北京斯利安药业有限公司 | Preparation method and application of L-5-methyltetrahydrofolate calcium |
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| CN115974725A (en) * | 2022-12-15 | 2023-04-18 | 深圳市祥根生物医药有限公司 | Method for preparing pharmaceutical intermediate |
| CN116514815A (en) * | 2023-03-28 | 2023-08-01 | 北京斯利安药业有限公司 | Preparation method and application of L-5-methyltetrahydrofolate calcium |
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