58-05-9

Basic information

• Product Name: Folinic acid
• Synonyms: 5-formyl-5,6,7,8-tetrahydropteroyl-l-glutamicacid;leucoverin;5-formyl-5,6,7,8-tetrahydrofolate;5-formyltetrahydrofolate;5-formyltetrahydrofolic acid;N5-formyl-5,6,7,8-tetrahydrofolate;N5-formyl-tetrahydrofolate;2-[4-[(2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]aminopentanedioic acid
• CAS NO: 58-05-9
• Molecular Formula: C₂₀H₂₃N₇O₇
• Molecular Weight: 473.44
• EINECS: 200-361-6
• Product Categories: Pharmaceutical Raw Materials
• Mol File: 58-05-9.mol

Chemical Properties

• Melting Point: 245°C (rough estimate)
• Boiling Point: 573.92°C (rough estimate)
• Appearance: /
• Density: 1.4485 (rough estimate)
• Refractive Index: 1.6800 (estimate)
• Storage Temp.: under inert gas (nitrogen or Argon) at 2–8 °C
• PKA: 3.1, 4.8, 10.4(at 25℃)
• Water Solubility: >1350g/L(25 oC)
• CAS DataBase Reference: Folinic acid(CAS DataBase Reference)
• NIST Chemistry Reference: Folinic acid(58-05-9)
• EPA Substance Registry System: Folinic acid(58-05-9)

Safety Data

• Hazardous Substances Data: 58-05-9(Hazardous Substances Data)

Usage

Uses

Used in Antidote Applications:
Folinic acid is used as an antidote for folic acid antagonists, such as methotrexate, pyrimethamine, or trimethoprim. It helps prevent severe toxic effects caused by methotrexate overdose or high-dose treatment.
Used in Treatment of Anemia:
Folinic acid is used to treat megaloblastic anemia caused by folic acid deficiency.
Used in Cancer Treatment:
When combined with fluorouracil, folinic acid is used to treat advanced colon cancer and rectal cancer. It is also used in combination with 5-fluorouracil for the treatment of colorectal cancers and functions as a useful antidotal therapy medication for decreasing the toxic effect of methotrexate overdosing.

Characteristics

L-leucovorin is used as an anti-tumor antidote and anti-megaloblastic anemia adjuvant. Its dosage is 1/2 of folinic acid. L-leucovorin does not need to be reduced by dihydrofolate reductase to participate in the use of folate as a The reaction is derived from carbon units, and L-leucovorin can actively or passively pass through the cell membrane; the basic function of L-leucovorin is the same as folic acid, but the effect is better than folic acid. At the same time, L-leucovorin also has the effect of stimulating the growth and maturation of white blood cells, which can improve the growth and maturation of white blood cells.

Pharmacology

Folic acid (pteroylglutamic acid), an essential water-soluble vitamin, consists of a pteridine ring joined to PABA (para-aminobenzoic acid) and glutamic acid.3?Folic acid is the most common of the many folate congeners that exist in nature and are essential for normal cellular metabolic functions. Folic acid is rarely called vitamin B9. After absorption, folic acid is reduced by dihydrofolic acid reductase (DHFR) to dihydrofolic acid and then tetrahydrofolic acid (THF), which accepts one-carbon groups. Tetrahydrofolic acid serves as the precursor for several biologically active forms of folic acid, including 5-formyltetrahydrofolic acid (5-formyl THF), which is best known as folinic acid, leucovorin, and citrovorum factor.

Preparation

In a 1L reaction flask, first add 0.45L of pure water, heat to 55-60℃ with stirring, then add 15g (0.0245mol, water 16.4%) of levofolinate, keep it at 55-60℃, and stir to It is almost dissolved, and the temperature is lowered to 0-10°C first, and an aqueous sodium carbonate solution (2.6g sodium carbonate (0.0245mol) dissolved in 45mL of pure water) is added dropwise, keeping the temperature at 0-10°C, after dripping, keep warm and stir for 1 hour. The precipitated solid is filtered out, the filter cake is washed once with 20 ml of pure water, and the filtrate is the sodium levofolinate solution. Put the filtrate into a 1L reaction flask, stir and lower the temperature to 0-5°C, control the temperature of the reaction system at 0-5°C, and add 1N dilute hydrochloric acid uniformly. When the pH of the acidification end point is 2.0-2.5, stop the dripping. Stir for about 30 minutes, then stand and age for 30 minutes, filter, and wash the filter cake twice with 75 mL of pure water. The wet product is freeze-dried to obtain 9.1 g of Folinic acid. Yield: 78%

