DEP0047312DA - Process for the preparation of pteroylglutamic acid (folinic acid) - Google Patents
Process for the preparation of pteroylglutamic acid (folinic acid)Info
- Publication number
- DEP0047312DA DEP0047312DA DEP0047312DA DE P0047312D A DEP0047312D A DE P0047312DA DE P0047312D A DEP0047312D A DE P0047312DA
- Authority
- DE
- Germany
- Prior art keywords
- acid
- preparation
- folinic
- pteroylglutamic
- folinic acid
- 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
- 229960000304 Folic Acid Drugs 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
- 235000008191 folinic acid Nutrition 0.000 title description 8
- 239000011672 folinic acid Substances 0.000 title description 8
- 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 description 8
- 229960001691 leucovorin Drugs 0.000 title description 8
- SYEYEGBZVSWYPK-UHFFFAOYSA-N 2,5,6-triamino-1H-pyrimidin-4-one Chemical compound NC1=NC(N)=C(N)C(O)=N1 SYEYEGBZVSWYPK-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- FNYCCOFOQIUTIM-UHFFFAOYSA-N 1,1,3-tribromopropan-2-one Chemical compound BrCC(=O)C(Br)Br FNYCCOFOQIUTIM-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000004220 glutamic acid Substances 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- BEWGXCJZMNOBIQ-UHFFFAOYSA-N 2,2,3-tribromopropanal Chemical compound BrCC(Br)(Br)C=O BEWGXCJZMNOBIQ-UHFFFAOYSA-N 0.000 description 1
- OJXLWGRUKFKOII-UHFFFAOYSA-N 3,3,3-tribromopropanal Chemical compound BrC(Br)(Br)CC=O OJXLWGRUKFKOII-UHFFFAOYSA-N 0.000 description 1
- 229940040526 Anhydrous Sodium Acetate Drugs 0.000 description 1
- 241000194032 Enterococcus faecalis Species 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- NBBJYMSMWIIQGU-UHFFFAOYSA-N propionic aldehyde Chemical class CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Description
Es sind bereits Synthesen von Folinsäure aus 2,4,5,- Triamino-6-oxy-pyrimidin, p-Amino-benzoylglutaminsäure und dihalogeniertem Propionaldehyd bzw. Dibromacrolein beschreiben worden, die in der Vorstufen zu hydrierten Produkten der Folinsäure führen, aus welchen durch gleichzeitige oder nachträgliche Einwirkung dehydrierender Mittel der Folinsäure gebildet werden muss.Syntheses of folinic acid from 2,4,5-triamino-6-oxy-pyrimidine, p-amino-benzoylglutamic acid and dihalogenated propionaldehyde or dibromacrolein have already been described, which lead in the preliminary stages to hydrogenated products of folinic acid, from which simultaneous or subsequent exposure to dehydrating agents of folinic acid must be formed.
Es wurde nun gefunden , dass die Bildung von hydrierten Produkten in der Zwischenstufe dadurch vermieden werden kann, dass man anstelle der dihalogenierten Ausgangsstoffe trihalogenierten bei der Kondensation verwendet. So gelingt es, durch Kondensation von 2,2,3-Tribrom-propionaldehyd oder 1,1,3-Tribrom-aceton mit 6-Oxy-2,4,5-Tribrom-pyrimidin und p-Amino-benzoyl-l-glutaminsäure Folinsäure in verbesserter Ausbeute herzustellen ( bis zu 9% d.Th., mit Streptococcus faecalis R mikrobiologisch bestimmt). Durch Verwendung von 1,1,3-Tribrom-aceton um Ueberschuss und Glykol als Lösungsmittel konnte die Ausbeute an Folinsäure bis auf 14% d.Th. gesteigert werden.It has now been found that the formation of hydrogenated products in the intermediate stage can be avoided by using trihalogenated starting materials in the condensation instead of the dihalogenated starting materials. It is possible, for example, to condense 2,2,3-tribromopropionaldehyde or 1,1,3-tribromo-acetone with 6-oxy-2,4,5-tribromopyrimidine and p-amino-benzoyl-1-glutamic acid Produce folinic acid in improved yield (up to 9% of theory, determined microbiologically with Streptococcus faecalis R). By using an excess of 1,1,3-tribromo-acetone and glycol as solvent, the yield of folinic acid could be reduced to 14% of theory. can be increased.
