59-30-3

Basic information

• Product Name: Folic acid
• Synonyms: EZNA KIT FUNGAL DNA MINI;KIT BLOOD DNA EZNA 5 TESTS;2-amino-6-((p-((1,3-dicarboxypropyl)carbamoyl)anilino)methyl)-4-pteridino PteGlu Pteroyl-L-glutamic acid Vitamin M PGA Pteroylglutamic acid Folic Acid Hydrate;PTEROYL-L-GLUTAMIC ACID;PTEROYLMONOGLUTAMIC ACID;PTEROYLGLUTAMIC ACID;PTEROYGLUTAMIC ACID;PTEGLU
• CAS NO: 59-30-3
• Molecular Formula: C₁₉H₁₉N₇O₆
• Molecular Weight: 441.4
• EINECS: 200-419-0
• Product Categories: Food and Feed Additive;Biochemistry;Vitamins;Nutritional Supplements;Vitamin Ingredients;Intermediates & Fine Chemicals;Pharmaceuticals;chemical reagent;pharmaceutical intermediate;phytochemical;reference standards from Chinese medicinal herbs (TCM).;standardized herbal extract;FOLICET;vitamin;food or feed additives;Inhibitors
• Mol File: 59-30-3.mol
• Article Data: 49

Chemical Properties

• Melting Point: 250 °C
• Boiling Point: 552.35°C (rough estimate)
• Appearance: Yellow to orange/Crystalline Powder
• Density: 1.4704 (rough estimate)
• Refractive Index: 1.6800 (estimate)
• Storage Temp.: 2-8°C
• Solubility: boiling water: soluble1%
• PKA: pKa 2.5 (Uncertain)
• Water Solubility: 1.6 mg/L (25 ºC)
• Stability: Stable. Incompatible with heavy metal ions, strong oxidizing agents, strong reducing agents. Solutions may be light and heat sen
• Merck: 14,4221
• BRN: 100781
• CAS DataBase Reference: Folic acid(CAS DataBase Reference)
• NIST Chemistry Reference: Folic acid(59-30-3)
• EPA Substance Registry System: Folic acid(59-30-3)

Safety Data

• Statements: 33-62-68
• Safety Statements: 24/25
• WGK Germany: 1
• RTECS: LP5425000
• F: 8
• TSCA: Yes
• Hazardous Substances Data: 59-30-3(Hazardous Substances Data)

Usage

Description

Folic acid (folate) is a kind of B-vitamin which is mainly present in the liver and kidney. It has various kinds of pharmacological and physiological effects. It is involved in amino acid metabolism, purine and pyrimidine synthesis, and is also essential for hematopoiesis and red blood cell generation. In women pregnancy, folate can effectively prevent neural tube defects in the baby. It plays important role in fertility through contributing to spermatogenesis. It can also reduce the incidence of heart disease, stroke and cancer.? Folate deficiency may lead to various kinds of diseases including glossitis, diarrhea, depression, confusion, anemia, and fetal neural tube defectsand brain defects (during pregnancy). Other symptoms may include fatigue, gray hair, mouth sores, poor growth, and swollen tongue.

Description

In the 1930s, brewer’s yeast was found to prevent anemia. Folic acid was later discovered to be the nutrient responsible for this effect and was purified in 1941 by Mitchell and coworkers (Mitchell et al., 1941). Folate is needed for biosynthesis of purines and thymidine for DNA and RNA synthesis in all cells. It is also involved in metabolism of some of the amino acids needed for protein synthesis, especially the conversions of serine to glycine and homocysteine to methionine. This makes the nutrient especially important during periods of rapid cell division, such as in pregnancy. Folate is also involved in transfer of one-carbon groups for methylation reactions. The role of folate in cell division was capitalized upon in the synthesis of aminopterin, a folate antagonist, which was one of the first anticancer drugs produced.

Description

Folic acid is an essential B vitamin. It is converted to folate in vivo, which is a necessary cofactor for a variety of biological processes, including nucleotide synthesis and, thus, DNA synthesis and repair, among others. A deficiency in dietary folic acid can lead to a range of developmental and cognitive disorders, most prominently neural tube defects and congenital heart defects.