InChI:InChI=1/C20H23N7O7/c21-20-25-16-15(18(32)26-20)27(9-28)12(8-23-16)7-22-11-3-1-10(2-4-11)17(31)24-13(19(33)34)5-6-14(29)30/h1-4,9,12-13,22H,5-8H2,(H,24,31)(H,29,30)(H,33,34)(H4,21,23,25,26,32)/t12-,13-/m0/s1

Synthetic route

Leucovorin Calcium (6035-45-6) → folinic acid (58-05-9)

Conditions	Yield
With hydrogenchloride In water at 6 - 10℃; for 4h; pH=2.8 - 3.2;	n/a
With acetic acid In water at 2 - 12℃; pH=2.5 - 3.5;

folinic acid (58-05-9) → disodium leucovorin

Conditions	Yield
With sodium hydroxide In water pH=8.0;

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

Conditions	Yield
In water

folinic acid (58-05-9) → N5,N10-methenyl-tetrahydrofolic acid (442634-22-2, 807328-63-8)

Conditions	Yield
With 1,4-bis(2-hydroxyethyl)piperazine; 5,10-methenyltetrahydrofolate synthetase; MgATP; 2-hydroxyethanethiol at 25℃; pH=6; Kinetics; Reagent/catalyst;
With hydrogenchloride In water at 20℃; for 4h; pH=1.9;

folinic acid (58-05-9) → N10-formyltetrahydrofolate

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride / water / 4 h / 20 °C / pH 1.9 2: 0.5 h / 30 °C / pH 7.5 / aq. buffer View Scheme

folinic acid (58-05-9) → tetrahydrofolic acid

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / water / 4 h / 20 °C / pH 1.9 2: 0.5 h / 30 °C / pH 7.5 / aq. buffer 3: recombinant formyltransferase Rft; recombinant monooxygenase Rmo; oxygen; NADPH; flavin adenine dinucleotide / 4 h / 30 °C / pH 7.5 / aq. buffer; Enzymatic reaction View Scheme

folinic acid (58-05-9) → Folitixorin

Conditions	Yield
With hydrogenchloride; 2-hydroxyethanethiol In water at 20℃; for 4h; pH=1.9;

Upstream product

• 135-16-0 tetrahydrofolic acid 
• 64-18-6 formic acid 
• 75-87-6 chloral 
• 93-61-8 N-methyl-N-phenylformamide 
• 2800-34-2 10-formyltetrahydrofolate 
• 623-11-0 1-methyl-4-nitrosobenzene 
• 134-05-4 N¹⁰-formylfolic acid 
• 442634-22-2 5,10-methylidyne-5,6,7,8-tetrahydrofolic acid 
• 59-30-3 folic acid 
• 4033-27-6 (S)-2-{4-[(2-Amino-4-oxo-3,4,7,8-tetrahydro-pteridin-6-ylmethyl)-amino]-benzoylamino}-pentanedioic acid 
• 98814-60-9 (6RS)-5,10-diformyl-5,6,7,8-tetrahydrofolic acid 
• 44234-35-7 formimidic acid ethyl ester 
• 135-16-0 (6S,S)-5,6,7,8-tetrahydrofolic acid 
• 107-31-3 Methyl formate 

Downstream Products

• 98814-60-9 (6RS)-5,10-diformyl-5,6,7,8-tetrahydrofolic acid 
• 59-30-3 folate 
• 442634-22-2 N₅,N₁₀-methenyl-tetrahydrofolic acid 

Relevant articles and documents

Synthesis and physicochemical characterization of (6: S)-5-formiminotetrahydrofolate; A reference standard for metabolomics

