CN112125906A - S-5-methyl tetrahydrofolic acid amino acid ester salt and synthesis method thereof - Google Patents

S-5-methyl tetrahydrofolic acid amino acid ester salt and synthesis method thereof Download PDF

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CN112125906A
CN112125906A CN202011159915.9A CN202011159915A CN112125906A CN 112125906 A CN112125906 A CN 112125906A CN 202011159915 A CN202011159915 A CN 202011159915A CN 112125906 A CN112125906 A CN 112125906A
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amino acid
acid ester
methyltetrahydrofolate
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由君
井彬
武文菊
喻艳超
刘波
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Harbin University of Science and Technology
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Abstract

The invention mainly relates to S-5-methyltetrahydrofolate amino acid ester salt and a synthesis method thereof. The S-5-methyltetrahydrofolate amino acid ester salt has the following structure: s-5-methyl tetrahydrofolic acid monoamino acid ester salt.
Figure DDA0002743937900000011
The S-5-methyltetrahydrofolate amino acid ester salt is prepared by the following method: suspending S-5-methyltetrahydrofolic acid in ethanol water solution with certain concentration, adding corresponding free amino acid ester ethanol solution with equal molar weight, stirring and reacting for 6-8 hours at certain temperature, and gradually dissolving S-5-methyltetrahydrofolic acid to generate transparent solution. Concentrating the reaction solution under reduced pressure to 1/4 of the original volume, standing at low temperature for 12 hours, and filtering to remove the mother solution to obtain the microcrystalline S-5-methyltetrahydrofolic acid monoamino acid ester salt. HPLC detection results show that the purity of the S-5-methyltetrahydrofolate amino acid ester salt is more than 97.5 percent.

Description

S-5-methyl tetrahydrofolic acid amino acid ester salt and synthesis method thereof
Technical Field
The invention relates to a structure of a series of S-5-methyltetrahydrofolate amino acid ester salts and a preparation method thereof, belonging to the technical field of fine chemical engineering.
Background
S-5-methyltetrahydrofolic acid is a novel folic acid drug, and is gradually known as a main component of food additives and nutritional health products. The S-5-methyltetrahydrofolic acid participates in a plurality of important biochemical reactions in vivo and has important pharmacological action. The medicine can penetrate blood brain barrier, and can be used for preventing senile dementia and cell anemia. Compared with other medicines, the S-5-methyltetrahydrofolic acid has the characteristics of remarkable curative effect, complete functions and less side effects, and gradually becomes a focus of common attention in the medical and pharmaceutical research fields.
S-5-methyltetrahydrofolic acid has low solubility in water and poor stability, so that S-5-methyltetrahydrofolic acid is generally converted into various salts in practical application, such as S-5-methyltetrahydrofolic acid sodium salt, S-5-methyltetrahydrofolic acid calcium salt, S-5-methyltetrahydrofolic acid glucosamine salt, amino acid salt and the like.
The aqueous solution of sodium S-5-methyltetrahydrofolate is strongly alkaline, which leads to a decrease in its stability. In addition, the strong alkalinity makes the biological agent enter into organisms and possibly causes some adverse reactions. Therefore, the S-5-methyl tetrahydrofolate sodium salt is rarely used as a preparation product and directly enters the market, and is more used as an intermediate in the synthesis of folic acid derivatives.
S-5-methyltetrahydrofolate calcium salt is also a more studied salt, and is classified into amorphous and crystalline. Compared with S-5-methyltetrahydrofolic acid, the water solubility and the stability of the compound are both improved to a certain extent. The calcium salt has potential high calcium intake risk in application as a medicament or food additive, and has the possibility of aggravating kidney stones, inducing hypercalcemia and interfering absorption of microelements such as iron, magnesium, zinc, phosphorus and the like. Therefore, calcium S-5-methyltetrahydrofolate is also generally used as an intermediate in the synthesis of 5-methyltetrahydrofolate derivatives.
The S-5-methyltetrahydrofolate glucosamine salt is the only S-5-methyltetrahydrofolate derivative entering health care medicines and food additives at present. It has better water solubility, high storage stability and good market prospect. Its salifying ligand is glucosamine, which has the function of assisting cartilage repair, but excessive ingestion of glucosamine still has a large risk. Research shows that excessive administration of glucosamine can cause adverse reaction of gastrointestinal tract, and symptoms such as nausea, abdominal distension, abdominal pain and the like are caused. In addition, in animal experiments, glucosamine is found to increase the sensitivity of insulin antagonism and increase the risk of diabetes.
