SE123797C1

SE123797C1 -

Info

Publication number: SE123797C1
Authority: SE
Publication date: 1948-01-01

Description

Uppfinnare: E. Kull och J. M. Smith Fr. Inventors: E. Kull and J. M. Smith Fr.

Prioritet begard frOin den 13 augusti 1946 (A2neri1-as forenta stater). Priority was given to frOin on 13 August 1946 (A2neri1-as United States).

FOreliggande uppfinning avser avskiljandet av folsyra fran en blandning av folsyra och med denna beslaktade pteriner, som atfolja denna. Folsyra har visat sig vara av betydande terapeutiskt vdrde, emedan den framjar hemoglobinbildningen och aven är terapeutiskt verksam vid behandlingen av vavnads-, hud- och liknande sjukdomar. The present invention relates to the separation of folic acid from a mixture of folic acid and related pterins which accompany it. Folic acid has been shown to be of significant therapeutic value, as it promotes hemoglobin formation and is also therapeutically effective in the treatment of tissue, skin and similar diseases.

Den syntetiska framstallningen av Mnnen med samma eller analoga biologiska aktivitet som f olsyra, framstalld ur naturliga amnen, har nyligen astadkommits genom reaktion mellan 2,4,5-triamino-6-h.ydroxipyrimidin, en aminosyraamid av para-aminobensoesyra, sasom para-aminobensoylglutaminsyra, och en lamplig forening med 3 kolatomer, vilken innehaller reaktiva aldehyd- och/ eller halogengrupper, shsom foretradesvis all a, beta-dibrompropionaldehyd. The synthetic preparation of Men with the same or analogous biological activity as folic acid, prepared from natural substances, has recently been accomplished by the reaction of 2,4,5-triamino-6-hydroxypyrimidine, an amino acid amide of para-aminobenzoic acid, such as para-acid. aminobenzoylglutamic acid, and a suitable compound having 3 carbon atoms, which contains reactive aldehyde and / or halogen groups, preferably all of which are beta-dibromopropionaldehyde.

Den viktigaste biologiskt verksamma produkten av denna reaktion har formeln N-[4-1[(2- amino-4-hydroxi-6-pyrimido [4,5-b] pyrazyl)metyll-aminol bensoy1J glutaminsyra, men vanligtvis brukar den betecknas sasom »pteroylglutaminsyra» (jfr Science, bd. 103, maj 1946, sid. 669). Andra nara beslaktade produkter, vilka aga biologisk aktivitet i olika hog grad, kunna framstallas pa sá sdtt, att lampliga utgangsmaterial valjas, i vilka glutaminsyraresten av para-aminobensoylglutaminsyran ersatts av en annan aminosyra eller av en av dess polypeptider, exempelvis para - aminobensoylglutamylglutamylglutaminsy'ra. Eftersom nagra av dessa syntetiska produkter figa liknande aktivitet som folsyra ur naturliga amnen, anvandes termen »folsyra» i fortsattningen sã, att den omfattar de biologiskt verksamma aminosyraamiderna av 4-1[(2-amino-4- hydroxi-6-pyrimido [4,5-b] pyrazyl)metyl}aminol bensoesyra och sarskilt glutaminsyraamiderna med 1,2,3 eller fler gluLaminsyrarester, sammanfogade till en peptidkedja. The most important biologically active product of this reaction has the formula N- [4-1 [(2-amino-4-hydroxy-6-pyrimido [4,5-b] pyrazyl) methyl] amino] benzoyl] glutamic acid, but it is usually referred to as sasom "Pteroylglutamic acid" (cf. Science, vol. 103, May 1946, p. 669). Other closely related products which exhibit biological activity to varying degrees can be prepared by selecting suitable starting materials in which the glutamic acid residue of the para-aminobenzoylglutamic acid is replaced by another amino acid or by one of its polypeptides, for example para-aminobenzoylglutamylglutamylglutamyl . Since some of these synthetic products have similar activity to folic acid from natural substances, the term "folic acid" is still used to include the biologically active amino acid amides of 4-1 [(2-amino-4-hydroxy-6-pyrimido [4 , 5-b] pyrazyl) methyl} amino benzoic acid and especially the glutamic acid amides with 1,2,3 or more glutamic acid residues, joined to a peptide chain.

