29347-89-5

Upstream product

• 59-30-3 folic acid 
• 86-01-1 Guanosine 5'-triphosphate 
• 1218-98-0 dihydro-7,8-D-neopterine 
• 73-40-5 2-amino-1,9-dihydro-6H-purin-6-one 
• 4271-30-1 N-(4-aminobenzoyl)-L-glutamic acid 
• 3672-03-5 7,8-dihydro-6-(hydroxymethyl)pterin 
• 3545-84-4 6-hydroxymethyl-7,8-dihydro-pterin pyrophosphate 
• 59-30-3 folate 
• 65165-92-6 folate 
• 142811-50-5 N-<4-<<2(S)-(benzylamino)-3-<(2-amino-5-nitro-4(3H)-oxopyrimidin-6-yl)amino>propyl>amino>benzoyl>-L-glutamic acid 
• 142811-48-1 [(R)-2-(2-Amino-5-nitro-6-oxo-1,6-dihydro-pyrimidin-4-ylamino)-1-formyl-ethyl]-benzyl-carbamic acid tert-butyl ester 
• 142811-47-0 2-amino-6-<<2'(R)--3'-hydroxypropyl>amino>-5-nitro-4(3H)-pyrimidinone 
• 142811-46-9 2-amino-6<<2'(R)-(benzylamino)-3'-hydroxypropyl>amino>-5-nitro-4(3H)-pyrimidinone 
• 142811-49-2 N-<4-<<2(S)--3-<(2-amino-5-nitro-4(3H)-oxopyrimidin-6-yl)amino>propyl>amino>benzoyl>-L-glutamic acid 

Downstream Products

• 31690-09-2 (6S)-N-[4-[[(2-amino-1,4,5,6,7,8-hexahydro-4-oxo-4-oxo-5-methyl-6-pteridinyl)methyl]amino]benzoyl]-L-glutamic acid 
• 31690-11-6 N⁵,N¹⁰-methylenetetrahydrofolate 
• 10538-99-5 5,6,7,8-tetrahydro-N⁵,N¹⁰-carbonylfolic acid 
• 10538-98-4 5,6,7,8-tetrahydro-N⁵,N¹⁰-(thiocarbonyl)folic acid 
• 72973-84-3 N⁵,N¹⁰-ethylene-5,6,7,8-tetrahydrofolic acid 
• 80402-46-6 5-(5-hydroxypentyl)-5,6,7,8-tetrahydrofolic acid 
• 72973-90-1 5-(carboxymethyl)-5,6,7,8-tetrahydrofolic acid 
• 1492-18-8 (6S)-5-formyltetrahydrofolic acid calcium salt 
• 82949-83-5 5,10-bis(uracil-5-ylmethyl)tetrahydropteroylglutamic acid 
• 65981-90-0 (6R)-5,10-methylylidenetetrahydrofolic acid chloride 
• 58-05-9 <6S>-N⁵-formyltetrahydrofolic acid 

Relevant academic research and scientific papers

Process for preparing L-5 - methyl tetrahydrofolinate

The invention relates to a preparation process of L-5 - methyl tetrahydrofolic acid, which adopts asymmetric catalytic hydrogenation to convert folic acid into (6S) - tetrahydro folic acid, and has high folic acid conversion rate, and (6S) - tetrahydrofolic acid diastereomeric excess degree. By salt formation and crystallization, the (6S) - tetrahydrofolic acid intermediate with extremely high diastereomeric excess can be easily enriched, and thus the yield and purity of L-5 - methyltetrahydrofolinate finally obtained are high. The catalytic hydrogenation process is very mature in industrial application and convenient to operate. The subsequent methylation and salt formation steps are easy to implement, and the preparation process has high economic value and practical value under the condition that the yield and purity of the product are improved.

Chemoenzymatic Assembly of Isotopically Labeled Folates

Pterin-containing natural products have diverse functions in life, but an efficient and easy scheme for their in vitro synthesis is not available. Here we report a chemoenzymatic 14-step, one-pot synthesis that can be used to generate 13C- and 15N-labeled dihydrofolates (H2F) from glucose, guanine, and p-aminobenzoyl-l-glutamic acid. This synthesis stands out from previous approaches to produce H2F in that the average yield of each step is >91% and it requires only a single purification step. The use of a one-pot reaction allowed us to overcome potential problems with individual steps during the synthesis. The availability of labeled dihydrofolates allowed the measurement of heavy-atom isotope effects for the reaction catalyzed by the drug target dihydrofolate reductase and established that protonation at N5 of H2F and hydride transfer to C6 occur in a stepwise mechanism. This chemoenzymatic pterin synthesis can be applied to the efficient production of other folates and a range of other natural compounds with applications in nutritional, medical, and cell-biological research.