The one-carbon carrier of the formate oxidation level derived from the interaction of tetrahydrofolate and formiminoglutamate, which has been tentatively identified as 5-formiminoltetrahydrofolate, has been prepared by chemical synthesis. Treatment of a solution of (6S)-tetrahydrofolate in aqueous base with excess ethyl formimidate in the presence of anti-oxidant under anaerobic conditions afforded a gummy solid which, based on mass spectral analysis, conformed to a monoformimino derivative of tetrahydrofolate. Further physicochemical characterization by validated methods strongly suggested that the product of chemical synthesis was identical to the enzymatically produced material and that it was, in fact, (6S)-5-formiminotetrahydrofolate. Conditions and handling methods toward maintaining the integrity of this highly sensitive compound were identified and are described, as is analytical methodology, useful for research studies using it.

THERAPEUTIC FOR HEPATIC CANCER

A novel pharmaceutical composition for treating or preventing hepatocellular carcinoma and a method of treatment are provided. A pharmaceutical composition for treating or preventing liver cancer is obtained by combining a chemotherapeutic agent with an anti-glypican 3 antibody. Also disclosed is a pharmaceutical composition for treating or preventing liver cancer which comprises as an active ingredient an anti-glypican 3 antibody for use in combination with a chemotherapeutic agent, or which comprises as an active ingredient a chemotherapeutic agent for use in combination with an anti-glypican 3 antibody. Using the chemotherapeutic agent and the anti-glypican 3 antibody in combination yields better therapeutic effects than using the chemotherapeutic agent alone, and mitigates side effects that arise from liver cancer treatment with the chemotherapeutic agent.

Anti-Claudin 3 Monoclonal Antibody and Treatment and Diagnosis of Cancer Using the Same

Monoclonal antibodies that bind specifically to Claudin 3 expressed on cell surface are provided. The antibodies of the present invention are useful for diagnosis of cancers that have enhanced expression of Claudin 3, such as ovarian cancer, prostate cancer, breast cancer, uterine cancer, liver cancer, lung cancer, pancreatic cancer, stomach cancer, bladder cancer, and colon cancer. The present invention provides monoclonal antibodies showing cytotoxic effects against cells of these cancers. Methods for inducing cell injury in Claudin 3-expressing cells and methods for suppressing proliferation of Claudin 3-expressing cells by contacting Claudin 3-expressing cells with a Claudin 3-binding antibody are disclosed. The present application also discloses methods for diagnosis or treatment of cancers.

METHOD FOR THE PRODUCTION OF CRYSTALLINE (6RS)-N(5)-FORMYL-5,6,7,8-TETRAHYDROFOLIC ACID

The inventive method for the production of crystalline (6RS)-N(5)-formyl-5,6,7,8-tetrahydrofolic acid or amorphic (6S)-N(5)-formyl-5,6,7,8-tetrahydrofolic acid is characterized in that an aqueous solution of (6RS)- or (6S)-calcium folinate, which has a temperature of 40 °C to 50 °C, and an aqueous solution of hydrochloric acid or acetic acid are added to stirred water having a temperature of 2 °C to 12 °C, such that the temperature is kept at 2 °C to 12 °C in the mixture thus obtained when the two above-mentioned solutions are added and the pH value is kept at 2,5 to 3,5, the solid thus arising is isolated by means of filtration or centrifugation, the solid is initially washed with cold water and then with an aqueous organic solvent, and the washed solid, i.e. crystalline (6RS)-N(5)-formyl-5,6,7,8-tetrahydrofolic acid or amorphous (6S)-N(5)-formyl-5,6,7,8-tetrahydrofolic acid is dried at reduced pressure and obtained.

