DEP0043567DA - Process for the preparation of pteroylglutamic acid (folinic acid) - Google Patents
Process for the preparation of pteroylglutamic acid (folinic acid)Info
- Publication number
- DEP0043567DA DEP0043567DA DEP0043567DA DE P0043567D A DEP0043567D A DE P0043567DA DE P0043567D A DEP0043567D A DE P0043567DA
- Authority
- DE
- Germany
- Prior art keywords
- acid
- folinic
- preparation
- ccm
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 title claims description 12
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 title claims description 12
- 235000008191 folinic acid Nutrition 0.000 title claims description 12
- 239000011672 folinic acid Substances 0.000 title claims description 12
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 title claims description 12
- 229960001691 leucovorin Drugs 0.000 title claims description 12
- 238000000034 method Methods 0.000 title claims description 3
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 title claims 2
- 235000019152 folic acid Nutrition 0.000 title claims 2
- 239000011724 folic acid Substances 0.000 title claims 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 title claims 2
- 229960000304 folic acid Drugs 0.000 title claims 2
- 238000002360 preparation method Methods 0.000 title claims 2
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims description 6
- ZMDDOWQHSDJXDW-UHFFFAOYSA-N 2,3-dibromopropanal Chemical compound BrCC(Br)C=O ZMDDOWQHSDJXDW-UHFFFAOYSA-N 0.000 claims description 5
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 239000004220 glutamic acid Substances 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- SYEYEGBZVSWYPK-UHFFFAOYSA-N 2,5,6-triamino-4-hydroxypyrimidine Chemical compound NC1=NC(N)=C(N)C(O)=N1 SYEYEGBZVSWYPK-UHFFFAOYSA-N 0.000 claims description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000009835 boiling Methods 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000194017 Streptococcus Species 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229960002989 glutamic acid Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- BCHONLIBKIBVRS-VIFPVBQESA-N (2s)-2-[amino(benzoyl)amino]pentanedioic acid Chemical compound OC(=O)CC[C@@H](C(O)=O)N(N)C(=O)C1=CC=CC=C1 BCHONLIBKIBVRS-VIFPVBQESA-N 0.000 description 1
- GADGMZDHLQLZRI-VIFPVBQESA-N N-(4-aminobenzoyl)-L-glutamic acid Chemical compound NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 GADGMZDHLQLZRI-VIFPVBQESA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000004061 bleaching Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
Description
Es ist bekannt, dass Folinsäure durch Kondensation von 2,4,5-Triamino-6-oxy-pyrimidin, p-Amino-benzoyl-l-glutaminsäure und 2,3-Dibrom-propionaldehyd gewonnen werden kann. Hierbei entsteht intermediär das Dihydroprodukt, welches durch anschliessende Dehydrierung in Folinsäure übergeht. Die erhaltenen Ausbeuten an Folinsäure sind jedoch sehr gering.It is known that folinic acid can be obtained by condensation of 2,4,5-triamino-6-oxy-pyrimidine, p-amino-benzoyl-1-glutamic acid and 2,3-dibromopropionaldehyde. The intermediate product is the dihydro product, which is converted into folinic acid by subsequent dehydration. However, the yields of folinic acid obtained are very low.
Es wurde nun gefunden, dass man durch gleichzeitige Anwendung eines milden Oxydationsmittels, wie Jod oder Chinon bei der Kondensation die Ausbeute an Folinsäure auf ein Mehrfaches steigern kann. Dass die dehydrierende Kondensation auf diese Weise gelingen würde, war nicht zu erwarten, da Triaminooxypyrimidin selbst gegen Oxydationsmittel empfindlich ist.It has now been found that the simultaneous use of a mild oxidizing agent such as iodine or quinone in the condensation can increase the yield of folinic acid several times over. It was not to be expected that the dehydrogenative condensation would succeed in this way, since triaminooxypyrimidine itself is sensitive to oxidizing agents.
Bei der Durchführung des Verfahrens wird das Oxydationsmittel zusammen mit 2,3-Dibrom-propionaldehyd in Alkohol gelöst und der Lösung von Triaminooxypyrimidin und Aminobenzoylglutaminsäure zugetropft. Durch Anwendung eines Ueberschusses an 2,3-Dibrom-propionaldehyd wird die Ausbeute der Folinsäure noch erhöht.When carrying out the process, the oxidizing agent is dissolved in alcohol together with 2,3-dibromopropionaldehyde and added dropwise to the solution of triaminooxypyrimidine and aminobenzoylglutamic acid. By using an excess of 2,3-dibromopropionaldehyde, the yield of folinic acid is further increased.
