80433-71-2 Usage
Description
Calcium levofolinate, also known as L-Folinic acid, is a reduced folic acid and isomer of DL-folinic acid. It is an intermediate product of the metabolism of Folic Acid and the active form into which that acid is converted in the body, with ascorbic acid being a necessary factor in the conversion process.
Uses
Used in Pharmaceutical Industry:
Calcium levofolinate is used as an anti-tumor drug for the treatment of osteosarcoma after high-dose methotrexate treatment and the symptoms related to folic acid antagonism. It is also used to treat giant cell anemia caused by folic acid deficiency.
Used in Oncology:
Calcium levofolinate is used in combination with fluorouracil to prolong the survival of patients with advanced colon cancer or relieve symptoms. It is also used in biological studies for the treatment of colorectal cancer.
Used as a Folate Supplement:
Calcium levofolinate is used as a folate supplement to prevent toxicity following therapy with high-dose methotrexate, to enhance the antitumor activity of 5-fluorouracil, and as an intermediate from Folic Acid metabolism. Clinical studies demonstrate that formulations containing L-folinic acid have similar efficacy and tolerability as those containing DL-folinic acid and have been used interchangeably for the modification of antitumor activity of 5-fluorouracil, while D-folinic acid is inactive.
Pharmaceutical Applications
Levoleucovorin is the biologically active substance of calcium folinate, and calcium folinate is a diastereomeric mixture of 5-formyl derivatives of tetrahydrofolate (THF). Calcium folinate does not need to be reduced by dihydrofolate reductase to directly participate in the biological reaction using folic acid as a carrier for transferring one-carbon groups in the body. L-leucovorin (L-5 leucovorin) is rapidly metabolized (5,10-methyltetrahydrofolate, 5,10-leucovorin tetrahydrofolate) to L-5-methyltetrahydrofolate. L-5-methyltetrahydrofolate can be metabolized into 5,10-methylenetetrahydrofolate through other pathways of , and 5,10-methylenetetrahydrofolate is irreversibly converted through the catalytic reduction of PDAH2 and NADPH coenzymes. It is 5-methyltetrahydrofolate. The use of folinic acid can counteract the therapeutic effects and toxicity of hydrochloric acid antagonists that inhibit dihydrofolate reductase (such as methotrexate). Leucovorin can also enhance the efficacy and toxicity of fluoropyrimidine (such as 5-fluorouracil) in tumor treatment. Simultaneous use of folinic acid does not change the pharmacokinetic process of 5-fluorouracil in plasma.
Indications
Levoleucovorin calcium is mainly used as an adjuvant drug for tumor chemotherapy in addition to megaloblastic anemia caused by various reasons. (1) The rescue therapy of high-dose methotrexate combined with levofolinate calcium is used to counter the resistance of tumor cells to methotrexate, and it can also antagonize the toxicity of methotrexate to normal cells; (2) Left sub The combination of calcium folic acid and 5?Fu enhances its therapeutic effect and prolongs the survival time of palliative treatment of advanced colorectal cancer.
Preparation
1) Add tetrahydrofolate, a reduction product of raw material folic acid, to formic acid for formylation with trifluoroacetic acid as a catalyst, and place it at a temperature of 10°C-30°C (room temperature) for 10-24 hours Afterwards, 5,10-methylenetetrahydrofolate is obtained; then hydrochloric acid is added, so that the formylation intermediate-5,10-methylenetetrahydrofolate is precipitated in the form of hydrochloride;2) Reconstitute the precipitated hydrochloride of 5,10-methylenetetrahydrofolate with formic acid, add hydrochloric acid and recrystallize to precipitate refined products of 5,10-methylenetetrahydrofolate;3) Suspend the recrystallized 5,10-methylenetetrahydrofolate hydrochloride in water, add an aqueous solution of a medium strong base such as piperazine to make a buffer system, and then add a medium strong base such as piperazine or strong Adjust the pH value of the ring-opening reaction system to 5.5-7.5 with an aqueous base such as sodium hydroxide, perform heating to hydrolyze the ring-opening, and directly add anhydrous CaCl2 equal to the weight (w/w) of the intermediate to the solution after ring-opening, and Adjust the pH value to 5.5-8.5, place it, the precipitated solid is calcium levofolinate;4) The precipitated calcium levofolinate is recrystallized with water to obtain a refined product of calcium levofolinate.