Enantioselective catalyses CXXXV [1]. Stereoselective hydrogenation of folic acid and 2-methylquinoxaline with optically active rhodium(I)-phosphane complexes

In the hydrogenation of the C=N double bonds of the pyrazine ring of folic acid to 5,6,7,8-tetrahydrofolic acid a new asymmetric center is formed at C6 of the pteridine system. With rhodium(I) catalysts made from optically active phosphanes, which are immobilized on silical gel, the hydrogenation in aqueous solution can be controlled stereoselectively. The highest diastereomeric excess of ca. 40% is obtained with (-)-BPPM containing catalysts. The hydrogenation of the biomolecule folic acid in aqueous solution is also possible homogeneously with rhodium(I)-phosphane catalysts, the ligands of which contain sulfonic acid groups and polyether fragments. The homogeneous hydrogenations proceed slower and with somewhat reduced diastereoselectivities compared to the heterogeneous catalyses. The hydrogenation of 2-methylquinoxaline is a model system for the reduction of folic acid. The usual rhodium(I)-phosphane catalysts afford only small enantioselectivities.

Stereoselective hydrogenation of folie acid with immobilized optically active rhodium(I)/diphosphane catalysts

For the hydrogenation of the C=N bonds in the pyrazine ring of the vitamin folic acid (1) optically active rhodium(I)/diphosphane complexes immobilized on supports such as silica gel or A12O3 were used. The reduction was carried out at 50 bar hydrogen pressure in an aqueous solution buffered to pH 7. Thus, 5,6,7,8-tetrahydrofolic acid (2) was obtained which contains a new asymmetric center at C-6 of the pterine system. Therefore, in combination with the (S) configuration of the natural L-glutamic acid part of the molecule two diastereomers with (6S,S) and (6fl,S) configuration arise. The relati-vely unstable tetrahydrofolic acid (2) was converted into its 5-formyl derivative folinic acid (4) by treatment with methyl formate/formic acid in a 5:1 mixture of DMSO/pyridine. The Ca salt of folinic acid (4) is the widely used drug leucovorin. The diastereomers were separated by silica gel HPLC. To the column bovine serum albumine (BSA) is covalently bound. With optically active rhodium(I)/diphosphane catalysts, immobilized on silica gel supports, a diastereoselectivity of up to 90 % could be achieved in the hydrogenation of folic acid (1)-. VCH Verlagsgesellschaft mbH.

Fluorine and phosphorous-containing amphiphilic molecules with surfactant properties

Compounds of the general formula: STR1 are useful as surfactants in the preparation of fluorocarbon emulsions, which can be used as oxygen-carrying blood substitutes, and for many other therapeutic and diagnostic applications. They are further useful in liposomal formulations which are themselves therapeutic agents or provide a vehicle for such agents.

Synthesis of Tetrahydropteridine C6-Stereoisomers, Including N5-Formyl-(6S)-tetrahydrofolic Acid

Chiral N1-protected vicinal diamines derived from amino acids were condensed with 2-amino-6-chloro-5-nitro-4(3H)-pyrimidinone, the nitro group reduced, and the amine deprotected.Oxidative cyclization of the resulting triaminopyrimidinone via quinoid pyrimidine intermediates gave a quinoid dihydropteridine, which was then reduced to a tetrahydropteridine C6-stereoisomer.Thus, 6(R)- and 6(S)-propyltetrahydropterin were stereospecifically synthesized (99 percent enantiomeric purity) in good yield from D- and L-norvaline, respectively.Reductive alkylation of (p-aminobenzoyl)-L-glutamate with a niropyrimidine aldehyde derived from D- or L-serine similarly afforded, after cyclization and reduction, (6R)- or (6S)-tetrahydrofolic acid.The latter was then converted to the natural isomer of leucovorin by regioselective N5-formylation with carbonyl diimidazole / formic acid without loss of enantiomeric purity.

Stereochemistry of Reduction of the Vitamin Folic acid by Dihydrofolate Reductase

Reduction of the vitamin folic acid (6) to the coenzyme 5,6,7,8-tetrahydrofolic acid (1) by the enzyme dihydrofolate reductase is shown to involve transfer of the 4-pro R hydrogen of NADPH to the same face at both C-6 and C-7 of the pteridine system (the re face at C-6 and the si face at C-7).The orientations of the pteridine system of folic acid (6) and of dihydrofolic acid (5) when bound to the enzyme are different from the orientation of the pteridine ring of the anti-cancer drug methotrexate (11) when bound to this enzyme.