The invention patents CN107304212A and CN103664945A report the preparation method of S-5-methyl tetrahydrofolate amino acid salt. The patent CN107304212A is that 5-methyl tetrahydrofolic acid is dissolved in alkali solution to generate alkali metal salt of 5-methyl tetrahydrofolic acid, then amino acid or amino acid salt is added, hydrochloric acid is used to adjust the acidity of the solution, and ethanol or acetone is added to precipitate and obtain the product. The method of patent CN103664945A is similar to the above method, except that 5-methyltetrahydrofolate calcium salt is used as raw material, and the subsequent operations are basically the same.
Amino acids are the constituent compounds of organisms and have the best compatibility with organisms. When the amino acid is used as the ligand of the 5-methyltetrahydrofolate for health care medicine and food additives, the side effect on human bodies is obviously less than that of other ligands, so the development direction of the 5-methyltetrahydrofolate is supposed to be in progress. However, there is a significant drawback in both of the above patents: the 5-methyltetrahydrofolate synthesized by the method is not a compound with a precise structure, but a mixture of 5-methyltetrahydrofolate amino acid salt and inorganic salt (sodium chloride or calcium chloride). Because the inorganic salt generated by the reaction has almost the same solubility property as 5-methyltetrahydrofolate amino acid salt, namely is easy to dissolve in water and not soluble in ethanol or acetone. The synthesis process is that double decomposition reaction of 5-methyl tetrahydrofolate and amino acid salt is carried out in aqueous solution to generate a mixture of 5-methyl tetrahydrofolate amino acid salt and inorganic salt (sodium chloride or calcium chloride), and then ethanol or acetone is added to precipitate the 5-methyl tetrahydrofolate amino acid salt, but the problem is that the inorganic salt is precipitated simultaneously under the condition, so that only the mixture of the 5-methyl tetrahydrofolate amino acid salt and the inorganic salt can be obtained. In addition, since the amino acid itself also has free carboxyl groups, under the synthesis conditions given in the patent art (pH6-7), the carboxyl groups in the amino acid molecule are also present in the form of negative ions, and it is also possible to bind inorganic ions such as Ca2+ or Na + and the like. In this way, the advantage of choosing an amino acid as a 5-methyltetrahydrofolate ligand is undermined, since the product contains almost equimolar amounts of inorganic ions.
In summary, the selection of amino acids as ligands for 5-methyltetrahydrofolate is the development of the product in the future, but the problems of using amino acids directly as ligands must be overcome.
Disclosure of Invention
In order to overcome the problems in the synthesis of 5-methyltetrahydrofolate, the invention creatively uses the amino acid ester as the ligand of the 5-methyltetrahydrofolate amino acid salt, and uses free 5-methyltetrahydrofolate without any metal ions to directly react with the free amino acid ester to generate the amino acid ester salt of the 5-methyltetrahydrofolate. The reaction formula is as follows:
Figure BDA0002743937880000021
as can be seen from the reaction formula, no by-product is generated in the reaction process, and the carboxyl in the 5-methyltetrahydrofolic acid can quantitatively react with the amino in the amino acid ester to generate the corresponding salt. At this time, the molecular composition of the 5-methyltetrahydrofolate amino acid ester salt is completely determined.
In consideration of the compatibility problem of human bodies, 8 kinds of human essential amino acids are selected as salifying ligands, and consumers using the product can supplement 5-methyltetrahydrofolic acid and take the human essential amino acids simultaneously, so that the double nutrition and health care effects are achieved.
The invention has the following beneficial effects:
1. the 5-methyltetrahydrofolic acid amino acid ester salt with determined composition is obtained by reacting free 5-methyltetrahydrofolic acid without metal with free amino acid, and the product has high purity and does not contain any inorganic salt.
2. The essential amino acid of human body is used as a salifying ligand, and the essential amino acid of human body is taken in by consumers while the 5-methyltetrahydrofolic acid is supplemented, so that double nutrition and health care effects are achieved.
The 3.5-methyltetrahydrofolate diamino acid ester salt increases the content of essential amino acid for human body, so that the product has the function of supplementing the essential amino acid for human body with higher efficiency.
