EP0314720A1 - Process for separation of folinic acids - Google Patents

Process for separation of folinic acids

Info

Publication number
EP0314720A1
EP0314720A1 EP88903810A EP88903810A EP0314720A1 EP 0314720 A1 EP0314720 A1 EP 0314720A1 EP 88903810 A EP88903810 A EP 88903810A EP 88903810 A EP88903810 A EP 88903810A EP 0314720 A1 EP0314720 A1 EP 0314720A1
Authority
EP
European Patent Office
Prior art keywords
folinate
calcium
acid
alkaline earth
recrystallization
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.)
Pending
Application number
EP88903810A
Other languages
German (de)
French (fr)
Inventor
Hans Rudolf Mueller
Martin Ulmann
Josef Conti
Günter MUERDEL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eprova AG
Original Assignee
Eprova AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=4220822&utm_source=***_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP0314720(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Eprova AG filed Critical Eprova AG
Publication of EP0314720A1 publication Critical patent/EP0314720A1/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
    • C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2

Definitions

  • the invention relates to a process for the preparation of (6S) -folic acid or salts thereof, in particular calcium, magnesium, potassium and sodium folinate.
  • Folinic acid is N- (5-formyl- (6R, S) -5,6,7,8-tetrahydro-pteroyl) -L-glutamic acid (5-CH0- (6R, S) -H 4 PteGlu).
  • Leucovorin is becoming increasingly important as a medicament for the treatment of ceremonioblastic folic acid deficiency anemia, as an antidote for increasing the tolerance of folic acid antagonists, especially of aminopterin and methotrexate in cancer therapy (leucovorin rescue), and for the treatment of autoimmune diseases such as psoriasis and rheumatic arthritis Increasing the tolerance of certain antiparasitic drugs such as trimethoprim sulfamethoxazole in chemotherapy.
  • Crystallization of an alkaline earth salt for example the calcium or strontium salt, of 5-formyl- (6R, S) -5,6,7,8-tetrahydropteroyl-L-glutamic acid from an aqueous solution.
  • the desired separation cannot be achieved under the conditions disclosed by B. Cosulich et al.
  • the calcium salt of 5-formyl- (6R, S) -5,6,7,8-tetrahydropteroyl-L-glutamic acid from water at pH 7-8 pure 6R, S form is always obtained obtained, as can be demonstrated quantitatively by means of chromatographic analysis on a chiral HPLC column and by means of optical rotation.
  • the (6S) form predominantly crystallizes out first, the content of the ( ⁇ S) form in the crystals being able to reach 85% and more .
  • the alkaline earth folinate with a high (6S) form content which is highly enriched with the (6S) form, can optionally be converted into optically pure alkaline earth metal (6S) by further recrystallization, preferably from water at approximately neutral pH. -Trolinate transfer.
  • the yield can be increased by adding alkaline earth ions, e.g. of calcium, magnesium or strontium chloride can be improved.
  • alkaline earth ions e.g. of calcium, magnesium or strontium chloride
  • the invention thus relates to a process for the preparation of ( ⁇ S) -folinic acid or salts thereof by recrystallization of alkaline earth metal salts of (6R, S) -folinic acid and, if appropriate, releasing the acid from the alkaline earth metal liners and / or if appropriate converting them to the alkali metal salts, which is characterized in that the recrystallization is carried out in the presence of a base.
  • the invention further relates to a process in which the crystals obtained are subjected to at least one further recrystallization in the presence of a base or at an approximately neutral pH.
  • the recrystallizations are carried out in the presence of additional alkaline earth metal ions.
  • Both pure alkaline earth metal (6R, S) folinates and raw alkaline earth metal (6R, S) folinates are suitable as starting materials for the process.
  • This process has made the calcium and magnesium salts of N- (5-formyl-6S) -5,6,7,8-tetrahydropteroyl) -L-glutamic acid technically accessible for the first time.
  • Calcium, magnesium, strontium and barium folinate are suitable as alkaline earth metal salts of folic acid. Calcium and magnesium folinate are preferred because, after separation, they can be used directly as medicinal products, while the strontium and especially the barium salt are subsequently converted into another, physiologically acceptable, salt.
  • suitable inorganic or organic bases are: alkali metal hydroxides such as sodium, potassium and lithium hydroxide,
  • Alkaline earth metal hydroxides such as, in particular, calcium and magnesium hydroxide
  • Ammonia, hydrazine, water-soluble organic bases especially simple primary, secondary, tertiary amines, e.g. Methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, methylethylamine, amino alcohols, e.g. Ethanolamine, diethanolamine, triethanolamine, propanolamine, butanolamine, dihydroxypropylamine (2,3-dihydroxy propylamine, serinol), trihydroxybutylamine (tris (hydroxymethyl) aminomethane), glucamine, N-methylglucamine, heterocyclic amines, e.g. Pyrrolidine, piperidine, morpholine or
  • the first recrystallization according to the inventive method is carried out at a pH between 8.5 and 12, preferably between 9.0 and 10.5.
  • a pH between 8.5 and 12, preferably between 9.0 and 10.5.
  • the stability of the folinic acid becomes noticeably lower and, moreover, the alkaline earth metal salts can hardly be brought to crystallization.
  • alkaline earth ( ⁇ S) - folinate can also be carried out in an approximately neutral environment, for example in the pH range from 6.5 to 8.5.
  • the solubility product can be reached more quickly by adding appropriate alkaline earth metal ions and the yield can thus be increased.
  • the alkaline earth ions preferably Ca, Mg, Sr, are added in the form of any readily soluble salts, for example in the form of the chlorides, sulfates or nitrates. They are usually used in 0.2 to 4 times the amount of folinate.
  • the invention also relates to those of the invention
  • the magnesium (6S) folinate is of outstanding importance because, because of its comparatively good water solubility of more than 2 g / 100 ml and its high tolerance, it forms the suitable starting material for the production of injection solutions. The same applies even more to the sodium and potassium (6S) folinate.
  • the calcium (6S) folinate can only form 0.95% aqueous solutions at 20 ° C., which makes the production of injection solutions more difficult. Examples to illustrate the invention:
  • Solubility in water 0.95 g / 100 ml at 20 ° C and 1.5 g / 100 ml at 40 ° C
  • CaFolinate content determined by HPLC against standard. Content of ( ⁇ S) form: determined by HPLC using a chiral column (resolvosil-BSA-7).
  • the solution is stirred at room temperature for 5 to 17 hours.
  • the crystals are filtered off, washed with a little 5% calcium chloride solution and with ethanol and dried.
  • a practically saturated aqueous solution of calcium ( ⁇ S) -folinate is passed through an ion exchange column, which is coated with cation exchange resin in the Na ⁇ form, e.g. with A berlite IR-120, Na ⁇ form, percolate.
  • the eluate is concentrated.
  • the sodium (6S) -folinate is precipitated by adding ethanol.
  • Sodium (6S) folinate is easily soluble in water.
  • the sodium (6S) -folinate can also be obtained by dissolving (6S) -folinic acid in the equivalent amount of sodium hydroxide.
  • the ( ⁇ S) -folic acid required for this is obtained according to Example 6.
  • This compound is obtained by dissolving (6S) -folinic acid obtained according to Example 6 in the equivalent amount of aqueous potassium hydroxide.
  • the potassium (6S) -folinate can be precipitated from its concentrated aqueous solutions by adding ethanol, isopropanol or acetone. Potassium (6S) folinate is easily soluble in water.
  • Dilute hydrochloric acid is carefully added to an aqueous solution of calcium ( ⁇ S) -folinate, whereby the ( ⁇ S) -folinic acid precipitates and is obtained by filtration.
  • ( ⁇ S) -folic acid is hardly soluble in water.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Un procédé permet de produire des acides (6S) foliniques et leurs sels par recristallisation de sels alcalino-terreux des acides (6R, S) foliniques, éventuellement par libération de ces acides contenus dans des folinates alcalino-terreux et/ou éventuellement leur conversion en sels alcalins au moyen d'au moins une recristallisation en présence d'une base. L'invention concerne également des folinates (6S) de calcium, de magnésium, de potassium et de sodium et les acides (6S) foliniques produits selon le procédé décrit.A process makes it possible to produce (6S) folinic acids and their salts by recrystallization of alkaline earth salts of (6R, S) folinic acids, optionally by liberation of these acids contained in alkaline earth folinates and / or optionally their conversion into alkaline salts by means of at least one recrystallization in the presence of a base. The invention also relates to folinates (6S) of calcium, magnesium, potassium and sodium and the folinic acids (6S) produced according to the process described.