Process For The Preparation Of Optically Pure Tetrahydropterins And Derivatives, And Specifically Of Optically Pure Tetrahydrofolic Acid And Derivatives Thereof, By Stereospecific Hydrogenation

Process for the preparation of tetrahydropterin and tetrahydropterin derivatives by hydrogenating pterin and pterin derivatives with hydrogen in the presence of a hydrogenating catalyst, in which the hydrogenation is carried out in a polar reaction medium and metal complexes that are soluble in the reaction medium are employed as the hydrogenation catalysts. The process is suited to the hydrogenation, particularly asymmetric hydrogenation, of folic acid, folio acid salts, folio acid esters, folio acid ester salts or dihydroforms thereof, with the proviso that in the event of using folic acid, carboxylic acid salts thereof or dihydroforms thereof the reaction medium is aqueous, and in the event of using folic acid esters, folic acid ester salts or dihydroforms thereof the reaction medium is an alcohol. The process opens up straightforward access to achiral and chiral pterin derivatives.

Aqueous diastereoselective hydrogenation of folic acid to tetrahydrofolic acid in the presence of water-soluble Rh and Ir diphosphine complexes

Rhodium and iridium catalysts with chiral, water soluble diphosphine ligands, were used for the diastereoselective hydrogenation of folic acid disodium salt in water. Using a modified Rh/Josiphos type at 30 °C, l-tetrahydrofolic acid, a relevant pharmaceutical intermediate, was obtained with a selectivity of up to 49% de; at 70 °C turnover numbers of up to 2800 were achieved, albeit with lower selectivity. These results define the state of the art for this reaction.

Stable crystalline (6R) -tetrahydrofolic acid

Pure and extremely stable crystalline (6S)- and (6R)-tetrahydrofolic acids, absolutely inert even when exposed to air and elevated temperature without stabilizers being added, are prepared by a crystallization process at a pH of ≧3.5 for the preparation of crystalline (6S)-tetrahydrofolic acid and at a pH of ≧2 for the preparation of crystalline (6R)-tetrahydrofolic acid.

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.

Large-scale Chemoenzymic Synthesis of Calcium (6S)-5-Formyl-5,6,7,8-tetrahydrofolate using the NADPH Recycling Method

Chemoenzymic large-scale synthesis of the calcium salt of (6S)-5-formyltetrahydrofolic acid was achieved from folic acid 1 via (6S)-tetrahydrofolic acid by using dihydrofolate reductase (DHFR) produced by Escherichia coli, harbouring a high-expression plasmid, pTP64-1.On the other hand, for the diastereoselective reduction of 7,8-dihydrofolic acid 2 to tetrahydrofolate (6S)-3, a new NADPH recycling system was constructed by coupling with glucose dehydrogenase from Gluconobacter scleroides.Having these enzymic systems to hand, compound 1 was reduced by zinc powder in alkaline solution to give compound 2 which, without isolation, was reduced enzymatically to afford tetrahydrofolate (6S)-3 (94 percent de).The pH adjustment of the reaction mixture containing dihydrofolate 2 was done with phosphoric acid in order to remove zinc ion which inhibited the following enzymic reduction.The formed tetrahydrofolate (6S)-3 was converted into entirely optically pure N-formyl compound (6S)-5 on a large scale.The specific rotation value of (-)-leucovorin was 20D -13.3 (c 1, water).For the comparison of pharmacological effects, a completely optically pure form of (+)-leucovorin was also prepared on a preparative scale.Compound (6S)-5 was 300-fold more active compared with the (6R)-diastereoisomer.

Process for the preparation of (6S)- and (6R)-tetrahydrofolic acid

For the preparation of (6S)- and (6R)-tetrahydrofolic acid and their addition salts with a sulfonic acid or with sulfuric acid, (6R,S)-tetrahydrofolic acid is reacted with a sulfonic acid or with sulfuric acid, the resulting acid addition salt is fractionally crystallized and, if desired, the (6S)- or (6R)-tetrahydrofolic acid is liberated from the resulting diastereomeric acid addition salts by treatment with a base and isolated.

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.

ASYMMETRIC REDUCTION OF DIHYDROFOLATE USING DIHYDROFOLATE REDUCTASE AND CHIRAL BORON-CONTAINING COMPOUNDS

The reduction of dihydrofolic acid to chiral tetrahydrofolic acid has been investigated by enzymic and non-enzymic means.With dihydrofolate reductase from E.coli as catalyst and recycling systems for NADPH, up to 1 g of optically pure stable tetrahydrofolate derivatives was obtained.The technique makes the possibility of synthesising chiral 5-formyltetrahydrofolate (leucovorin) for use in cancer rescue therapy attainable.In contrast, although dihydrofolate was reduced by a number of chiral boranes and borates built from amino acids and amino alcohols, enantiomeric excesses were minimal.