4. The synthesis process is simple, the atom utilization rate of the reaction is 100 percent, and the synthesis process is an environment-friendly green synthesis process.
5. The product is in a microcrystalline state and has good water solubility and storage stability.
Drawings
FIG. 1 shows the preparation of S-5-Methyltetrahydrofolate monophenylalanine ethyl ester salt according to example 11HNMR spectrogram;
FIG. 2 shows the preparation of ethyl S-5-methyltetrahydrofolate monophenylalanine salt according to example 113C NMR chart;
FIG. 3 is an IR spectrum of S-5-methyl tetrahydrofolate monophenylalanine ethyl ester salt prepared in example 1;
FIG. 4 is a mass spectrum of ethyl ester of S-5-methyltetrahydrofolate monophenylalanine prepared in example 1;
FIG. 5 is a high performance liquid chromatography spectrum of S-5-methyl tetrahydrofolate monophenylalanine ethyl ester salt prepared in example 1;
FIG. 6 shows the preparation of S-5-methyltetrahydrofolate monophenylalanine methyl ester salt according to example 21HNMR spectrogram;
FIG. 7 is an IR spectrum of S-5-methyl tetrahydrofolate monophenylalanine methyl ester salt prepared in example 2;
FIG. 8 shows the preparation of n-butyl S-5-methyltetrahydrofolate monophenylalanine ester salt according to example 31HNMR spectrogram;
FIG. 9 is an infrared spectrum of the n-butyl ester salt of S-5-methyl tetrahydrofolate monophenylalanine prepared in example 3;
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The following examples describe the specific implementation processes of the present invention, but the present invention is not limited to the specific implementation modes listed below, and includes any combinations of the specific implementation modes.
HPLC test conditions:
the instrument is an UltMate 3000 column model CHRIALPAK QN-AX
The column temperature is 22 ℃, the sample injection amount is 10 mu L
Flow rate of 0.5 wavelength 254nm
The mobile phase comprises methanol, acetonitrile, glacial acetic acid and triethylamine, wherein the ratio of the mobile phase to the mobile phase is 50:50:2:1.6
Example 1.5 g of S-5-methyltetrahydrofolic acid was suspended in 50ml of 20% ethanol aqueous solution, 3.2g of ethyl phenylalanine were dissolved in 10ml of ethanol solution, and the reaction was stirred at 50 ℃ for 8 hours, whereby S-5-methyltetrahydrofolic acid gradually reacted and dissolved to give a transparent solution. The reaction solution was concentrated under reduced pressure to 1/4 parts by volume, left at low temperature for 12 hours, and the mother liquor was removed by filtration to obtain a microcrystalline S-5-methyltetrahydrofolate monophenylalanine ester salt. The yield thereof was found to be 80%.
Structural data:1H NMR(300MHz,D2O)7.47(d,J＝8.6Hz,2H),7.29–7.06(m,5H),6.51(d,J＝9.1 Hz,2H),4.24–4.15(m,2H),4.11(q,J＝7.1Hz,2H),3.52–3.37(m,1H),3.25(d,J＝12.5Hz,2H),3.19– 3.03(m,2H),3.00(d,J＝8.3Hz,2H),2.59(s,3H),2.27–2.11(m,2H),2.11–1.79(m,2H),1.09(t,J＝7.2 Hz,3H)；13C NMR(75MHz,DMSO-d6)175.1,167.0,151.9,151.5,129.7,129.2,128.9,127.5,120.9, 111.5,99.6,61.7,55.0,54.4,43.4,43.0,36.1,31.1,27.2,14.1 ppm; IR (KBr pellet cm)-1): 3403, 2934, 1736, 1607, 1540, 1507, 1397, 1343, 1303, 1258, 1192, 1112, 1041, 838, 776, 701, 616; HRMS (m/z): 653.30480(M + H). ee value: 97.1 percent.
Example 2.5 g of S-5-methyltetrahydrofolate is suspended in 50ml of 20% aqueous methanol, 3.1g of phenylalanine methyl ester is dissolved in 10ml of methanol, and the reaction is carried out at 50 ℃ for 8 hours with stirring, whereby S-5-methyltetrahydrofolate gradually reacts and dissolves to give a transparent solution. The reaction solution was concentrated under reduced pressure to 1/4 parts by volume, left at low temperature for 12 hours, and the mother liquor was removed by filtration to obtain a microcrystalline S-5-methyltetrahydrofolate monophenylalanine methyl ester salt. The yield thereof was found to be 86%.