Description

Verfahren zur Trennung von Folinsäure Process for the separation of folic acid
Die Erfindung betrifft ein Verfahren zur Herstellung von (6S)-Folin- säure bzw. von deren Salzen, insbesondere des Calcium-, Magnesium-, Kalium- und Natriu folinats.The invention relates to a process for the preparation of (6S) -folic acid or salts thereof, in particular calcium, magnesium, potassium and sodium folinate.
Folinsäure ist N-(5-Formyl-(6R,S)-5,6,7,8-tetrahydro-pteroyl)-L- gluta insäure (5-CH0-(6R,S)-H4PteGlu). N-(5-Formyl-(6S)-5,6,7,8- tetrahydropteroyD-L-glutaminsäure (5-CHO-(6S)-H.pteGlu) ist der Citrovorum-Faktor (= Wachstumsfaktor für Leuconostoc citrovorum).Folinic acid is N- (5-formyl- (6R, S) -5,6,7,8-tetrahydro-pteroyl) -L-glutamic acid (5-CH0- (6R, S) -H 4 PteGlu). N- (5-Formyl- (6S) -5,6,7,8-tetrahydropteroyD-L-glutamic acid (5-CHO- (6S) -H.pteGlu) is the citrovorum factor (= growth factor for Leuconostoc citrovorum).
Folinsäure enthält 2 asymmetrische Zentren. Dabei liegt aufgrund der Synthese der Folinsäure aus Folsäure, der N-(Pteroyl)-L-glutamin- säure, das im Glutaminsäure-Rest enthaltene optisch aktive C-Atom in der L-Form vor, während das durch Hydrierung der Doppelbindung in 5,6-Stellung des Pteroyl-restes entstandene optisch aktive C-Atom in Position 6 in der racemischen, der (6R,S)-Form, vorliegt. Synthe- tische Folinsäure (= Leucovorin) besteht demnach aus einer 1:1-Mi- schung von zwei Diastereomeren.Folic acid contains 2 asymmetric centers. Due to the synthesis of folic acid from folic acid, N- (pteroyl) -L-glutamic acid, the optically active C atom contained in the glutamic acid residue is in the L-form, while the hydrogenation of the double bond in 5, 6-position of the pteroyl residue, the optically active carbon atom in position 6 is in the racemic, the (6R, S) form. Accordingly, synthetic folic acid (= leucovorin) consists of a 1: 1 mixture of two diastereomers.
Leucovorin findet zunehmende Bedeutung als Arzneimittel zur Behand¬ lung von egaloblastischer Folsäuremangel-Anämie, als Antidot zur Verstärkung der Verträglichkeit von Folsäure-Antagonisten speziell von Aminopterin und Methotrexat in der Krebstherapie (leucovorin rescue) und der Behandlung von Autoimmunkrankheiten wie Psoriasis und rheumatischer Arthritis sowie zur Verstärkung der Verträglichkeit von bestimmten Antiparasitika etwa Trimethoprim-Sulfamethoxazol in der Chemotherapie.Leucovorin is becoming increasingly important as a medicament for the treatment of egaloblastic folic acid deficiency anemia, as an antidote for increasing the tolerance of folic acid antagonists, especially of aminopterin and methotrexate in cancer therapy (leucovorin rescue), and for the treatment of autoimmune diseases such as psoriasis and rheumatic arthritis Increasing the tolerance of certain antiparasitic drugs such as trimethoprim sulfamethoxazole in chemotherapy.
In natürlichen Vorkommen, z.B. in der Leber, findet man die Folin¬ säure nur in der S-Form. Die biochemische Wirkung von Leucovorin als Folsäure Cofaktor beruht auf dessen Gehalt an 5-CHO-(6S)-H.PeGlu. Die inverse (R)-Form -5-CH0-(6R)-H4PteGlu- dagegen wird kaum metaboli- siert und langsam durch den Urin ausgeschieden. Sie ist biochemisch unwirksam. J.A. Straw et al, Cancer Research 44, 3114 (1984).In natural occurrences, for example in the liver, folinic acid is only found in the S form. The biochemical effects of leucovorin as Folic acid cofactor is based on its 5-CHO- (6S) -H.PeGlu content. In contrast, the inverse (R) form -5-CH0- (6R) -H 4 PteGlu- is hardly metabolized and slowly excreted in the urine. It is biochemically ineffective. JA Straw et al, Cancer Research 44, 3114 (1984).
Es sind daher mehrfach Anstrengungen zur Trennung von 5-Formyl-(6R,S)- 5,6.,7,8-tetrahydropteroyl-L-glutaminsäure und zur asymmetrischen Synthese von 5-Formyl-(6S)-5,6,7,8-tetrahydropteroyl-Lglutaminsäure und Isolierung der physiologisch aktiven Form unternommen worden. D. Cosulich et al, J. Amer. ehem. Soc. 74, 4215-16 (1952), US Patent- schrift 2'688'018 haben versucht, die Trennung durch fraktionierteThere are multiple efforts to separate 5-formyl- (6R, S) - 5.6 . , 7,8-tetrahydropteroyl-L-glutamic acid and for the asymmetric synthesis of 5-formyl- (6S) -5,6,7,8-tetrahydropteroyl-lglutamic acid and isolation of the physiologically active form. D. Cosulich et al., J. Amer. former Soc. 74, 4215-16 (1952), US Patent 2,688,018 have attempted fractional separation
Kristallisation eines Erdalkali-salzes, z.B. des Calcium- oder Stron- tium-salzes, von 5-Formyl-(6R,S)-5,6,7,8-tetrahydropteroyl-L-glutamin- säure aus wässriger Lösung zu bewerkstelligen. Unter den von B. Cosulich et al offenbarten Bedingungen lässt sich die gewünschte Trennung nicht realisieren. Bei der Kristallisation z.B. des Calcium-salzes von 5-Formyl-(6R,S)-5,6,7,8-tetrahydro- pteroyl-L-glutaminsäure aus Wasser bei pH 7-8 wird immer wieder reine 6R,S-Form erhalten, wie sich mittels chromatographischer Analyse an einer chiralen HPLC-Säule sowie anhand der optischen Drehung quanti- tativ nachweisen lässt. Dabei ist es unerheblich, ob man rohes oder reines Calcium-salz von 5-CH0-(6R,S)-H4PteGlu zur Kristallisation einsetzt, stets wird die optisch reine (6R,S)-Form zurückerhalten. Eine Trennung und Anreicherung der (6S)-Form kann auch nicht erreicht werden, wenn man die übersättigte wässrige Lösung von Erdalkali- (6R,S)-Folinat mit authentischem Erdalkali-(6S)-Folinat impft.Crystallization of an alkaline earth salt, for example the calcium or strontium salt, of 5-formyl- (6R, S) -5,6,7,8-tetrahydropteroyl-L-glutamic acid from an aqueous solution. The desired separation cannot be achieved under the conditions disclosed by B. Cosulich et al. In the crystallization of, for example, the calcium salt of 5-formyl- (6R, S) -5,6,7,8-tetrahydropteroyl-L-glutamic acid from water at pH 7-8, pure 6R, S form is always obtained obtained, as can be demonstrated quantitatively by means of chromatographic analysis on a chiral HPLC column and by means of optical rotation. It is irrelevant whether raw or pure calcium salt of 5-CH0- (6R, S) -H 4 PteGlu is used for crystallization, the optically pure (6R, S) form is always retained. A separation and enrichment of the (6S) form can also not be achieved if the supersaturated aqueous solution of alkaline earth (6R, S) forminate is inoculated with authentic alkaline earth (6S) formate.
Damit blieb bis heute die asymmetrische Synthese als einzige Möglich¬ keit zur Gewinnung von N-(5-Formyl-(6S)-5,6,7,8-tetrahydropteroyl)-L- glutaminsäure. Die bisher bekannten Methoden der asymmetrischen Synthese von (6S)-Folinsäure sind jedoch zur Herstellung dieser Verbindung im technischen Massstab nicht geeignet. Es gibt daher bis heute keine technisch brauchbare Methode zur Gewinnung von (δS)-Folinsäure. Es bestand somit die Aufgabe, eine einfache, technisch brauchbare und wirtschaftliche Methode zur Herstellung von (δS)-Folinsäure und ihrer Salze zu erarbeiten.To date, asymmetric synthesis has remained the only way to obtain N- (5-formyl- (6S) -5,6,7,8-tetrahydropteroyl) -L-glutamic acid. However, the previously known methods of asymmetric synthesis of (6S) -folinic acid are not suitable for the preparation of this compound on an industrial scale. To date, there is therefore no technically usable method for obtaining (δS) -folinic acid. The task was therefore to develop a simple, technically usable and economical method for producing (δS) -folinic acid and its salts.