Reaktionsforloppet vid det forfaringssatt, med vilket syntetisk folsyra framstalles, är starkt komplext, sarskilt med avseende pa det faktum, att de olika ovan namnda mellanprodukterna kunna reagera pa mycket olika satt. Faclunannen ph omradet for heterocykliska organiska foreningar av denna typ skulle nu vanta sig, och detta har av erfarenheten visat sig vara riktigt, att talrika bireaktioner aga rum antingen samtidigt med eller efter huvudreaktionen. Som foljd harav innehaller reaktionsprodukten en relativt stor andel av icke onskvarda substanser inklusive icke omsatta mellanprodukter, kondensationsoch/eller polymerisationsprodukter av tva eller flera mellanprodukter, stdllnings-isomerer, oxidationsprodukter, olika hypotetiskt mojliga nedbrytningsprudukter, hydrolyseringsprodukter o. dyl. Manga av dessa icke identifierade produkter innehalla en pyrimidopyrazinkarna och kunna helt allmant betecknas som pteriner. The course of the reaction in the process by which synthetic folic acid is produced is highly complex, especially with respect to the fact that the various intermediates mentioned above can react in very different ways. Faclunannen ph the field of heterocyclic organic compounds of this type would now become accustomed, and this has been shown by experience to be true, that numerous side reactions take place either simultaneously with or after the main reaction. As a result, the reaction product contains a relatively large proportion of undesirable substances, including unreacted intermediates, condensation and / or polymerization products of two or more intermediates, positioning isomers, oxidation products, various hypothetically possible degradation products, hydrolysis products and the like. Many of these unidentified products contain a pyrimidopyrazine nucleus and can be generally referred to as pterins.

Nagra av reaktionens biprodukter kunna vara skadliga, och ndr reaktionsprodukten skall anvandas sasom terapeutiskt preparat, ãr det uppenbart, att dessa pteriner bor avldgsnas fran den biologiskt verksamma folsyran. Some of the by-products of the reaction may be harmful, and if the reaction product is to be used as a therapeutic preparation, it is obvious that these pterins should be derived from the biologically active folic acid.

Olyckligtvis aga manga av dessa pteriner, vilka a.tfOlja folsyran i den raa reaktionsprodukten, delvis samma kemiska och fysikaliska egenskaper som den Asyftade biologiskt verksamma slutprodukten, och det har visat sig ytterst svArt att avskilja dessa biprodukter utan att samtidigt valla en allvarlig forlust av verksamt material. Flera fOrfaringssatt ha foreslagits, genom vilka det bliver mojligt att utvinna folsyra med en renhetsgrad av 85-90 % ur den raa reaktionsblandningen, men hOgre renhet har kunnat astadkommas endast under stern forluster av de verksamma bestandsdelarna i den raa blandningen. Unfortunately, many of these pterins, which follow the folic acid in the crude reaction product, have in part the same chemical and physical properties as the unintended biologically active end product, and it has been found extremely difficult to separate these by-products without causing a serious loss of activity. material. Several methods have been proposed, by which it becomes possible to extract folic acid with a purity of 85-90% from the crude reaction mixture, but higher purity has been achieved only during stern losses of the active ingredients in the crude mixture.

Foreliggande uppfinning avser ett forfaringssatt att avskilja folsyra fran en blandning av folsyra och beslaktade pteriner, som atfOlja syran, pa fOljande satt. En dylik blandning behandlas med en magnesiumforening, det bildade magnesitunfolatet overfores till vattenlOsning, olosliga. 2— — amnen avskiljas fran det liisliga magnesiumfolatet, och slutligen behandlas losningen sh, attantingen magnesiumfolat eller folsyra utfalles. The present invention relates to a process for separating folic acid from a mixture of folic acid and related pterins which accompany the acid, in the following manner. Such a mixture is treated with a magnesium compound, the magnesitunfolate formed is transferred to aqueous solution, insoluble. 2 - - the substances are separated from the soluble magnesium folate, and finally the solution is treated sh, either magnesium folate or folic acid is precipitated.