Structural data:1H NMR(300MHz,D2o)7.61(d, J ═ 8.6Hz,2H),7.43 to 7.22(m,5H),6.66(d, J ═ 8.6Hz,2H), 4.47 to 4.24(m,2H),3.81(s,3H),3.72 to 3.40(m,3H),3.36 to 3.14(m,4H),2.82(s,3H),2.45 to 2.29(m,2H),2.25 to 1.94(m, 2H); IR (KBr pellet cm)-1): 3387, 2925, 2856, 1607, 1556, 1544, 1503, 1450, 1401, 1381, 1344, 1262, 1185, 1131, 874, 867, 772, 702, 608, 596, 490; ee value: 97.8 percent.
Example 3.5 g S-5-methyltetrahydrofolic acid was suspended in 50ml of 20% n-butanol solution, 3.4g of n-butyl phenylalanine was dissolved in 10ml of n-butanol solution, and the reaction was stirred at 50 ℃ for 8 hours, whereby S-5-methyltetrahydrofolic acid was gradually reacted and dissolved to give a clear solution. The reaction solution was concentrated under reduced pressure to 1/4 parts by volume, left at low temperature for 12 hours, and the mother liquor was removed by filtration to obtain a microcrystalline n-butyl-S-5-methyltetrahydrofolate monophenylalanine. The yield thereof was found to be 71%.
Structural data:1H NMR(300MHz,D2o)7.63(d, J ═ 1.4Hz,2H), 7.51-7.04 (m,5H),6.65(d, J ═ 9.1 Hz,2H), 4.47-4.28 (m,2H),4.20(t, J ═ 7.0Hz,2H), 3.84-3.43 (m,3H), 3.42-3.13 (m,4H),2.91(s,3H), 2.39(d, J ═ 7.8Hz,2H), 2.28-1.93 (m,2H), 1.71-1.46 (m,2H), 1.39-1.16 (m,2H),0.86(t, J ═ 7.2Hz, 3H); IR (KBr pellet cm)-1): 3363, 2932, 1607, 1542, 1509, 1396, 1342, 1269, 1190, 1137, 838, 768, 704, 624; ee value: 98.1 percent.
Example 4.5 g S-5-methyltetrahydrofolic acid was suspended in 50ml of 20% ethanol aqueous solution, 2.4g of valine ester was dissolved in 10ml of ethanol solution, and the reaction was carried out at 50 ℃ for 8 hours with stirring, and S-5-methyltetrahydrofolic acid was gradually dissolved and reacted to give a transparent solution. Concentrating the reaction solution to 1/4 of the original volume by rotary evaporation under reduced pressure, standing at low temperature for 12 hours, and filtering to remove the mother liquor to obtain the micro-crystalline S-5-methyltetrahydrofolic acid monovaline ethyl ester salt. The yield thereof was found to be 79.3%.
Structural data:1H NMR(300MHz,D2o)7.59(d, J ═ 7.8Hz,2H),6.62(d, J ═ 9.3Hz,2H),4.41 to 4.03 (m,3H),3.95(d, J ═ 4.6Hz,1H),3.78 to 3.05(m,6H),2.84(s,3H),2.46 to 1.88(m,6H),1.20(dt, J ═ 37.3, 7.1Hz,3H),1.00(dd, J ═ 7.0,4.4Hz, 5H); IR (KBr pellet cm)-1): 3363, 2936, 1736, 1608, 1542, 1396, 1337, 1192, 1139, 1040, 842, 770, 629; HRMS (m/z): 605.30451(M + H). ee value: 97.6 percent.
Example 5.5 g S-5-methyltetrahydrofolic acid was suspended in 50ml of 20% ethanol aqueous solution, 2.6g of leucine ester was dissolved in 10ml of ethanol solution, and the reaction was stirred at 50 ℃ for 8 hours, whereby S-5-methyltetrahydrofolic acid was gradually dissolved to give a transparent solution. Concentrating the reaction solution to 1/4 of the original volume by rotary evaporation under reduced pressure, standing at low temperature for 12 hours, and filtering to remove the mother liquor to obtain the microcrystalline S-5-methyltetrahydrofolate monoleucine ethyl ester. The yield thereof was found to be 76%.