Es wurde nun überraschend gefunden, dass bei der Umkristallisation von Erdalkalisalzen von (6R,S)-Folinsäure, z.B. von Calcium-, Magne¬ sium- oder Strontium-N-(5-Formyl-(6R,S)-5,6,7,8-tetrahydroptero- yl)-L-glutaminat (= Erdalkali-(6R,S)-Folinat), vorzugsweise aus Was¬ ser, in Gegenwart von anorganischen oder organischen Basen in alkali¬ schem Milieu zunächst vorwiegend die (6S)Form auskristallisiert, wobei der Gehalt an der (δS)-Form im Kristallisat 85 % und mehr er¬ reichen kann.It has now surprisingly been found that in the recrystallization of alkaline earth metal salts of (6R, S) -folinic acid, e.g. of calcium, magnesium or strontium N- (5-formyl- (6R, S) -5,6,7,8-tetrahydropteroyl) -L-glutaminate (= alkaline earth metal (6R, S) - Folinate), preferably from water, in the presence of inorganic or organic bases in an alkaline medium, the (6S) form predominantly crystallizes out first, the content of the (δS) form in the crystals being able to reach 85% and more .
Das mit der (6S)-Form stark angereicherte Erdalkali-Folinat mit einem hohen (6S)-Form-Gehalt lässt sich gegebenenfalls durch weitere Umkri¬ stallisation, vorzugsweise aus Wasser bei etwa neutralem pH, in op- tisch reines Erdalkali-(6S)-Folinat überführen.The alkaline earth folinate with a high (6S) form content, which is highly enriched with the (6S) form, can optionally be converted into optically pure alkaline earth metal (6S) by further recrystallization, preferably from water at approximately neutral pH. -Trolinate transfer.
Bei der Kristallisation kann die Ausbeute durch Zusatz von Erdalkali¬ ionen, z.B. von Calcium-, Magnesium- oder Strontiumchlorid, verbes¬ sert werden.In the crystallization, the yield can be increased by adding alkaline earth ions, e.g. of calcium, magnesium or strontium chloride can be improved.
Gegenstand der Erfindung ist somit ein Verfahren zur Herstellung von (δS)-Folinsäure bzw. deren Salzen durch Umkristallisation von Erdal¬ kalisalzen der (6R,S)-Folinsäure und gegebenenfalls Freisetzung der Säure aus den Erdalkalifolinaten und/oder gegebenenfalls Ueberführung in die Alkalisalze, das sich dadurch auszeichnet, dass die Umkristal¬ lisation in Gegenwart einer Base durchgeführt wird.The invention thus relates to a process for the preparation of (δS) -folinic acid or salts thereof by recrystallization of alkaline earth metal salts of (6R, S) -folinic acid and, if appropriate, releasing the acid from the alkaline earth metal liners and / or if appropriate converting them to the alkali metal salts, which is characterized in that the recrystallization is carried out in the presence of a base.
Gegenstand der Erfindung ist ferner ein Verfahren, bei dem das erhal¬ tene Kristallisat in Gegenwart einer Base oder bei annähernd neutra¬ lem pH-Wert mindestens einer weiteren Umkristallisation unterworfen wird. Nach einer bevorzugten Ausführungsform werden die Umkristalli- sationen in Gegenwart von zusätzlichen Erdalkali-Ionen durchgeführt. Als Ausgangsmaterial für das Verfahren sind sowohl reine Erdal¬ kali-(6R,S)-Folinate als auch rohe Erdalkali-(6R,S)-Folinate geeig¬ net.The invention further relates to a process in which the crystals obtained are subjected to at least one further recrystallization in the presence of a base or at an approximately neutral pH. According to a preferred embodiment, the recrystallizations are carried out in the presence of additional alkaline earth metal ions. Both pure alkaline earth metal (6R, S) folinates and raw alkaline earth metal (6R, S) folinates are suitable as starting materials for the process.
Durch dieses Verfahren sind das Calcium- und Magnesium-salz von N-(5-Formyl-6S)-5,6,7,8-tetrahydropteroyl)-L-glutaminsäure erstmals technisch zugänglich geworden.This process has made the calcium and magnesium salts of N- (5-formyl-6S) -5,6,7,8-tetrahydropteroyl) -L-glutamic acid technically accessible for the first time.
Als Erdalkalisalze von Folinsäure kommen in Betracht das Calcium-, Magnesium-, Strontium- und Barium-Folinat. Vorgezogen werden das Calcium- und Magnesium-Folinat, weil diese nach erfolgter Trennung direkt als Arzneimittel verwendbar sind, während etwa das Strontium- und vor allem das Barium-Salz anschliessend in ein anderes, physiolo¬ gisch annehmbares, Salz umgewandelt werden.Calcium, magnesium, strontium and barium folinate are suitable as alkaline earth metal salts of folic acid. Calcium and magnesium folinate are preferred because, after separation, they can be used directly as medicinal products, while the strontium and especially the barium salt are subsequently converted into another, physiologically acceptable, salt.
Als anorganische oder organische Basen kommen beispielsweise in Be¬ tracht: Alkalihydroxide wie Natrium-, Kalium- und Lithium-hydroxid,Examples of suitable inorganic or organic bases are: alkali metal hydroxides such as sodium, potassium and lithium hydroxide,
Erdalkalihydroxide wie insbesondere Calcium- und Magnesium-hydroxid,Alkaline earth metal hydroxides such as, in particular, calcium and magnesium hydroxide,
Ammoniak, Hydrazin, wasserlösliche organische Basen, insbesonders einfache primäre, sekundäre, tertiäre Amine, z.B. Me- thylamin, Dimethylamin, Trimethylamin, Ethylamin, Diethylamin, Tri- ethylamin, Propylamin, Dipropylamin, Methylethylamin, Aminoalkohole, z.B. Ethanolamin, Diethanolamin, Triethanolamin, Propanolamine, Butanolamine, Dihydroxypropylamine (2,3-Dihyroxy- propylamin, Serinol), Trihydroxybutylamine (Tris-(hydroxymethyl)- aminomethan), Glucamin, N-Methyl-glukamin, heterocyklische Amine, z.B. Pyrrolidin, Piperidin, Morpholin oderAmmonia, hydrazine, water-soluble organic bases, especially simple primary, secondary, tertiary amines, e.g. Methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, methylethylamine, amino alcohols, e.g. Ethanolamine, diethanolamine, triethanolamine, propanolamine, butanolamine, dihydroxypropylamine (2,3-dihydroxy propylamine, serinol), trihydroxybutylamine (tris (hydroxymethyl) aminomethane), glucamine, N-methylglucamine, heterocyclic amines, e.g. Pyrrolidine, piperidine, morpholine or
Piperazin.Piperazine.
Die erste Umkristallisation nach dem erfindungsgemässen Verfahren wird bei einem pH-Wert zwischen 8,5 und 12, vorzugsweise zwischen 9,0 und 10,5, durchgeführt. Bei tieferem pH erfolgt keine deutliche An¬ reicherung der (δS)-Form im Kristallisat, bei höherem pH wird die Stabilität der Folinsäure merklich geringer und zudem sind die Erdal- kalisalze kaum noch zur Kristallisation zu bringen.The first recrystallization according to the inventive method is carried out at a pH between 8.5 and 12, preferably between 9.0 and 10.5. At a lower pH there is no significant accumulation of the (δS) form in the crystals, at a higher pH the stability of the folinic acid becomes noticeably lower and, moreover, the alkaline earth metal salts can hardly be brought to crystallization.