Det har nu visat sig, att medelst forfaringssattet enligt fOreliggande uppfinning folsyra av nits- tan teoretisk renhet kan avskiljas Iran blandningar, som innehalla pteriner och andra biprodukter, som finnas i reaktionsprodukten niir folsyra framstalles ph syntetisk vag. Reningsprocessen Or relativt enkel och bygger ph det faktum, att magnesiumsalterna av pteroylglutaminsyra och beslaktade aminosyraamider av pteroinsyra intaga en sarstallning och figa loslighetsegenskaper, som i sh hog grad avvika frail dem has de icke onskvarda pterinerna, att de kunna avskiljas medelst enkel %suing, filtrering och utffillning, antingen genom kristallisering ur varm, koncentrerad vattenlosning eller shsom fri syra efter be-handling med en syra. It has now been found that by the process of the present invention folic acid of nineteen theoretical purity can be separated from mixtures containing pterins and other by-products contained in the reaction product of which folic acid is prepared ph synthetically. The purification process is relatively simple and is based on the fact that the magnesium salts of pteroylglutamic acid and related amino acid amides of pteroic acid have a composition and low solubility properties which differ greatly from those of the undesirable pterins, that they can be separated by simple filtration. and precipitation, either by crystallization from hot, concentrated aqueous solution or as free acid after treatment with an acid.

Ehuru forfaringssattet enligt foreliggande uppfinning Or sarskilt lampligt fOr reningen av folsyrapreparat med en andel av omkring 80-90 °,,"„' folsyra, atfbljd av andra pteriner, kan det Oven anvandas for reningen av raa reaktionsprodukter, som innehalla en sa. pass lag andel scan 10 % av sjalva folsyran. Although the process according to the present invention is particularly suitable for the purification of folic acid preparations with a proportion of about 80-90 °, "" '' folic acid, in addition to other pterins, it can also be used for the purification of crude reaction products containing such a layer. share scan 10% of the folic acid itself.

Vid genomforandet av fOrfaringssattet enligt foreliggande uppfinning behandlas den framstallda icke renade folsyran, vilken atfoljes av beslaktade pteriner, med en magnesiumforening i och for omvandling av folsyran till dess magnesium-salt. For detta andamal anviindes foretradesvis magnesiumoxid, men Oven andra magnesiumforeningar, vilka kunna reagera med folsyra, kunna anvandas for att bilda dess magnesiumsalt, sasom t. ex. magnesiumkarbonat. Magnesiumfolatet kan Oven bildas i losningen av ett annat av dess losliga salter medelst en dubbel omsattning sasom askadliggores i nagot av exemplen. Nagnesiumfolatlosningen gores klar genom filtrering, dekantering, centrifugering eller ph annat satt, som Or lampligt for att avlagsna de olosliga fOroreningarna. En folsyra av fOrbattrad renhet kan sedan erhallas genom enkel surgoring med en syra, fOretradesvis till pl-f-vardet omkring 3. Den olosliga folsyran, som utkristalliserar ur liisningen, kan sedan atervinnas genom filtrering. Denna atgard kan upprepas tills produkten har den Onskade renhetsgraden. In carrying out the process of the present invention, the prepared unpurified folic acid, which is followed by coated pterins, is treated with a magnesium compound in order to convert the folic acid to its magnesium salt. For this purpose magnesium oxide is preferably used, but also other magnesium compounds which can react with folic acid can be used to form its magnesium salt, such as e.g. magnesium carbonate. The magnesium folate can also be formed in the solution of another of its soluble salts by means of a double reaction which is ash-damaged in some of the examples. The magnesium folate solution is prepared by filtration, decantation, centrifugation or other means which are suitable for removing the insoluble contaminants. A folic acid of improved purity can then be obtained by simple acidification with an acid, preferably to the pI-f value of about 3. The insoluble folic acid which crystallizes out of the solution can then be recovered by filtration. This procedure can be repeated until the product has the desired degree of purity.