Chemical Properties

orange to yellow crystalline powder

Physical properties

The folates include a large number of chemically related species, each differing with respect to the various substituents possible at three sites on the pteroylglutamic acid basic structure. More than 170 different folates are theoretically possible. Not all of these occur in nature; but it has been estimated that as many as 100 different forms are found in animals. The folates from most natural sources usually have a single carbon unit at N-5 and/or N-10; these forms participate in the metabolism of the single-carbon pool.Folic acid (pteroylmonoglutamic acid) is an orange-yellow crystalline substance that is soluble in water but insoluble in ethanol or less polar organic solvents. It is unstable to light, to acidic or alkaline conditions, to reducing agents, and, except in dry form, to heat. It is reduced in vivo enzymatically (or in vitro with a reductant such as dithionite) first to 7,8-dihydrofolic acid (FH2) and then to FH4; both of these compounds are unstable in aerobic environments and must be protected by the pres ence of an antioxidant (e.g., ascorbic acid, 2-merTwo derivatives of folic acid, each having an amino group in the place of the hydroxyl at C-4, are folate antagonists of biomedical use: aminopterin (4-aminofolic acid) and methotrexate (4-amino-N10-methylfolic acid). Aminopterin is used as a rodenticide; methotrexate is an antineoplastic agent.

Originator

Folvite, Lederle, US ,1946

Occurrence

Synthetic

Uses

folic acid is generally used as an emollient. In vitro and in vivo skin studies now indicate its capacity to aid in DnA synthesis and repair, promote cellular turnover, reduce wrinkles, and promote skin firmness. There is some indication that folic acid may also protect DnA from uV-induced damage. Folic acid is a member of the vitamin B complex and is naturally occurring in leafy greens.

Uses

Literature tends to indicate that B vitamins cannot pass through the layers of the skin and, therefore, are of no value in the skin surface. Current experiments demonstrate, however, that vitamin B2 acts as a chemical reaction accelerator, enhancing the performance of tyrosine derivatives in suntan-accelerating preparations.

Uses

Folic Acid is a water-soluble b-complex vitamin that aids in the for- mation of red blood cells, prevents certain anemias, and is essential in normal metabolism. high-temperature processing affects its sta- bility. it is best stored at lower than room temperatures. it is also termed folacin. it is found in liver, nuts, and green vegetables.

Uses

A vitamin needed to synthesize DNA, conduct DNA repair and methylate DNA, it also acts as a cofactor in biological reactions involving folate.

Uses

hematopoietic vitamin

Definition

ChEBI: An N-acyl-amino acid that is a form of the water-soluble vitamin B9. Its biologically active forms (tetrahydrofolate and others) are essential for nucleotide biosynthesis and homocysteine remethylation.

Manufacturing Process

The following description is taken from US Patent 2,956,057. 100 grams of 1,3,3-trichloroacetone are heated on a boiling water bath and 95 grams of bromine are added thereto in drops while being stirred and the stirring is continued for about 1 hour. The resulting reaction solution is distilled under reduced pressure. 115 grams of 1-bromo-1,3,3- trichloroacetone are obtained having a boiling point of 85° to 95°C/17 mm (Hg). For the preparation of the hydrate, 100 grams of water are added to 100 grams of 1bromo-1,3,3-trichloroacetone, which is agitated and cooled. A white scaly crystal of hydrate of 1-bromo-1,3,3-trichloroacetone is obtained (100 grams), having a melting point of 52° to 53°C. 8.9 grams of 2,4,5-triamino-6-hydroxypyrimidine hydrochloride and 8 grams of p-aminobenzoylglutamic acid are dissolved in 400 cc warm water, which is cooled at 35° to 27°C and adjusted to pH 4 by using 20% caustic soda solution. To this solution was simultaneously added dropwise a solution obtained by dissolving 13.4 grams of 1-bromo-1,3,3-trichloroacetone hydrate in 90 cc of 50% methanol and 24 grams of 35% aqueous sodium bisulfite solution over a period of approximately 2 hours. During this period, in order to maintain the pH value of the reaction solution at 4 to 5, 20% caustic soda solution is added from time to time. The precipitate, formed by stirring for 5 hours after dropping was finished, is filtered, and the filtrated precipitate is refined; 5.6 grams of pure pteroylglutamic acid is obtained.

Therapeutic Function

Treatment of B vitamin (folacin) deficiency

General Description

Odorless orange-yellow needles or platelets. Darkens and chars from approximately 482°F.

Air & Water Reactions

Insoluble in water. Aqueous solutions have pHs of 4.0-4.8.

Reactivity Profile

Acid solutions of Folic acid are sensitive to heat, but towards neutrality, stability progressively increases. Solutions are inactivated by ultraviolet light and alkaline solutions are sensitive to oxidation. Folic acid is also inactivated by light. Folic acid is incompatible with oxidizing agents, reducing agents and heavy metal ions.

Fire Hazard

Flash point data for Folic acid are not available; however, Folic acid is probably combustible.