Zur Entfernung restlicher Mengen von (δR)-Folinat aus Erdalkali-(δS)- Folinat können weitere Umkristallisationen auch in annähernd neutra¬ lem Milieu z.B., im pH-Bereich von 6,5 bis 8,5, durchgeführt werden. Bei den Umkristallisationen kann durch Zusatz von entsprechenden Erdalkali-Ionen das Löslichkeitsprodukt rascher erreicht und damit die Ausbeute gesteigert werden. Die Erdalkali-Ionen, vorzugsweise Ca, Mg, Sr, werden in Form beliebiger leicht löslicher Salze zugefügt, beispielsweise in Form der Chloride, Sulfate oder Nitrate. Sie werden in der Regel in der 0,2 bis 4fachen Menge des Folinats eingesetzt.To remove residual amounts of (δR) -folinate from alkaline earth (δS) - folinate, further recrystallizations can also be carried out in an approximately neutral environment, for example in the pH range from 6.5 to 8.5. In the recrystallizations, the solubility product can be reached more quickly by adding appropriate alkaline earth metal ions and the yield can thus be increased. The alkaline earth ions, preferably Ca, Mg, Sr, are added in the form of any readily soluble salts, for example in the form of the chlorides, sulfates or nitrates. They are usually used in 0.2 to 4 times the amount of folinate.
Gegenstand der Erfindung sind auch die durch das erfindungsgemässeThe invention also relates to those of the invention
Verfahren erstmals technisch zugänglichen (δS)-Folinate, insbesondere das Calcium-folinat und die (δS)-Folinsäure sowie, unabhängig von der Methode seiner Herstellung, das neue Magnesiumsalz und das aus den nun gut zugänglichen Erdalkali-(6S)-Folinaten, z.B. durch Umsalzen leicht erhältliche neue Natrium- und Kalium-(6S)-Folinat.Process for the first time technically accessible (δS) -folinates, in particular calcium folinate and (δS) -folinic acid and, regardless of the method of its preparation, the new magnesium salt and that from the now easily accessible alkaline earth (6S) -folinates, e.g. readily available by salting new sodium and potassium (6S) folinate.
Das Magnesium-(6S)-Folinat ist von herausragender Bedeutung, weil es aufgrund seiner vergleichsweise guten Wasserlöslichkeit von mehr als 2 g/100 ml und seiner hohen Verträglichkeit das geeignete Ausgangsma¬ terial für die Herstellung von Injektionslösungen bildet. Noch mehr gilt dasselbe für das Natrium- und Kalium-(6S)-Folinat.The magnesium (6S) folinate is of outstanding importance because, because of its comparatively good water solubility of more than 2 g / 100 ml and its high tolerance, it forms the suitable starting material for the production of injection solutions. The same applies even more to the sodium and potassium (6S) folinate.
Das Calcium-(6S)-Folinat vermag bei 20°C nur 0.95 &ige wässrige Lö¬ sungen zu bilden, was die Herstellung von Injektionslösungen er¬ schwert. Beispiele zur Illustrierung der Erfindung:The calcium (6S) folinate can only form 0.95% aqueous solutions at 20 ° C., which makes the production of injection solutions more difficult. Examples to illustrate the invention:
Beispiel 1 Calcium-(6S)-FolinatExample 1 Calcium (6S) folinate
1. Kristallisation: 100 g rohes Calcium-(6R,S)-Folinat in ca 1 Liter warmem Wasser von 50 - 60°C werden mit 12 - 36 g Calciumchlorid (CaCl2 β2H _)) versetzt, bei 30°C durch Zusatz von wässrigem Ammoniak (25 %ig) auf pH 10 ein¬ gestellt und bei 18°C kristallisieren gelassen. Nach 18 - 20 Stunden wird das ausgeschiedene Produkt abfiltriert, mit verdünnter Calcium- chlorid-Lösung und danach mit wasserfeuchtem Ethanol gewaschen.1. Crystallization: 100 g of raw calcium (6R, S) folinate in approx. 1 liter of warm water at 50 - 60 ° C are mixed with 12 - 36 g of calcium chloride (CaCl 2 β 2H _)), at 30 ° C Addition of aqueous ammonia (25%) adjusted to pH 10 and allowed to crystallize at 18 ° C. After 18-20 hours, the product which has separated out is filtered off, washed with dilute calcium chloride solution and then with water-moist ethanol.
Man erhält 41 g Calcium-Folinat enthaltend 88 % Calcium-(6S)-Folinat und 12 % Calcium-(6R)-Folinat. Optische Ausbeute 72 %.41 g of calcium folinate containing 88% calcium (6S) folinate and 12% calcium (6R) folinate are obtained. Optical yield 72%.
2. Kristallisation:2. Crystallization:
40 g rohes Calcium-(δS)-Folinat aus der 1. Kristallisation enthaltend 88 % (δS)-Folinat, werden bei 55 - 60°C in Wasser gelöst und langsam mit wässriger Salzsäure (20 %ig) bis zum pH 6,1 und mit 40 bis 160 g Calciumchlorid versetzt. Bei 55°C wird durch Zusatz von Natronlauge das pH der Lösung auf 7 bis 7.5. eingestellt. Bei etwa 35°C wird mit authentischem Calcium-(6S)-Folinat geimpft und bei 18 - 20°C das Produkt kristallisieren gelassen.40 g of crude calcium (δS) -folinate from the 1st crystallization containing 88% (δS) -folinate are dissolved in water at 55-60 ° C. and slowly with aqueous hydrochloric acid (20%) to pH 6.1 and mixed with 40 to 160 g calcium chloride. At 55 ° C by adding sodium hydroxide solution the pH of the solution to 7 to 7.5. set. At about 35 ° C, vaccination is carried out with authentic calcium (6S) folinate and the product is allowed to crystallize at 18 - 20 ° C.
Nach etwa 40 Stunden wird das auskristallisierte Produkt abfiltriert, mit wässrigem Ethanol gewaschen und getrocknet.After about 40 hours, the product which has crystallized out is filtered off, washed with aqueous ethanol and dried.
Man erhält 30,4 g Calcium-(S)-Folinat mit einem Gehalt an (S)-Folinat von 98 %. Optische Ausbeute: 79 - 81 %.30.4 g of calcium (S) -folinate with a (S) -folinate content of 98% are obtained. Optical yield: 79 - 81%.
3. Kristallisation:3. Crystallization:
10 g Calcium-(6S)-Folinat mit einem Gehalt an (δS)-Form von 94 - 98 % werden in heissem Wasser gelöst, mit 10 g Calciumchlorid versetzt und bei pH 7.0 bis 7.5 und 18 - 20°C kristallisieren gelassen. Nach 3 bis 4 Tagen wird das Produkt abfiltriert, mit wenig Wasser und mit feuch¬ tem Ethanol gewaschen und getrocknet. Man erhält 8 g reines Calcium-(6S)-Folinat. Gehalt an Calcium-(6S)-Folinat = 99 - 100 Flächen%10 g calcium (6S) -folinate with a (δS) -form of 94-98% are dissolved in hot water, 10 g calcium chloride are added and allowed to crystallize at pH 7.0 to 7.5 and 18-20 ° C. After 3 to 4 days the product is filtered off, washed with a little water and with moist ethanol and dried. 8 g of pure calcium (6S) folinate are obtained. Calcium (6S) folinate content = 99 - 100 area%
Löslichkeit in Wasser: 0,95 g/100 ml bei 20°C und 1.5 g/100 ml bei 40°CSolubility in water: 0.95 g / 100 ml at 20 ° C and 1.5 g / 100 ml at 40 ° C
Spezifische Drehung [ ] 20 = - 15° (bezogen auf wasserfreies Ca-Salz)Specific rotation [] 20 = - 15 ° (based on anhydrous Ca salt)
Anmerkungen:Remarks:
Gehalt an CaFolinat: Bestimmt mittels HPLC gegen Standard. Gehalt an (δS)-Form: Bestimmt mittels HPLC unter Verwendung einer chiralen Säule (Resolvosil-BSA-7).CaFolinate content: determined by HPLC against standard. Content of (δS) form: determined by HPLC using a chiral column (resolvosil-BSA-7).
Beispiel 2Example 2
