Product Overview

Folic Acid is a water-soluble vitamin with the molecular formula C19H19N7O6. Named for its abundance in green leaves, it is also known as Pteroylglutamic Acid. It exists in several forms in nature, with its parent compound being a combination of pteridine, para-aminobenzoic acid, and glutamic acid.

Folic Acid contains one or more glutamyl groups, and most naturally occurring folic acid exists in polyglutamate form. The biologically active form of folic acid is tetrahydrofolate. Folic Acid appears as a yellow crystalline powder, slightly soluble in water, but its sodium salt is highly soluble in water. It is insoluble in ethanol. Folic Acid is unstable in acidic solutions and easily degrades in the presence of heat and light, leading to significant losses at room temperature.

Folic Acid is absorbed in the body through active transport and passive diffusion, primarily in the upper small intestine. The reduced form of folic acid has a higher absorption rate; the more glutamyl groups, the lower the absorption rate. Glucose and vitamin C can enhance absorption. After absorption, folic acid is stored in the intestinal wall, liver, bone marrow, and other tissues. It is reduced to tetrahydrofolate (THFA or FH4) by folic acid reductase in the presence of NADPH, participating in the synthesis of purines and pyrimidines. Thus, folic acid plays a crucial role in protein synthesis, cell division, and growth, and promotes the formation of normal red blood cells. A deficiency can lead to reduced hemoglobin production in red blood cells and hinder cell maturation, causing megaloblastic anemia.

Folic Acid Production Process

Using nitrobenzoic acid as a raw material

The traditional method for synthesizing folic acid involves nitrobenzoic acid and goes through acyl chloride formation, condensation, reduction, and cyclization to finally produce folic acid. Although this method can synthesize folic acid, it has a complex synthetic route, long production time, high production cost, and low yield, making it unsuitable for large-scale production. The reaction equation is shown in Figure 1.1:

Using 2-hydroxypropanal as an intermediate

In 1994, C. Villey and others proposed using 2-hydroxypropanal as an intermediate to synthesize folic acid via a one-pot method. 2-Substituted propanal exists in two tautomeric forms, Ia and Ib, as shown in Figure 1.2:

The reaction involves 2-hydroxypropanal and two molecules of L-N-para-aminobenzoylglutamic acid to produce a corresponding diimine structure. In the presence of sulfite, the mixture reacts with 6-hydroxy-2,4,5-triaminopyrimidine at pH 3-8 and 0-100°C to produce folic acid. The reaction can occur in an aqueous solution or a water-miscible inert organic solvent like acetonitrile, dimethylformamide, tetrahydrofuran, methanol, or ethanol. Preferably, water is used as the solvent. If a mixed solvent is used, the inert solvent must be water-miscible, with a water content greater than 30%. The reaction equation is shown in Figure 1.3:

Specific procedure: Under nitrogen protection, add 5.32g of para-aminobenzoylglutamic acid, 20mL of 0.1 mol/L HCl to a 100mL five-neck flask, then add 0.88g of 2-hydroxypropanal and 3mL of water, and stir at room temperature for 1 hour. Then add 2.52g of Na2SO3, stir, and heat to 38°C, adding 2.39g of triaminopyrimidine sulfate in batches over 1 hour. Adjust the pH to 6.0 with 2mol/L Na2CO3 solution and react for 4 hours. Adjust the pH of the reaction mixture to 3.0 with acetic acid to precipitate folic acid, filter, and obtain 3.08g of crude folic acid with a yield of 63.5% after purification.

Although the yield is improved, the production cost is high, requiring nitrogen protection, and 2-hydroxypropanal is difficult to prepare.

C. Villey et al. attempted another method, using 1,1,3,3-tetramethoxypropane hydrolyzed under acidic conditions to obtain 2-hydroxypropanal, as shown in Figure 1.4. 2-Hydroxypropanal reacts with para-aminobenzoyl-L-glutamic acid to obtain the corresponding diimine solid, which is then reacted with triaminopyrimidine sulfate to obtain folic acid. Although this method has a simpler synthesis process and higher yield compared to the nitrobenzoic acid method, the purification of crude folic acid is complex, requiring silica gel column separation, making it unsuitable for large-scale production.

Using trichloroacetone as an intermediate

In 1948, Hultquist et al. used 1,1,3-trichloropropanone to condense with 2,4,5-triamino-6-hydroxypyrimidine to produce 4-amino-4-hydroxy-6-chloromethylpterin, as shown in Figure 1.9:

Currently, domestic production mainly uses trichloroacetone, 2,4,5-triamino-6-hydroxypyrimidine sulfate, and para-aminobenzoylglutamic acid as raw materials to synthesize folic acid. Trichloroacetone, L-N-para-aminobenzoylglutamic acid, and 6-hydroxy-2,4,5-triaminopyrimidine sulfate react in the presence of sodium metabisulfite and sodium carbonate at a pH of 3.0-3.5, and a reaction temperature of 40-45°C for 5 hours to yield folic acid. The reaction equation is shown in Figure 1.10:

This process is simple, with a short reaction time, easily controlled conditions, and low production cost. However, it generates large amounts of wastewater and exhaust gases. The production of trichloroacetone also results in significant pollution, mainly in the following two aspects:

(1) Severe wastewater pollution. The chlorinated mixture requires extensive water extraction to obtain a trichloroacetone water extract with a usable concentration, leading to the generation of large amounts of wastewater.

(2) Severe exhaust gas pollution. Factories commonly produce trichloroacetone by reacting acetone with chlorine, simultaneously generating large amounts of hydrogen chloride gas. If this exhaust gas is not adequately recovered and treated, it will lead to severe air pollution.

In addition to the wastewater and exhaust gas pollution in the production of trichloroacetone, similar issues arise in the folic acid synthesis steps. Due to the poor solubility of 2,4,5-triamino-6-hydroxypyrimidine sulfate, a large amount of water is used in the reaction process, and the trichloroacetone water extract brings a significant amount of water into the reaction system. Moreover, in the final purification step, acid dissolution and water precipitation are required, all contributing to severe wastewater pollution.

Folic Acid Application Scenarios

Animal production, pharmaceutical applications, etc.

Folic Acid Packaging and Storage

Storage Conditions: This product should be stored sealed, protected from light, and in a cool, dry, well-ventilated place.

Packaging: Bulk 25kg/paper drum, sample 1kg/aluminum foil bag, can also be packaged according to customer requirements

Transportation: Express or logistics, domestic express delivery within three days, logistics within five days. Quotation generally includes domestic transportation costs

Shelf Life: Two years

Plant Sources

Folic acid is widely found in leafy green plants such as spinach, beet greens, and broccoli. It's also commonly present in animal-based foods (like liver, kidneys, and egg yolks), fruits (such as oranges and kiwis), and yeast. However, it's less abundant in root vegetables, corn, rice, and pork. Among these leafy green vegetables, those with the highest folic acid content are Aster scaber, water shield, New Zealand spinach, Artemisia, Eleutherococcus senticosus, and wild asparagus, with levels of 36.195, 23.478, 20.137, 67.600, 59.553, and 22.032 μg/g, respectively.

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