Biochem/physiol Actions

A nutritional delivery form of folate. Folic acid and its derivatives are essential mediators of one-carbon metabolism within cells.

Clinical Use

Folate-deficient megaloblastic anaemiaSupplement in HD patients

Safety Profile

Poison by intraperitoneal and intravenous routes. Experimental teratogenic effects. Mutation data reported. When heated to decomposition it emits toxic fumes of NOx.

Veterinary Drugs and Treatments

Folic acid is used to treat folic acid deficiency in dogs, cats, and horses (theoretically in other animal species as well) often due to small intestinal disease. Cats with exocrine pancreatic insufficiency appear to be most at risk for folate and cobalamin deficiencies secondary to malabsorption of folic acid in the diet. Dogs with exocrine pancreatic insufficiency often are noted to have increased folate levels secondary to overgrowths of folate-synthesizing bacteria in the proximal small intestine. Chronic administration of dihydrofolate reductase inhibiting drugs such as pyrimethamine, ormetoprim or trimethoprim can potentially lead to reduced activated folic acid (tetrahydrofolic acid); folic acid supplementation is sometimes prescribed in an attempt to alleviate this situation.

Drug interactions

Potentially hazardous interactions with other drugs Antiepileptics: reduces phenytoin, primidone and phenobarbital levels. Cytotoxics: avoid with raltitrexed.

Metabolism

Folic acid given therapeutically enters the portal circulation largely unchanged, since it is a poor substrate for reduction by dihydrofolate reductase. It is converted to the metabolically active form 5-methyltetrahydrofolate in the plasma and liver. Folate undergoes enterohepatic circulation. Folate metabolites are eliminated in the urine and folate in excess of body requirements is excreted unchanged in the urine.

Purification Methods

If paper chromatography indicates impurities, then recrystallise it from hot H2O or from dilute acid [Walker et al. J Am Chem Soc 70 19 1948]. Impurities may be removed by repeated extraction with n-BuOH of a neutral aqueous solution of folic acid (by suspending in H2O and adding N NaOH dropwise till the solid dissolves, then adjusting the pH to ~7.0-7.5) followed by precipitation with acid, filtration, or better collected by centrifugation and recrystallised form hot H2O. [Blakley Biochem J 65 331 1975, Kalifa et al. Helv Chim Acta 6 1 2739 1978.] Chromatography on cellulose followed by filtration through charcoal has also been used to obtain pure acid. [Sakami & Knowles Science 129 274 1959.] UV: max 247 and 296nm ( 12,800 and 18,700) in H2O pH 1.0; 282 and 346nm ( 27.600 and 7,200) in H2O pH 7.0; 256, 284 and 366nm ( 24600, 24,500 and 86,00) in H2O pH 13 [Rabinowitz in The Enzymes (Boyer et al. Eds), 2 185 1960]. [Beilstein 26 III/IV 3944.]

InChI:InChI=1/C19H19N7O6/c20-19-25-15-14(17(30)26-19)23-11(8-22-15)7-21-10-3-1-9(2-4-10)16(29)24-12(18(31)32)5-6-13(27)28/h1-4,8,12,21H,5-7H2,(H,24,29)(H,27,28)(H,31,32)(H3,20,22,25,26,30)/p-2/t12-/m1/s1

Synthetic route

N-(4-aminobenzoyl)-L-glutamic acid (4271-30-1) + 2,5,6-triamino-1,4-dihydropyrimidin-4-one hydrochloride → folate (59-30-3)

Conditions	Yield
With 1,1,1-trichloroacetone; sodium sulfite In water at 40 - 50℃; for 1h; pH=3 - 4; pH-value; Temperature;	85%

1,1,3-trichloroacetone (921-03-9) + N-(4-aminobenzoyl)-L-glutamic acid (4271-30-1) + 2,4,5-triamino-6-hydroxypyrimidine sulfate (35011-47-3) → folate (59-30-3)

Conditions	Yield
With sodium metabisulfite at 20 - 30℃; for 2h; Temperature; Ionic liquid;	83.2%
With sodium metabisulfite; sodium acetate at 45℃; for 3h; Temperature;	46.2%

1,1,1-trichloroacetone (918-00-3) + p-Nitrobenzoyl-L-(+)-glutamic acid (6758-40-3) + 2,4-diamino-5-nitroso-6-hydroxypyrimidine (2387-48-6) → folate (59-30-3)