Trennung von Calcium-(6R,S)-Folinat durch Kristallisation in Gegenwart von verschiedenen BasenSeparation of calcium (6R, S) -folinate by crystallization in the presence of different bases
1. Umkristallisation in Gegenwart von Basen.1. Recrystallization in the presence of bases.
30 g Calcium-(6R,S)-Folinat werden bei 50°C in 200 - 300 ml Wasser gelöst, bei 30 - 40°C mit 0,5 - 0,6 Aequivalent Base pro Mol Calcium-30 g of calcium (6R, S) -folinate are dissolved in 200 - 300 ml of water at 50 ° C, at 30 - 40 ° C with 0.5 - 0.6 equivalent base per mole of calcium
(6R,S)-Folinat versetzt.(6R, S) -folinate added.
Die Lösung wird bei Raumtemperatur während 5 bis 17 Stunden gerührt.The solution is stirred at room temperature for 5 to 17 hours.
Gewöhnlich tritt bald spontane Kristallisation ein.Spontaneous crystallization usually occurs soon.
Das Kristallisat wird abfiltriert, mit wenig 5 %iger Calciumchlorid- Lösung und mit Ethanol gewaschen und getrocknet.The crystals are filtered off, washed with a little 5% calcium chloride solution and with ethanol and dried.
Die Ergebnisse sind aus der Tabelle 1 ersichtlich. Tabelle 1The results are shown in Table 1. Table 1
Base pH Gehalt an optische (6S)-Form Ca-Folinat«5H20 Ausbeute Flächen% Gew.% %Base pH content of optical (6S) form Ca-folinate «5H 2 0 Yield area%% by weight%
Kein Basenzusatz 7.5 50.1 99 keine AuftrennungNo base addition 7.5 50.1 99 no separation
Natriumhydroxid 8.5 52 101 beginn. AuftrenngSodium hydroxide 8.5 52 101 beginning. Auftrenng
NaOH 10 80 96 70NaOH 10 80 96 70
Magnesiumhydroxid 10 72 97.2 60Magnesium hydroxide 10 72 97.2 60
Calciumhydroxid 10.2 79 93.4 65Calcium hydroxide 10.2 79 93.4 65
Amiπobutanol 9.6 71 96.5 70Amiobobanol 9.6 71 96.5 70
Ethanolamin 10 85 97.5 75Ethanolamine 10 85 97.5 75
Diethanolamin 9.7 75 97.2 60Diethanolamine 9.7 75 97.2 60
Serinol 9.6 75 98.2 75Serinol 9.6 75 98.2 75
Methylamin 10 79 96.5 76Methylamine 10 79 96.5 76
Ethylamin 9.9 82 97.5 78Ethylamine 9.9 82 97.5 78
Ammoniak 10 84 98.9 72Ammonia 10 84 98.9 72
Hydrazin 10 83 97 72Hydrazine 10 83 97 72
Kaliumhydroxid 9.5 77 98.2 70Potassium hydroxide 9.5 77 98.2 70
2. Umkristallisation der nach 1. erhaltenen rohen Calcium-(δS)- Folinate.2. Recrystallization of the crude calcium (δS) - folinates obtained after 1.
Die nach vorstehender Methode 1 erhaltenen rohen Calcium-(βS)- Folinate werden unter Zusatz von 1 - 4 Teilen Calciumchlorid bei pH 6.5 bis 7.5 aus Wasser umkristallisiert. Eine etwas schwerer lösliche Fraktion wird dabei durch Filtration abgetrennt. Aus dem Filtrat kristallisiert nach Einengen und Abkühlen reines Calcium-(δS)- Folinat. Gehalt an Calcium-(δS)-Folinat = 99.9 Flächend Beispiel 3 Magnesium-(6S)-FolinatThe crude calcium (βS) folinates obtained according to method 1 above are recrystallized from water with the addition of 1-4 parts of calcium chloride at pH 6.5 to 7.5. A slightly less soluble fraction is separated off by filtration. After concentration and cooling, pure calcium (δS) folinate crystallizes from the filtrate. Calcium (δS) -folinate content = 99.9 areal Example 3 Magnesium (6S) folinate
1. Kristallisation:1. Crystallization:
30 g Magnesium-(6R,S)-Folinat, hergestellt aus einer wässrigen Lösung von Natrium-(6R,S)-Folinat durch Fällung mit Magnesiumchlorid, werden in heissem Wasser gelöst, mit 100 g Magnesiumchlorid versetzt und durch Zusatz von wässrigem Natriumhydroxid auf pH 10 gestellt. Nun wird unter Rühren auf 16-18°C abgekühlt.30 g of magnesium (6R, S) -folinate, prepared from an aqueous solution of sodium (6R, S) -folinate by precipitation with magnesium chloride, are dissolved in hot water, mixed with 100 g of magnesium chloride and by adding aqueous sodium hydroxide pH 10 set. Now it is cooled to 16-18 ° C. with stirring.
Nach einigen Tagen wird das auskristallisierte rohe Magnesium-(6S)- Folinat abfiltriert, mit Ethanol gewaschen und getrocknet. Man erhält ein Magnesiu -Folinat mit einem Gehalt von 80 % an (S)-Folinat.After a few days, the crystallized crude magnesium (6S) folinate is filtered off, washed with ethanol and dried. A magnesium folinate containing 80% of (S) folinate is obtained.
2. Umkristallisation:2. Recrystallization:
Durch Umkristallisation bei annähernd neutralem pH aus wenig Wasser unter Zusatz von Magnesiumchlorid erhält man aus dem rohen reines Magnesium-(6S)-Folinat mit einem Gehalt an (δS)-Folinat von mehr als 95 % der Theorie. Löslichkeit in Wasser: 2,4 g/100 ml bei 20°C.By recrystallization at approximately neutral pH from a little water with the addition of magnesium chloride, raw crude magnesium (6S) -folinate with a (δS) -folinate content of more than 95% of theory is obtained. Solubility in water: 2.4 g / 100 ml at 20 ° C.
Beispiel 4 Natrium-(6S)-FolinatExample 4 Sodium (6S) folinate
Eine praktisch gesättigte wässrige Lösung von Calcium-(δS)-Folinat wird durch eine Ionenaustauscher-Säule, die mit Kationenaustauscher¬ harz in der Na^ -Form, z.B. mit A berlite IR-120, Na^-Form, be¬ schickt ist, perkolieren gelassen. Das Eluat wird konzentriert. Durch Zusatz von Ethanol wird das Natrium-(6S)-Folinat ausgefällt. Natrium-(6S)-Folinat ist leicht löslich in Wasser.A practically saturated aqueous solution of calcium (δS) -folinate is passed through an ion exchange column, which is coated with cation exchange resin in the Na ^ form, e.g. with A berlite IR-120, Na ^ form, percolate. The eluate is concentrated. The sodium (6S) -folinate is precipitated by adding ethanol. Sodium (6S) folinate is easily soluble in water.
Alternativ lässt sich das Natrium-(6S)-Folinat auch durch Lösen von (6S)-Folinsäure in der äquivalenten Menge von Natriumhydroxid gewin¬ nen. Die dazu erforderliche (δS)-Folinsäure wird nach Beispiel 6 erhalten. Beispiel 5 Kalium-(6S)-FolinatAlternatively, the sodium (6S) -folinate can also be obtained by dissolving (6S) -folinic acid in the equivalent amount of sodium hydroxide. The (δS) -folic acid required for this is obtained according to Example 6. Example 5 Potassium (6S) folinate
Diese Verbindung wird erhalten, indem man nach Beispiel 6 erhaltene (6S)-Folinsäure in der äquivalenten Menge von wässrigem Kalium- hydroxid auflöst.This compound is obtained by dissolving (6S) -folinic acid obtained according to Example 6 in the equivalent amount of aqueous potassium hydroxide.
Aus seinen konzentrierten wässrigen Lösungen lässt sich durch Ver¬ setzen mit Ethanol, Isopropanol oder Aceton das Kalium-(6S)-Folinat ausfällen. Kalium-(6S)-Folinat ist leicht löslich in Wasser.The potassium (6S) -folinate can be precipitated from its concentrated aqueous solutions by adding ethanol, isopropanol or acetone. Potassium (6S) folinate is easily soluble in water.
Beispiel 6Example 6
(δS)-Folinsäure(δS) -folic acid
Eine wässrige Lösung von Calcium-(δS)-Folinat wird vorsichtig mit verdünnter Salzsäure versetzt, wobei die (δS)-Folinsäure ausfällt und durch Filtration gewonnen wird. (δS)-Folinsäure ist kaum löslich in Wasser. Dilute hydrochloric acid is carefully added to an aqueous solution of calcium (δS) -folinate, whereby the (δS) -folinic acid precipitates and is obtained by filtration. (δS) -folic acid is hardly soluble in water.