Clinical Use
#N/A
Drug interactions
Potentially hazardous interactions with other drugs
Antiepileptics: possibly reduces fosphenytoin,
phenytoin, primidone and phenobarbital levels.
Cytotoxics: avoid with raltitrexed.
Should not be administered simultaneously with a
folic acid antagonist as this may nullify the effect of
the antagonist.
Metabolism
The active isomeric form levofolinic acid (l-5-
formyltetrahydrofolic acid) is quickly metabolised to
5-methyltetrahydrofolic acid in the liver
Check Digit Verification of cas no
The CAS Registry Mumber 80433-71-2 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 8,0,4,3 and 3 respectively; the second part has 2 digits, 7 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 80433-71:
(7*8)+(6*0)+(5*4)+(4*3)+(3*3)+(2*7)+(1*1)=112
112 % 10 = 2
So 80433-71-2 is a valid CAS Registry Number.
InChI:InChI=1/C20H23N7O7.Ca/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);/q;+2/p-2/t12-,13+;/m0./s1
80433-71-2Relevant articles and documents
A novel synthetic method for preparation of some folates
Zhou, Minghao,Hong, Mei,Xiao, Guomin
, p. 2211 - 2218 (2013/06/05)
An improved method was developed for preparation of 5,6,7,8-tetrahydrofolic acid (THF) and calcium-5-methyltetrahydrofolate (5-MTHF-Ca) by reduction of folic acid using KBH4 catalyzed by Pb(NO3)2. The yields of THF and 5-MTHF-Ca were 56.5 and 42.7 %, respectively. A convenient method for measurement of THF and 5-MTHF-Ca using liquid chromatography-mass spectrometry (LC-MS) was also established, enabling analysis of those folates within 10 min without application of gradient elution.
The Preparation of the (6R)- and (6S)-Diastereoisomers of 5-Formyltetrahydrofolate (Leucovorin)
Owens, Jonathan,Rees, Lilias,Suckling, Colin J.,Wood, Hamish C. S.
, p. 871 - 876 (2007/10/02)
The separation of the (6R)- and (6S)-diastereoisomers of tetrahydrofolic acid by derivatisation on N-5 with chiral auxiliary reagents followed by fractional crystallisation or extraction is described.Chloroformates of chiral alcohols were used as chiral auxiliaries and those derived from cyclic terpene alcohols were found to be most effective for the separation.The cleavage of the derivative and conversion in situ into 5,10-methenyltetrahydrofolic acid which was subsequently hydrolysed to afford 5-formyltetrahydrofolate (leucovorin) was investigated for the derivatised tetrahydrofolates; that from (-)-menthol was the only one that combined satisfactory separation with sufficient lability for efficient conversion into 5-fornyltetrahydrofolate.The characterisation and optical purity of the products is described.
Asymmetric Catalysis, 67. - Diastereoselective Hydrogenation of Folic Acid with Optically Active Rhodium(I)-Diphosphane Complexes
Brunner, Henri,Huber, Christian
, p. 2085 - 2094 (2007/10/02)
With immobilized rhodium(I)-diphosphane catalysts supported on silica gel, the C=N bonds of the pyrazine ring of folic acid (1) are reduced with hydrogen in aqueous solution to give 5,6,7,8-tetrahydrofolic acid.A mixture of the two diastereomers 2a and 3a is obtained with (6S)-and (6R)-configuration, respectively, at the newly formed asymmetric center in the pterine system and (S)-configuration in the L-glutamic acid moiety.The unstable hydrogenation products are derivatized with (-)-menthyl chloroformate.An improved HPLC procedure for the analysis of the products has been developed.By using optically active chelate phosphanes as cocatalysts together with 2, a diastereomeric excess of up to 24percent of the natural isomer 2a with (6S,S)-configuration is attained in the heterogeneous hydrogenation of folic acid. Key Words: Diastereoselective hydrogenation / Immobilized enantioselective rhodium(I)-diphosphan catalysts / Folic acid / (6S,S)-Folinic acid / 5,6,7,8-Tetrahydrofolic acid, N-5-(menthyloxycarbonyl)-
