- Process for preparing L-5 - methyl tetrahydrofolinate
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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.
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Paragraph 0050-0051; 0055-0056; 0058-0059; 0061-0062
(2021/11/06)
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- Chemoenzymatic Assembly of Isotopically Labeled Folates
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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.
- Angelastro, Antonio,Dawson, William M.,Luk, Louis Y. P.,Loveridge, E. Joel,Allemann, Rudolf K.
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supporting information
p. 13047 - 13054
(2017/09/26)
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- Process For The Preparation Of Optically Pure Tetrahydropterins And Derivatives, And Specifically Of Optically Pure Tetrahydrofolic Acid And Derivatives Thereof, By Stereospecific Hydrogenation
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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.
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Page/Page column 19-20
(2009/01/20)
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- Aqueous diastereoselective hydrogenation of folic acid to tetrahydrofolic acid in the presence of water-soluble Rh and Ir diphosphine complexes
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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.
- Pugin, Benoit,Groehn, Viola,Moser, Rudolf,Blaser, Hans-Ulrich
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p. 544 - 549
(2007/10/03)
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- Stable crystalline (6R) -tetrahydrofolic acid
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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.
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- Enantioselective catalyses CXXXV [1]. Stereoselective hydrogenation of folic acid and 2-methylquinoxaline with optically active rhodium(I)-phosphane complexes
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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.
- Brunner, Henri,Rosenboem, Sabine
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p. 1371 - 1382
(2007/10/03)
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- Stereoselective hydrogenation of folie acid with immobilized optically active rhodium(I)/diphosphane catalysts
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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.
- Brunner, Henri,Bublak, Petra,Helget, Martina
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- Large-scale Chemoenzymic Synthesis of Calcium (6S)-5-Formyl-5,6,7,8-tetrahydrofolate using the NADPH Recycling Method
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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.
- Kuge, Yukihiro,Inoue, Kunimi,Ando, Kyoji,Eguchi, Tamotsu,Oshiro, Takashi,et al.
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p. 1427 - 1432
(2007/10/02)
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- Process for the preparation of (6S)- and (6R)-tetrahydrofolic acid
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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.
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- NADPH regeneration by glucose dehydrogenase from Gluconobacter scleroides for l-leucovorin synthesis.
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A new process for (6S)-tetrahydrofolate production from dihydrofolate was designed that used dihydrofolate reductase and an NADPH regeneration system. Glucose dehydrogenase from Gluconobacter scleroides KY3613 was used for recycling of the cofactor. The reaction mixture contained 200 mM dihydrofolate, 220 mM glucose, 2 mM NADP, 14.4 U/ml dihydrofolate reductase, and 14.4 U/ml Glucose dehydrogenase, and the reaction was complete after incubation at pH 8.0, and 40 degrees C for 2.5 hr. With (6S)-tetrahydrofolate as the starting material, l-leucovorin was synthesized via a methenyl derivative. The purity of the l-leucovorin was 100%, and its diastereomeric purity was greater than 99.5% d.e. as the (6S)-form.
- Eguchi,Kuge,Inoue,Yoshikawa,Mochida,Uwajima
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p. 701 - 703
(2007/10/02)
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- Synthesis of Tetrahydropteridine C6-Stereoisomers, Including N5-Formyl-(6S)-tetrahydrofolic Acid
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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.
- Bailey, Steven W.,Chandrasekaran, Rama Y.,Ayling, June E.
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p. 4470 - 4477
(2007/10/02)
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- Asymmetric Catalysis, 67. - Diastereoselective Hydrogenation of Folic Acid with Optically Active Rhodium(I)-Diphosphane Complexes
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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)-
- Brunner, Henri,Huber, Christian
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p. 2085 - 2094
(2007/10/02)
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- ASYMMETRIC REDUCTION OF DIHYDROFOLATE USING DIHYDROFOLATE REDUCTASE AND CHIRAL BORON-CONTAINING COMPOUNDS
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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.
- Rees, Lilias,Valente, Edward,Suckling, Colin J.,Wood, Hamish C. S.
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p. 117 - 136
(2007/10/02)
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- Investigation of a Chemical Model for the Methylation of Deoxyuridine Monophosphate by Thymidylate Synthetase
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The compound (4a; R2 = H), long regarded as a putative intermediate in a chemical model for thymine biosynthesis, has been reformulated as the bis-adduct (4b; R2 = H); a chemical model for the action of thymidylate synthetase has been achieved and the result is discussed.
- Charlton, Peter A.,Young, Douglas W.
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p. 614 - 616
(2007/10/02)
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