Claims

- H-Patentansprüche - H claims
1. Verfahren zur Herstellung von (δS)-Folinsäure bzw. deren Salzen durch Umkristallisation von Erdalkalisalzen der (6R,S)-Folin- säure und gegebenenfalls Freisetzung der Säure aus den Erd- alkalifolinaten und/oder gegebenenfalls Ueberführung in die1. Process for the preparation of (δS) -folinic acid or its salts by recrystallization of alkaline earth metal salts of (6R, S) -folinic acid and, if appropriate, release of the acid from the alkaline-earth phenolates and / or, if appropriate, conversion into the
Alkalisalze, dadurch gekennzeichnet, dass die Umkristallisation in Gegenwart einer Base durchgeführt wird.Alkali salts, characterized in that the recrystallization is carried out in the presence of a base.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass das erhaltene Kristallisat in Gegenwart einer Base oder bei an- nähernd neutralem pH-Wert mindestens einer weiteren Umkristalli¬ sation unterworfen wird.2. The method according to claim 1, characterized in that the crystals obtained in the presence of a base or at approximately neutral pH is subjected to at least one further recrystallization.
3. Verfahren nach Anspruch 1 und 2, dadurch gekennzeichnet, dass man die Umkristallisationen in Gegenwart von -zusätzlichen Erd¬ alkali-Ionen durchführt.3. The method according to claim 1 and 2, characterized in that one carries out the recrystallizations in the presence of additional alkaline earth ions.
4. (δS)-Folinsäure und deren Calcium-Salz, hergestellt nach An¬ spruch 1 oder 2.4. (δS) -folic acid and its calcium salt, prepared according to claim 1 or 2.
5. Magnesium-Salz der (δS)-Folinsäure.5. Magnesium salt of (δS) -folic acid.
6. Natrium- und Kalium-Salz der (δS)-Folinsäure. 6. Sodium and potassium salt of (δS) -folinic acid.
EP88903810A 1987-05-15 1988-04-22 Process for separation of folinic acids Pending EP0314720A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH1883/87 1987-05-15
CH1883/87A CH673459A5 (en) 1987-05-15 1987-05-15

Publications (1)

Publication Number Publication Date
EP0314720A1 true EP0314720A1 (en) 1989-05-10

Family

ID=4220822

Family Applications (2)

Application Number Title Priority Date Filing Date
EP88200864A Expired - Lifetime EP0293029B1 (en) 1987-05-15 1988-04-22 Process for the preparation of folic acid
EP88903810A Pending EP0314720A1 (en) 1987-05-15 1988-04-22 Process for separation of folinic acids

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP88200864A Expired - Lifetime EP0293029B1 (en) 1987-05-15 1988-04-22 Process for the preparation of folic acid

Country Status (22)

Country Link
US (3) US5134235A (en)
EP (2) EP0293029B1 (en)
JP (1) JPH089618B2 (en)
KR (1) KR950010074B1 (en)
CN (1) CN1024553C (en)
AR (1) AR243890A1 (en)
AT (1) ATE67498T1 (en)
AU (1) AU603673B2 (en)
CA (1) CA1340290C (en)
CH (1) CH673459A5 (en)
DD (1) DD270073A5 (en)
DE (1) DE3864904D1 (en)
DK (1) DK173708B1 (en)
ES (1) ES2040321T3 (en)
FI (1) FI93729C (en)
GR (1) GR3002756T3 (en)
HU (1) HU201072B (en)
IE (1) IE60839B1 (en)
NZ (1) NZ224361A (en)
PT (1) PT87355B (en)
WO (1) WO1988008844A1 (en)
ZA (1) ZA883344B (en)