Conditions	Yield
Stage #1: p-Nitrobenzoyl-L-(+)-glutamic acid; 2,4-diamino6-hydroxy-5-nitroso pyrimidine With hydrogen In water at 82℃; under 6000.6 Torr; Stage #2: 1,1,1-trichloroacetone With sodium metabisulfite; sodium hydroxide In water at 45℃; pH=4.5; pH-value; Pressure; Temperature;	80%

1,1,1-trichloroacetone (918-00-3) + N-(4-aminobenzoyl)-L-glutamic acid (4271-30-1) + 2,4,5-triamino-6-hydroxypyrimidine sulfate (35011-47-3) → folate (59-30-3)

Conditions	Yield
Stage #1: 1,1,1-trichloroacetone; N-(4-aminobenzoyl)-L-glutamic acid With sodium acetate; sodium sulfite In acetic acid at 43℃; for 0.5h; Stage #2: 2,4,5-triamino-6-hydroxypyrimidine sulfate In acetic acid at 38℃; for 5h;	75.5%

1,1,3-tribromoacetone (3475-39-6) + N-(4-aminobenzoyl)-L-glutamic acid (4271-30-1) + 2,4,5-triamino-6-hydroxypyrimidine sulfate (35011-47-3) → folate (59-30-3)

Conditions	Yield
With sodium carbonate In ethanol; water at 40℃; pH=7.5; Temperature; pH-value;	60%

folate (65165-92-6) + 2-hydroxy-3-oxopropionaldehyde (497-15-4) + N-(4-aminobenzoyl)-L-glutamic acid (4271-30-1) → folate (59-30-3)

7,8-dihydrofolic acid (188497-71-4) + Na-folate + sodium citrate (68-04-2) → folate (59-30-3)

Conditions	Yield
With sodium hydroxide

folinic acid (58-05-9) + alpha cyclodextrin (10016-20-3) → folate (59-30-3)

Conditions	Yield
In water

folate (59-30-3) + N-tert-butoxycarbonyl cystamine (485800-26-8) → tert-butyl 2-{[2-({N2-(4-{[(2-amino-4-hydroxypteridin-6-yl)methyl]amino}benzoyl)-N1-[2-({2-[(tert-butoxycarbonyl)amino]ethyl}dithio)ethyl]-α-glutaminyl}amino)ethyl]dithio}ethylcarbamate (1301165-94-5)

Conditions	Yield
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water at 100℃;	96%

folate (59-30-3) + calcium chloride → C19H17N7O6(2-)*Ca(2+)

Conditions	Yield
Stage #1: folate With sodium hydroxide at 50℃; for 2h; pH=7.4; Stage #2: calcium chloride In ethanol; water at 50℃; for 1h;	96%

folate (59-30-3) + strontium chloride → C19H17N7O6(2-)*Sr(2+)

Conditions	Yield
Stage #1: folate With sodium hydroxide at 50℃; for 2h; pH=7.4; Stage #2: strontium chloride In ethanol; water at 50℃; for 1h;	95%

ethanol (64-17-5) + folate (59-30-3) → C23H27N7O6

Conditions	Yield
With methanesulfonic acid at 20℃;	95%

1-hydroxy-pyrrolidine-2,5-dione (6066-82-6) + folate (59-30-3) → N-hydroxysuccinimide folate (153445-05-7)

Conditions	Yield
With dicyclohexyl-carbodiimide In dimethyl sulfoxide at 20℃; for 24h; Darkness;	94%
With dicyclohexyl-carbodiimide In dimethyl sulfoxide at 20℃; for 0.0833333h; Inert atmosphere;	53%
With dicyclohexyl-carbodiimide In dimethyl sulfoxide at 50℃; for 6h;

1-amino-2-azidoethane (87156-40-9) + folate (59-30-3) → C21H23N11O5

Conditions	Yield
Stage #1: folate With 4-methyl-morpholine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In dimethyl sulfoxide; N,N-dimethyl-formamide at 0℃; for 1h; Inert atmosphere; Cooling with ice; Stage #2: 1-amino-2-azidoethane In dimethyl sulfoxide; N,N-dimethyl-formamide at 0℃; for 2h; Inert atmosphere; Cooling with ice;	94%
Stage #1: folate With 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide In dimethyl sulfoxide at 20℃; Inert atmosphere; Darkness; Stage #2: 1-amino-2-azidoethane In dimethyl sulfoxide for 24h; Inert atmosphere; Darkness;	84%

folate (59-30-3) + Propargylamine (2450-71-7) → propargylfolate

Conditions	Yield
Stage #1: folate With 1-hydroxy-pyrrolidine-2,5-dione; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: Propargylamine In N,N-dimethyl-formamide at 20℃; for 24h;	93%