En bathe rening astadkommes genom framstallning av en koncentrerad magnesiumfolatlosning i vatten vid en temperatur av 75-100° C, vid vilken temp eratur losningen filtreras och magnesiumsaltet atervinnes genom den koncentrerade hisningens kylning. Nlagnesiumfolatet kan omkristalliseras ur vatten tills en produkt med den onskade renhetsgraden erhallits. SurgOringen av en losning av magnesiumsaltet resulterar i en utMining av folsyrakristaller med hog renhetsgrad. De foljande exemplen Oro avsedda aft' aska.dligOra uppfinningen i detalj. A bath purification is accomplished by preparing a concentrated magnesium folate solution in water at a temperature of 75-100 ° C, at which temperature the solution is filtered and the magnesium salt is recovered by cooling the concentrated lift. The nlagnesium folate can be recrystallized from water until a product with the desired degree of purity is obtained. The acidification of a solution of the magnesium salt results in a precipitation of folic acid crystals of high purity. The following examples are intended to detail the invention in detail.

Exempel 1. g ra reaktionsprodukt, innehallande 15,7 viktsprocent av sjalva folsyran och for ovrigt be- slaktade pteriner och andra, icke identifierade reaktionsprodukter, blandas i en mortel med 6 g magnesiumoxid, blandningen forsattes med 1500 cm° vatten och uppvarmes till ° C. Darefter filtreras losningen och filtratet tvattas med vat-ten. Sedan surgores filtratet med utspadd saltsyra till ett pH-varde 3 och fallningen samlas genom filtrering och tvattas med vatten och alkohol. Produktens renhet hiiides till 34 %. Example 1. Crude reaction product, containing 15.7% by weight of the folic acid itself and otherwise related pterins and other, unidentified reaction products, is mixed in a mortar with 6 g of magnesium oxide, the mixture is continued with 1500 cm ° of water and heated to ° C. The solution is then filtered and the filtrate is washed with water. Then the filtrate is acidified with dilute hydrochloric acid to a pH of 3 and the precipitate is collected by filtration and washed with water and alcohol. The purity of the product is 34%.

Exempel 2. Example 2.

Omkring 1,6 g folsyra med renhetsgraden 78 %, som innehaller beslaktade pteriner, losas i 800 cm3 n/10 natriumhydroxidlosning. 8 g Hyflo Su- percel (diatomejord) tillsattas och lOsningens pHvarde installes med attiksyra pa omkring 3. Ut- fallningen samlas p0. ett filter och tvattas Tiled vatten. Den fuktiga filtermassan fOrsattes med 500 cm3 vatten och 5 g magnesiumoxid och blandningen uppvarmes till 55-60° C. Det olosliga materialet avlagsnas genom filtrering och filtermassan tvattas i en ringa mfingd varmt vat-ten. Filtratet behandlas sedan med en losning av kausLik soda tills ett pH-varde omkring 11,5 ar uppnatt, varefter ett filteringen gynnande amne tillfogas och losningen filtreras. Filtratet uppvarmes till 60° C och Mlles i en varm losning av 25 cm3 attiksyra och 75 cm3 vatten. Blandningen kyles till 50° C och filtreras. Efter produktens tvattning med vatten och alkohol samt dess torkning visade den framstallda folsyran en renhetsgrad av 87,3 %. About 1.6 g of folic acid with a purity of 78%, which contains related pterins, is dissolved in 800 cm 3 of n / 10 sodium hydroxide solution. 8 g of Hyflo Supercel (diatomaceous earth) are added and the pH value of the solution is installed with acetic acid of about 3. The precipitate is collected at 0. a filter and washed Tiled water. The moist filter mass was charged with 500 cm 3 of water and 5 g of magnesium oxide and the mixture was heated to 55-60 ° C. The insoluble material was removed by filtration and the filter mass was washed in a little warm water. The filtrate is then treated with a solution of caustic soda until a pH of about 11.5 is reached, after which a filtration-promoting substance is added and the solution is filtered. The filtrate is heated to 60 ° C and Mlles in a hot solution of 25 cm 3 of acetic acid and 75 cm 3 of water. The mixture is cooled to 50 ° C and filtered. After washing the product with water and alcohol and drying it, the folic acid produced showed a purity of 87.3%.