Structural data:1H NMR(300MHz,D2o)7.61(d, J ═ 8.5Hz,2H),6.64(d, J ═ 8.8Hz,2H), 4.40-4.16 (m,3H),4.08(dd, J ═ 7.9,6.1Hz,1H), 3.76-3.07 (m,5H),2.81(s,3H), 2.42-1.57 (m,8H),1.26(t, J ═ 7.2Hz, 3H),0.92(dd, J ═ 6.1,3.5Hz, 6H); IR (KBr pellet cm)-1): 3398, 2960, 1742, 1608, 1385, 1334, 1303, 1287, 1275, 1217, 1191, 1137, 843, 776, 624, 484; HRMS (m/z): 619.31948(M + H). ee value: 97.6 percent.
Example 6.5 g S-5-methyltetrahydrofolic acid was suspended in 50ml of 20% ethanol aqueous solution, 3.8g of tryptophan ester was dissolved in 10ml of ethanol solution, and the reaction was stirred at 50 ℃ for 8 hours, whereby S-5-methyltetrahydrofolic acid gradually reacted and dissolved to give a transparent solution. Concentrating the reaction solution to 1/4 of the original volume by rotary evaporation under reduced pressure, standing at low temperature for 12 hours, and filtering to remove the mother liquor to obtain the microcrystalline S-5-methyltetrahydrofolic acid ethyl ester salt of mono-amino-acetic acid. The yield thereof was found to be 58.5%.
Structural data:1H NMR(300MHz,D2O)7.57(t,J＝8.3Hz,4H),7.47(d,J＝8.1Hz,2H),7.29–7.09(m, 6H),6.64(d,J＝8.7Hz,2H),4.35(t,J＝6.4Hz,2H),4.18(q,J＝7.2Hz,4H),3.62(q,J＝7.1Hz,4H) 3.41 (dd, J ═ 6.5,2.2Hz,4H),2.54(s,3H),1.15(td, J ═ 7.1,3.4Hz, 11H); IR (KBr pellet cm)-1): 3392, 2974, 2931, 1736, 1608, 1458, 1388, 1341, 1303, 1258, 1234, 1189, 1156, 1126, 1099, 1046, 871, 744, 619; HRMS (m/z): 692.31587(M + H). ee value: 97.7 percent.
Example 7.5 g S-5-methyltetrahydrofolic acid was suspended in 50ml of 20% ethanol aqueous solution, 2.9g of lysine ester was dissolved in 10ml of ethanol solution, and the reaction was stirred at 50 ℃ for 8 hours, whereby S-5-methyltetrahydrofolic acid was gradually dissolved and reacted to give a transparent solution. Concentrating the reaction solution to 1/4 of the original volume by rotary evaporation under reduced pressure, standing at low temperature for 12 hours, and filtering to remove the mother liquor to obtain the microcrystalline S-5-methyltetrahydrofolate monolysine ethyl ester. The yield thereof was found to be 88.6%.
Structural data:1H NMR(300MHz,D2o)7.61(d, J ═ 8.3Hz,2H),6.66(d, J ═ 7.9Hz,2H), 4.38-4.15 (m,3H),4.03(t, J ═ 6.4Hz,1H),3.62(q, J ═ 7.1Hz,3H),3.46(d, J ═ 12.5Hz,1H), 3.34-2.83 (m,6H), 2.52(s,3H),2.29(t, J ═ 7.2Hz,2H), 2.20-1.77 (m,4H), 1.75-1.30 (m,4H),1.19(dt, J ═ 28.0,7.1Hz, 8H); IR (KBr pellet cm)-1): 3354, 2940, 1741, 1608, 1385, 1340, 1306, 1193, 1139, 1087, 840, 777, 628, 457; HRMS (m/z): 634.33100(M + H). ee value: 97.7 percent.
Example 8.5 g S-5-methyltetrahydrofolic acid was suspended in 50ml of 20% ethanol aqueous solution, 2.9g of methionine ester was dissolved in 10ml of ethanol solution, and the reaction was stirred at 50 ℃ for 8 hours, whereby S-5-methyltetrahydrofolic acid was gradually dissolved to give a transparent solution. Concentrating the reaction solution to 1/4 of the original volume by rotary evaporation under reduced pressure, standing at low temperature for 12 hours, and filtering to remove the mother liquor to obtain the micro-crystalline S-5-methyltetrahydrofolate monomethionate. The yield thereof was found to be 76.8%.