folate (59-30-3) + butan-1-ol (71-36-3) → C27H35N7O6

Conditions	Yield
With methanesulfonic acid at 20℃;	92%

formaldehyd (50-00-0) + folate (59-30-3) → calcium 5-methyl-tetrahydrofolate

Conditions	Yield
Stage #1: folate With sodium tetrahydroborate; edetate disodium; sodium hydroxide In water at 25 - 92℃; Stage #2: formaldehyd With hydrogenchloride In water at 0 - 10℃; pH=9; Further stages;	91.35%

tert-butyl N-(6-aminohexyl)carbamate (51857-17-1) + folate (59-30-3) → γ-{[tert-butyl-N-(6-aminohexyl)]carbamate}folic acid (850754-81-3)

Conditions	Yield
With pyridine; dicyclohexyl-carbodiimide In dimethyl sulfoxide at 20℃; for 18h; Inert atmosphere;	91%

folate (59-30-3) + Propargylamine (2450-71-7) → propargyl folic acid (1009599-12-5)

Conditions	Yield
Stage #1: folate With 1-hydroxy-pyrrolidine-2,5-dione; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: Propargylamine In N,N-dimethyl-formamide at 20℃; Cooling with ice;	90%
Stage #1: folate With 1-hydroxy-pyrrolidine-2,5-dione; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: Propargylamine In N,N-dimethyl-formamide at 25℃; for 24h;	71.2%
Stage #1: folate With 1-hydroxy-pyrrolidine-2,5-dione; 1,2-dichloro-ethane In N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: Propargylamine In N,N-dimethyl-formamide at 20℃; for 24h;

nickel(II) chloride hexahydrate + water (7732-18-5) + hydrazine hydrate (7803-57-8) + folate (59-30-3) → [Ni2(FA)(N2H4)3(H2O)2(OH-)2]

Conditions	Yield
Stage #1: nickel(II) chloride hexahydrate; water; folate In ethanol for 0.166667h; Sonication; Stage #2: hydrazine hydrate In ethanol at 120℃; for 12h; pH=10.5; Autoclave;	90%

propan-1-ol (71-23-8) + folate (59-30-3) → C25H31N7O6

Conditions	Yield
With methanesulfonic acid at 20℃;	89%

methanol (67-56-1) + folate (59-30-3) → C21H23N7O6 (319919-60-3)

Conditions	Yield
With methanesulfonic acid at 20℃;	87%

adamantylmethylamine (17768-41-1) + folate (59-30-3) → C30H36N8O5

Conditions	Yield
Stage #1: folate With 1-hydroxy-pyrrolidine-2,5-dione; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dimethyl sulfoxide for 1h; Inert atmosphere; Darkness; Stage #2: adamantylmethylamine With triethylamine In dimethyl sulfoxide for 48h; Inert atmosphere; Darkness;	86%

Upstream product

• 532-82-1 Basic Orange 2 
• 1603-02-7 2,5,6-Triaminopyrimidin-4-ol sulphate 
• 921-03-9 1,1,3-Trichloroacetone 
• 5221-17-0 3,5-DI-T-BUTYL-4-METHOXYBENZALDEHYDE 
• 7681-57-4 Sodium metabisulfite 

Downstream Products

• 59303-03-6 3-Methyl-2-propionylthiophene 
• 59303-05-8 methylfurfurylthiol,5-methyl-2-furfurylthiol 
• 59303-07-0 2-FURFURYLTHIO-3-METHYLPYRAZINE 
• 59303-08-1 Pyrazine, 2-(2-furanylmethyl)thio-5-methyl- 
• 59303-09-2 Pyrazine, 2-(2-furanylmethyl)thio-6-methyl- 
• 59303-10-5 2-CHLORO-5-METHYLPYRAZINE 
• 59303-12-7 2-(methoxymethyl)-6-methylpyridine 
• 59303-13-8 2-Methyl-5-propionylthiophene 
• 59303-17-2 Ethanone, 1-(5-methyl-2-thiazolyl)- (9CI) 
• 59303-19-4 propyl thiophene-2-carboxylate 
• 593-03-3 3-Hexadecanol 
• 5930-37-0 N-{2-methyl-4-[(2-nitrophenyl)sulfanyl]phenyl}acetamide 
• 5930-38-1 1-{5-[(1H-benzimidazol-2-ylsulfanyl)methyl]furan-2-yl}-2,2,2-trifluoroethanone 
• 59303-93-4 4-methyl-N'-[2-(2-toluidino)benzoyl]benzenesulfonohydrazide 

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