Families Citing this family (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8621268D0 (en) * 1986-09-03 1986-10-08 Univ Strathclyde Separation of substances
CH673459A5 (en) * 1987-05-15 1990-03-15 Eprova Ag
DE3821875C1 (en) * 1988-06-29 1990-02-15 Eprova Ag, Forschungsinstitut, Schaffhausen, Ch
CH676981A5 (en) * 1988-11-11 1991-03-28 Eprova Ag
CA2021042A1 (en) * 1989-07-21 1991-01-22 Fabrizio Marazza Salts of n ,n -methylene-5,6,7,8-tetrahydrofolic acid
CH680731A5 (en) * 1990-04-12 1992-10-30 Sapec Fine Chemicals
CH681303A5 (en) * 1991-01-16 1993-02-26 Eprova Ag
US5217974A (en) * 1991-03-29 1993-06-08 Eli Lilly And Company Method for treating gar-transformylase tumors in mammals and reducing mammalian toxicity
CH684270A5 (en) * 1991-10-04 1994-08-15 Sapec Fine Chemicals A process for preparing alkaline earth metal salts of (6R) -N (10) formyl-5,6,7,8-tetrahydrofolic acid.
DE4136921A1 (en) * 1991-11-11 1993-05-13 Knoll Ag METHOD FOR SEPARATING 5-METHYL-TETRAHYDROFOLIC ACID
CH683690A5 (en) * 1991-12-21 1994-04-29 Sapec Fine Chemicals A process for preparing diastereoisomerenreinen tetrahydrofolates.
CH683262A5 (en) * 1992-01-22 1994-02-15 Applied Pharma Res Process for the separation of diastereomers of the calcium salt of (6 (R, S) -N-formiltetraidrofolico).
US5599931A (en) * 1992-02-20 1997-02-04 Bracco S.P.A. Process for separating stereoisomers of folinic acid
IT1254635B (en) * 1992-02-20 1995-09-28 Bracco Spa PROCESS FOR SEPARATION OF FOLINIC ACID STEREOISOMERS
US5441960A (en) * 1992-04-16 1995-08-15 Zeneca Limited 1-pyrimidinylacetamide human leukocyte elastate inhibitors
US5698693A (en) * 1992-11-16 1997-12-16 The United States Of America As Represented By The Department Of Health And Human Services Process of separating the diastereomers of (6R,6S) -5,6,7,8-tetrahydrofolic acid derivatives
CH686672A5 (en) * 1992-12-01 1996-05-31 Cerbios Pharma Sa Process for the preparation of (6S) -5,6,7,8-tetrahydrofolic acid.
CH686369A5 (en) * 1994-05-09 1996-03-15 Eprova Ag Stable crystalline (6S) - and (6R) -Tetrahydrofolseure.
CH687062A5 (en) * 1994-02-14 1996-09-13 Cerbios Pharma Sa Concentrated injection solution of alkali metal salts of reduced folates.
NL9400530A (en) 1994-04-05 1995-11-01 Pharmachemie Bv Stable aqueous folinate solution.
US20020032160A1 (en) * 1995-02-24 2002-03-14 Nyce Jonathan W. Compositions & formulations with an epiandrosterone or a ubiquinone & kits & their use for treatment of asthma symptoms & for reducing adenosine/adenosine receptor levels
US5660835A (en) * 1995-02-24 1997-08-26 East Carolina University Method of treating adenosine depletion
WO2000007566A1 (en) * 1998-08-03 2000-02-17 Epigenesis Pharmaceuticals, Inc. A new analgesic, anti-inflammatory and wound healing agent
AU2002303427A1 (en) * 2001-04-24 2002-11-05 East Carolina University Compositions and formulations with a non-glucocorticoid steroid and/or a ubiquinone and kit for treatment of respiratory and lung disease
AU2002303425A1 (en) * 2001-04-24 2002-11-05 Epigenesis Pharmaceuticals, Inc. Composition, formulations and kit for treatment of respiratory and lung disease with non-glucocorticoid steroids and/or ubiquinone and a bronchodilating agent
GB0206711D0 (en) 2002-03-21 2002-05-01 Isis Innovation HIF Inhibitor
JP2005530820A (en) * 2002-06-17 2005-10-13 エピジェネシス ファーマシューティカルズ リミティド ライアビリティー カンパニー Method for treating asthma or chronic obstructive pulmonary disease using dihydrate dehydroepiandrosterone and composition thereof
US7405207B2 (en) * 2002-06-17 2008-07-29 Epigenesis Pharmaceuticals, Inc. Nebulizer formulations of dehydroepiandrosterone and methods of treating asthma or chronic obstructive pulmonary disease using compositions thereof
US20050026848A1 (en) * 2003-07-31 2005-02-03 Robinson Cynthia B. Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a methylxanthine derivative for treatment of asthma or chronic obstructive pulmonary disease
US20050026883A1 (en) * 2003-07-31 2005-02-03 Robinson Cynthia B. Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a PDE-4 inhibitor for treatment of asthma or chronic obstructive pulmonary disease
US20050026884A1 (en) * 2003-07-31 2005-02-03 Robinson Cynthia B. Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a beta-agonist bronchodilator for treatment of asthma or chronic obstructive pulmonary disease
US20090297611A1 (en) * 2003-07-31 2009-12-03 Robinson Cynthia B Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a tyrosine kinase inhibitor, delta opioid receptor antagonist, neurokinin receptor antagonist, or vcam inhibitor for treatment of asthma or chronic obstructive pulmonary disease
US20050026880A1 (en) * 2003-07-31 2005-02-03 Robinson Cynthia B. Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a cromone for treatment of asthma or chronic obstructive pulmonary disease
US20050038004A1 (en) * 2003-07-31 2005-02-17 Robinson Cynthia B. Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with an anticholinergic bronchodilator for treatment of asthma or chronic obstructive pulmonary disease
US20050026881A1 (en) * 2003-07-31 2005-02-03 Robinson Cynthia B. Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with an anti-IgE antibody for treatment of asthma or chronic obstructive pulmonary disease
US20050085430A1 (en) * 2003-07-31 2005-04-21 Robinson Cynthia B. Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a PDE-4 inhibitor for treatment of asthma or chronic obstructive pulmonary disease
US20050026879A1 (en) * 2003-07-31 2005-02-03 Robinson Cynthia B. Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a tyrosine kinase inhibitor, delta opioid receptor antagonist, neurokinin receptor antagonist, or VCAM inhibitor for treatment of asthma or chronic obstructive pulmonary disease
US20050113318A1 (en) * 2003-07-31 2005-05-26 Robinson Cynthia B. Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a beta-agonist bronchodilator for treatment of asthma or chronic obstructive pulmonary disease
US20050043282A1 (en) * 2003-07-31 2005-02-24 Robinson Cynthia B. Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a lipoxygenase inhibitor for treatment of asthma or chronic obstructive pulmonary disease
US20050101545A1 (en) * 2003-07-31 2005-05-12 Robinson Cynthia B. Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with an anticholinergic bronchodilator for treatment of asthma or chronic obstructive pulmonary disease
US20090285900A1 (en) * 2003-07-31 2009-11-19 Robinson Cynthia B Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a beta-agonist bronchodilator for treatment of asthma or chronic obstructive pulmonary disease
US20090263381A1 (en) * 2003-07-31 2009-10-22 Robinson Cynthia B Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with an anti-ige antibody for treatment of asthma or chronic obstructive pulmonary disease
US20090285899A1 (en) * 2003-07-31 2009-11-19 Robinson Cynthia B Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a methylxanthine derivative for treatment of asthma or chronic obstructive pulmonary disease
US20050026882A1 (en) * 2003-07-31 2005-02-03 Robinson Cynthia B. Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a leukotriene receptor antagonist for treatment of asthma or chronic obstructive pulmonary disease
US20090274676A1 (en) * 2003-07-31 2009-11-05 Robinson Cynthia B Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a pde-4 inhibitor for treatment of asthma or chronic obstructive pulmonary disease
US20050026890A1 (en) * 2003-07-31 2005-02-03 Robinson Cynthia B. Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with an antihistamine for treatment of asthma or chronic obstructive pulmonary disease
CH696717A5 (en) * 2004-02-20 2007-10-31 Cerbios Pharma Sa Concentrated, stable solution, in particular an injection solution or infusion solution, which Sodium folinate or (6S) Entholt -potassium folinate together with water either (6S)
CH696699A5 (en) * 2006-01-19 2007-10-15 Cerbios Pharma Sa Process for regioselective N (5) -Formylierung of (6S) -5, 6, 7, 8-Tetrahydropteroinsäure and derivatives thereof.
CN101407518A (en) * 2007-10-11 2009-04-15 南京莱尔生物化工有限公司 Method for resolving and salifying (6R,S)-5-formyl-tetrahydrofolic acid
CN101792444B (en) * 2009-02-02 2011-10-12 天津康鸿医药科技发展有限公司 Sodium levofolinate and preparation method and drug combination thereof
CN101863889B (en) * 2009-04-20 2013-07-03 重庆华邦胜凯制药有限公司 Method for purifying calcium levofolinate
CN102101862B (en) * 2009-12-21 2013-01-09 天津康鸿医药科技发展有限公司 Method for preparing L-sodium folinate or DL-sodium folinate
EP2502625A1 (en) 2011-03-21 2012-09-26 GMT Fine Chemicals SA Process for the preparation of crystalline levofolinic acid
WO2014025807A1 (en) 2012-08-06 2014-02-13 Spectrum Pharmaceuticals, Inc. Pharmaceutical compositions comprising l-leucovorin
US9629846B1 (en) 2013-11-14 2017-04-25 Argent Development Group, Llc Nutritional supplements for women desiring to become pregnant, and pregnant and nursing women
US9492421B1 (en) 2013-11-14 2016-11-15 Argent Development Group, Llc Nutritional supplements for treatment of iron deficiency anemia
CN105367574A (en) * 2015-10-27 2016-03-02 浙江大为药业有限公司 Process for preparing high purity sinistral leucovorin calcium
CN111138434A (en) * 2019-09-18 2020-05-12 南京海纳医药科技股份有限公司 Preparation method of levofolinic acid
CN112649524B (en) * 2020-12-02 2022-05-17 重庆华邦胜凯制药有限公司 Method for separating and detecting folic acid and folic acid optical isomer in folic acid