Structural data:1H NMR(300MHz,D2o)7.59(d, J ═ 8.6Hz,2H),6.62(d, J ═ 8.7Hz,2H), 4.47-4.09 (m,4H), 3.61(q, J ═ 7.1Hz,2H), 3.56-3.09 (m,4H),2.79(s,3H),2.63(t, J ═ 7.2Hz,2H), 2.49-2.09 (m,5H), 2.07(s,4H),1.20(dt, J ═ 36.4,7.1Hz, 5H); IR (KBr pellet cm)-1)：3350，2922，1742，1607，1586，1511， 1446，1398，1340，1303，1283，1217，1191, 1139, 1037, 1009, 837, 775, 628; HRMS (m/z): 637.27692(M + H). ee value: 97.7 percent.

Claims (7)

1. An S-5-methyl tetrahydrofolate amino acid ester salt and a synthesis method thereof are characterized in that the S-5-methyl tetrahydrofolate amino acid ester salt has the following structure: s-5-methyl tetrahydrofolic acid monoamino acid ester salt.
Figure FDA0002743937870000011
。
2. The S-5-methyltetrahydrofolate amino acid ester salt and the synthesis method thereof according to claim 1, wherein the amino acid ester of the S-5-methyltetrahydrofolate amino acid ester salt comprises 8 amino acids essential to human body, which are valine ester, leucine ester, isoleucine ester, methionine ester, tryptophan ester, phenylalanine ester, threonine ester and lysine ester.
3. The S-5-methyltetrahydrofolate amino acid ester salt and the synthesis method thereof according to claim 1, wherein the amino acid ester in the S-5-methyltetrahydrofolate amino acid ester salt comprises amino acid methyl ester, amino acid ethyl ester, amino acid propyl ester, amino acid isopropyl ester and amino acid butyl ester.
4. A synthetic method of S-5-methyl tetrahydrofolate amino acid ester salt is characterized by adopting the following synthetic method: suspending S-5-methyltetrahydrofolic acid in ethanol water solution with certain concentration, adding corresponding free amino acid ester ethanol solution with equal mole, stirring and reacting for 6-8 hours at a certain temperature, and gradually reacting and dissolving S-5-methyltetrahydrofolic acid to generate transparent solution. Concentrating the reaction solution under reduced pressure to 1/4 of the original volume, standing at low temperature for 12 hours, and filtering to remove the mother solution to obtain the microcrystalline S-5-methyltetrahydrofolic acid monoamino acid ester salt.
HPLC detection results show that the purity of the S-5-methyltetrahydrofolate amino acid ester salt is more than 97.5 percent.
5. The method for synthesizing S-5-methyltetrahydrofolate amino acid ester salt according to claim 4, wherein the concentration of the ethanol aqueous solution is 10-50% (V/V), and the more optimized concentration is 29-30% (V/V).
6. The method for synthesizing S-5-methyltetrahydrofolate amino acid ester salt according to claim 4, wherein the concentration of the free amino acid ester ethanol solution is 20%.
7. The method for synthesizing S-5-methyltetrahydrofolate amino acid ester salt according to claim 4, wherein the reaction temperature is 20-60 ℃.
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US20160207925A1 (en) * 2013-12-31 2016-07-21 Gianni Fracchia L-methylfolate salt preparations, medicaments, and nutritional supplements comprising such salts thereof
CN107304212A (en) * 2016-04-21 2017-10-31 常州爱诺新睿医药技术有限公司 A kind of unformed L-5- methyl tetrahydrofolates amino-acid salt and preparation method thereof
WO2020007839A1 (en) * 2018-07-06 2020-01-09 Merck Patent Gmbh Crystalline salts of 5-methyl-(6s)-tetrahydrofolic acid and l-leucine ethyl ester

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103664945B (en) * 2012-09-07 2016-01-20 南京莱因医药科技有限公司 The preparation method of L-5-methyl tetrahydrofolate amino acid salts
US20160207925A1 (en) * 2013-12-31 2016-07-21 Gianni Fracchia L-methylfolate salt preparations, medicaments, and nutritional supplements comprising such salts thereof
CN107304212A (en) * 2016-04-21 2017-10-31 常州爱诺新睿医药技术有限公司 A kind of unformed L-5- methyl tetrahydrofolates amino-acid salt and preparation method thereof
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