Beispiel 1example 1
1,9 g Triaminooxypyrimidin-chlorhydrat, 2,1 g p-Amino-benzoyl-l-glutaminsäure und 6 g krist. Natriumacetat werden in 200 ccm Wasser heiss gelöst. Hierzu wird unter Rühren Lösung von 2,4 g 2,2,5 Tribrompropionaldehyd in 200 ccm Aethanol einge- tropft. Nach 1/2 stündigem Kochen wird heiss filtriert (Rückstand A) das Filtrat auf p(sub)H 3,5 gebracht und abgekühlt. Der dabei entstehende braune Niederschlag wird mit verdünnter Natriumacetatlösung ausgekocht, worauf sich aus dem Filtrat nach Zusatz von 2-n. HCI (bis zu p(sub)H = 3,5 120 mg eines gelbbraunen Niederschlags abscheiden, der 60 % Folinsäure enthält.1.9 g of triaminooxypyrimidine chlorohydrate, 2.1 g of p-amino-benzoyl-1-glutamic acid and 6 g of crystalline. Sodium acetate are dissolved in 200 ccm hot water. For this purpose, a solution of 2.4 g of 2.2.5 tribromopropionaldehyde in 200 ccm of ethanol is added with stirring. drips. After boiling for 1/2 hour, the mixture is filtered hot (residue A), the filtrate is brought to p (sub) H 3.5 and cooled. The resulting brown precipitate is boiled with dilute sodium acetate solution, whereupon the filtrate, after the addition of 2-n. HCI (up to p (sub) H = 3.5 separate 120 mg of a yellow-brown precipitate which contains 60% folinic acid.
Beispiel 2Example 2
0,8 g Triamino-oxypirimidin-sulfat, 0,85 g p-Aminobenzoyl-l-glutaminsäure und 0,7 g wasserfreies Natriumacetat werden in 35 ccm Glykol suspendiert. Unter Rühren werden 1,5 g 1,1,3-Tribrom-aceton, gelöst in 3 ccm Glykol + 7 ccm Methanol, zugetropft. Das sich alsbald dunkelbraun färbende Gemisch wird zunächst 1/2 Stunden bei Zimmertemperatur gerührt, dann 1/2 Stunden unter Rühren auf 70-80° erhitzt. Darauf wird noch heiss in 100 ccm Wasser gegossen und mit verdünnter Natronlauge auf p(sub)H = 3,5 gebracht. Der nach einigen Stunden abgetrennte Niederschlag wird mit 500 ccm Wasser, dem verdünnte Natronlauge und Natriumacetat zugesetzt würde (p(sub)H = 7), ausgekocht, wobei braune Begleitstoffe mit Bleicherde entfernt werden. Das Filtrat wird bis auf p(sub)H = 3,5 angesäuert und abgekühlt, worauf sich 45% Folinsäure enthaltender Niederschlag abscheidet. Zur weiteren Reinigung wird nochmals mit Bleicherde behandelt, und bei p(sub)H = 3,5 ausgefällt und aus Wasser umkristallisiert.0.8 g of triamino-oxypirimidine sulfate, 0.85 g of p-aminobenzoyl-1-glutamic acid and 0.7 g of anhydrous sodium acetate are suspended in 35 cc of glycol. While stirring, 1.5 g of 1,1,3-tribromo-acetone, dissolved in 3 cc of glycol + 7 cc of methanol, are added dropwise. The mixture, which soon turns dark brown, is first stirred for 1/2 hour at room temperature, then heated to 70-80 ° for 1/2 hour while stirring. Then it is poured into 100 ccm of water while still hot and brought to p (sub) H = 3.5 with dilute sodium hydroxide solution. The precipitate separated off after a few hours is boiled with 500 ccm of water to which dilute sodium hydroxide solution and sodium acetate would be added (p (sub) H = 7), brown accompanying substances being removed with fuller's earth. The filtrate is acidified to p (sub) H = 3.5 and cooled, whereupon 45% folinic acid-containing precipitate separates out. For further purification, it is treated again with fuller's earth, and at p (sub) H = 3.5 it is precipitated and recrystallized from water.
Claims (1)
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