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2688018A (en) * 1952-06-28 1954-08-31 American Cyanamid Co Method of preparing alkaline earth metal salts of 1-leucovorin
US5223500A (en) * 1977-02-22 1993-06-29 Bioresearch S.P.A. Stable pharmaceutical composition of alkaline or alkaline earth 5-methyl tetrahydrofolate
CH649550A5 (en) * 1984-02-09 1985-05-31 Eprova Ag Process for the preparation of alkaline earth metal salts of 5-methyltetrahydrofolic acid
US4665176A (en) * 1984-10-23 1987-05-12 Mitsui Toatsu Chemicals, Incorporated Process for the preparation of 5,6,7,8-tetrahydrofolic acid
GB8621268D0 (en) * 1986-09-03 1986-10-08 Univ Strathclyde Separation of substances
CH673459A5 (en) * 1987-05-15 1990-03-15 Eprova Ag
DE3821875C1 (en) * 1988-06-29 1990-02-15 Eprova Ag, Forschungsinstitut, Schaffhausen, Ch
CH676981A5 (en) * 1988-11-11 1991-03-28 Eprova Ag
CH684270A5 (en) * 1991-10-04 1994-08-15 Sapec Fine Chemicals A process for preparing alkaline earth metal salts of (6R) -N (10) formyl-5,6,7,8-tetrahydrofolic acid.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8808844A1 *

Also Published As

Publication number Publication date
FI93729C (en) 1995-05-26
IE60839B1 (en) 1994-08-24
DK254688A (en) 1988-11-16
DE3864904D1 (en) 1991-10-24
AU1703188A (en) 1988-12-06
FI890195A (en) 1989-01-13
KR950010074B1 (en) 1995-09-06
US6160116A (en) 2000-12-12
NZ224361A (en) 1989-10-27
PT87355A (en) 1989-06-30
CN1024553C (en) 1994-05-18
ES2040321T3 (en) 1993-10-16
EP0293029B1 (en) 1991-09-18
FI93729B (en) 1995-02-15
KR890700590A (en) 1989-04-26
AR243890A1 (en) 1993-09-30
JPH089618B2 (en) 1996-01-31
AU603673B2 (en) 1990-11-22
US5134235A (en) 1992-07-28
US5347005A (en) 1994-09-13
CN88102709A (en) 1988-12-28
HU201072B (en) 1990-09-28
GR3002756T3 (en) 1993-01-25
CA1340290C (en) 1998-12-29
WO1988008844A1 (en) 1988-11-17
JPH01503787A (en) 1989-12-21
CH673459A5 (en) 1990-03-15
DK254688D0 (en) 1988-05-09
FI890195A0 (en) 1989-01-13
HUT49880A (en) 1989-11-28
EP0293029A1 (en) 1988-11-30
ZA883344B (en) 1988-11-09
DK173708B1 (en) 2001-07-09
ATE67498T1 (en) 1991-10-15
PT87355B (en) 1995-03-01
IE881450L (en) 1988-11-15
DD270073A5 (en) 1989-07-19

Similar Documents

Publication Publication Date Title
EP0293029B1 (en) Process for the preparation of folic acid
DE3821875C1 (en)
EP0612322B1 (en) Method of separating the enantiomers of 5-methyl-tetrahydrofolic acid
EP0367902B1 (en) Process for the separation of folinic acid
EP0455013B1 (en) Ammoniumsalts of N(5)-methyl-5,6,7,8-tetrahydrofolic acid
EP0495204B1 (en) Process for the preparation of (6S)- and (6R)-tetrahydrofolic acid
EP0682026B1 (en) "Stable crystalline (6S)- and (6R)-tetrahydrofolic acid"
EP0773221A1 (en) Stable crystalline tetrahydrofolic acid salts
EP0312726A1 (en) Optically active salt of a substituted thiazolidine-4-carboxylic acid and a 3-chlor-2-hydroxypropyl trimethyl ammonium, their preparation and use
DE69319420T2 (en) METHOD FOR SEPARATING STEREOISOMERS FROM FOLIC ACID
DE69717076T2 (en) METHOD FOR PRODUCING GALANTHANINE
DE2641388A1 (en) PROCESS FOR THE PREPARATION OF DERIVATIVES OF 3 ', 4'-DIDEOXYKANAMYCINE B
DE2901537C2 (en)
DE1767612C (en) Process for the production of 5-dehydroshikimic acid by aerobically growing microorganisms
DE1470160C (en) 2-chloro-9-piperazinopropylidene-thioxanthenes and a process for their preparation
DE2459077A1 (en) ALKYLESTERS, DIALKYLAMIDES AND SATURATED HETEROCYCLIC AMIDES OF 4-AMINOALKYL-4-CYANO-4-PHENYL-BUTANE- AND -BUT-2-ENACIDS
DE1767612B (en) Process for the production of 5 dehydroshikimic acid by aerobic culturing of microorganisms
EP0031456A1 (en) Substituted 4-amino-2,6-diaryl-tetrahydrothiopyranes, their acid-addition salts, processes for their preparation and pharmaceutical compositions
CH680856A5 (en) New salts of N-5-methyl-5,6,7,8-tetra-hydro-folic acid
CH680857A5 (en) New salts of N-5-methyl-5,6,7,8-tetra-hydro-folic acid
DE1593647A1 (en) Process for the preparation of derivatives of prostane carboxylic acid
DE1183097B (en) Process for the preparation of phenylalanine derivatives
CH678854A5 (en) N,N-methylene-5,6,7,8-tetra:hydro-folic acid salt (I)
DE1568379B (en) Process for the separation of trans 4 aminomethylcyclohexane 1 carboxylic acid from Iso merengermschen with the ice compound

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 19881024

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

DX Miscellaneous (deleted)
XX Miscellaneous (additional remarks)

Free format text: VERFAHREN ABGESCHLOSSEN INFOLGE VERBINDUNG MIT 88200864.2/0293029 (EUROPAEISCHE ANMELDENUMMER/VEROEFFENTLICHUNGSNUMMER) VOM 27.08.90.