Beispiel 1:Example 1:
5,2 g Triaminooxypyrimidinsulfat, 5,2 g p-Amino-benzoyl-l-glutaminsäure und 5,4 g kristallisiertes Natriumacetat werden in 500 ccm Wasser in der Wärme gelöst. Nach Abkühlen der Lösung auf 20° wird unter Rühren eine Lösung von 9 g 2,3-Dibrom-propionalde- hyd und 4,2 g Jod in 500 ccm Alkohol in 60 Min. eingetropft und dabei durch Zugabe von wenigen ccm 2-n.Natronlauge der p(sub)H-Wert bei 4 gehalten. Anschliessend wird noch eine Stunde weiter gerührt, darauf der erhaltene braune Niederschlag abgesaugt, mit Wasser und Alkohol gewaschen, in 1000 ccm siedendem Wasser aufgekocht und die Lösung schliesslich mit verdünnter Natronlauge auf p(sub)H = 7 gebracht. Von einem braunen Rückstand wird abfiltriert, das Filtrat auf p(sub)H = 3,5 eingestellt und in Eis gekühlt. Der abgeschiedene Niederschlag wird in 750 ccm siedendem Wasser suspendiert und die Lösung mit 2-n.Natronlauge wieder auf p(sub)H = 7 gebracht. Nach Zugabe von 5 g kristallisiertem Natriumacetat werden 5 g Bleicherde eingerührt, die Lösung heiss abfiltriert, das Filtrat auf p(sub)H = 3,5 gebracht und langsam abkühlen gelassen, wobei sich Folinsäure abscheidet. Die erhaltene Säure wird abgesaugt und mit Wasser und Alkohol gewaschen. Ausbeute: 820 mg = 8,6% der Theorie. Ihr Gehalt ergibt sich im Streptococcus faecalis-R-Test zu 100%.5.2 g of triaminooxypyrimidine sulfate, 5.2 g of p-amino-benzoyl-1-glutamic acid and 5.4 g of crystallized sodium acetate are dissolved in 500 cc of warm water. After cooling the solution to 20 °, a solution of 9 g of 2,3-dibromo-propionalde- hyd and 4.2 g of iodine in 500 cc of alcohol were added dropwise in 60 minutes and the p (sub) H value was kept at 4 by adding a few cc of 2N sodium hydroxide solution. The mixture is then stirred for a further hour, then the brown precipitate obtained is filtered off with suction, washed with water and alcohol, boiled in 1000 ccm of boiling water and the solution is finally brought to p (sub) H = 7 with dilute sodium hydroxide solution. A brown residue is filtered off, the filtrate is adjusted to p (sub) H = 3.5 and cooled in ice. The deposited precipitate is suspended in 750 ccm of boiling water and the solution is brought back to p (sub) H = 7 with 2N sodium hydroxide solution. After adding 5 g of crystallized sodium acetate, 5 g of bleaching earth are stirred in, the solution is filtered off while hot, the filtrate is brought to p (sub) H = 3.5 and allowed to cool slowly, with folinic acid separating out. The acid obtained is filtered off with suction and washed with water and alcohol. Yield: 820 mg = 8.6% of theory. Their content is 100% in the Streptococcus faecalis-R test.
Beispiel 2.Example 2.
2,6 g Triaminooxypyrimidin, 2,6 g p-Aminobenzoyl-l-glutaminsäure und 2,7 g kristallisiertes Natriumacetat werden in 250 ccm Wasser heiss gelöst und in die auf 20° abgekühlte Lösung unter Rühren eine Lösung von 4,5 g 2,3-Dibrom-propionaldehyd und 0,8 g Chinon in 250 ccm Alkohol langsam eingetropft. Nach 2 stündigem Weiterrühren wird abgesaugt, der braune Niederschlag mit Wasser und Alkohol gewaschen und getrocknet. Das Rohprodukt von 1,9 g mit einem Gehalt von etwa 50% Folinsäure wird mit 2000 ccm und darauf mit 500 ccm Wasser ausgekocht. Die Filtrate werden mit wenig Essigsäure versetzt und nach dem Abkühlen auf 0° die Folinsäure abgesaugt. Die Säure wird in 1000 ccm siedendes Wasser eingetragen, mit 2-n.Natronlauge auf den Neutralpunkt eingestellt, 5 g Bleicherde eingerührt und heiss filtriert. Zur Umkristallisierung wird die Folinsäure in 250 ccm Wasser und 5 ccm 2-n.Natronlauge kalt gelöst, diese Lösung in eine siedende Lösung von 750 ccm Wasser und 3 ccm 2-n.Salzsäure und 30 ccm 2-n.Essigsäure eingetragen und heiss filtriert. Beim Abkühlen scheiden sich 392 mg reine Folinsäure = 8,4% der Theorie aus. Ihr Gehalt ergibt sich im Streptococcus faecalis-R-Test zu 100%.2.6 g of triaminooxypyrimidine, 2.6 g of p-aminobenzoyl-l-glutamic acid and 2.7 g of crystallized sodium acetate are dissolved in 250 ccm of hot water and, while stirring, a solution of 4.5 g of 2, 3-Dibromo-propionaldehyde and 0.8 g of quinone in 250 cc of alcohol were slowly added dropwise. After stirring for a further 2 hours, the mixture is filtered off with suction, the brown precipitate is washed with water and alcohol and dried. The crude product of 1.9 g with a content of about 50% folinic acid is boiled with 2000 ccm and then with 500 ccm of water. A little acetic acid is added to the filtrates and, after cooling to 0 °, the folinic acid is filtered off with suction. The acid is introduced into 1000 cc of boiling water, adjusted to the neutral point with 2N sodium hydroxide solution, stirred in 5 g of fuller's earth and filtered while hot. For recrystallization, the folinic acid is dissolved cold in 250 ccm water and 5 ccm 2N sodium hydroxide solution, this solution is added to a boiling solution of 750 ccm water and 3 ccm 2N hydrochloric acid and 30 ccm 2N acetic acid and filtered hot . On cooling, 392 mg of pure folinic acid = 8.4% of theory are eliminated. Their content is 100% in the Streptococcus faecalis-R test.
Claims (1)
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