Exempel 3. 1 g folsyra med en renhetsgrad av 93,1 `;',) forsattes med 30 cm vatten och 0,5 g magnesiumoxid. Blandningen uppvarmes sedan till kokning och filtreras. Genom kylning av filtratet erhalles en gal fanning av magnesiumfolat i form av tunna nalar. Lasningen filtreras och den fuktiga filtermassan loses i omkring 25 cm° kokande vat-ten. Under kylning erhalles anyo en fanning av gull magnesiumfolat, vilken samlas pa filtret. Efter 5 omkristalliseringar av magnesiumfolatet ur vatten torkas produkten vid 1° C/0,5 mm Hg under 31/2 timmar. Vid analysen visar sig denna produkt vara 98 %-igt rent magnesiumfolat. Example 3. 1 g of folic acid with a purity of 93.1 .mu.l was added with 30 cm @ 3 of water and 0.5 g of magnesium oxide. The mixture is then heated to boiling and filtered. By cooling the filtrate, a crazy formation of magnesium folate in the form of thin needles is obtained. The weld is filtered and the moist filter mass is dissolved in about 25 cm ° boiling water. During cooling, anyo is obtained a formation of gold magnesium folate, which collects on the filter. After recrystallization of the magnesium folate from water, the product is dried at 1 ° C / 0.5 mm Hg for 31/2 hours. In the analysis, this product turns out to be 98% pure magnesium folate.

Exempel 4. Example 4.

Efter magnesiumfolatets tredubbla omkristalIisering ur vatten tillsattes saltet langsamt till en varm 30 %-ig attiksyralbsning. Vid kylning utMlles folsyra, vilken utvinnes genom filtrering. Efter torkning vid 115° C/0,5 mm 1-1g under 31/2 timmar analyserades produkten, som visade sig innehalla 98 %-ig folsyra. After the triple recrystallization of the magnesium folate from water, the salt was slowly added to a hot 30% attic acid solution. On cooling, folic acid is formed, which is recovered by filtration. After drying at 115 ° C / 0.5 mm 1-1g for 31/2 hours, the product was analyzed, which was found to contain 98% folic acid.

Exempel 5. Example 5.

Den medelst ammoniak ur 30 g AlgS01, 7 H20 i 1 liter vatten utfallda magnesiumhydroxiden samlas pa ett filter, tvattas med vatten och blandas med 10 g folsyra (86 % enligt kemisk besMmning och innehallande 7,1 % vatten) i 400 cm3 vatten. Sedan tillsattes ytterligare magnesium- — —3 hydroxid, som utfallts ur 30 g MgSO4, 7 H20 i 1000 cm3 vatten medelst natriumhydroxid, filtrerats och tyattats med vatten. Vatskan uppvarmes darefter till 85° C. Den lamnar pa fenolftaleinpapper en syagt rodfargad flack. Den varma blandningen filtreras och det halmfdrgade filtratet kyles. Den gula massan, som utfalles, loses i 200 cm3 vatten vid 85° C. \rid kylning uppkommer en gul fanning, som samlas pa filtret och loses 1100 cm3 vatten Yid 8° C. Kylningen fOretages langsamt och vatskan far sta. i omkring 16 timmar. Sedan visar sig en orangefargad fallning pa karlets batten med ett ljusgult slat aro-yen Det ljusgula amnet isoleras och samlas pa filtret, loses i 100 cm3 varmt vatten och till denna lOsning sattas 50 cm3%-ig attiksyra vid 85° C. Den kristalliniska produkten torkas i en vakuumdesickator Over fast natriumhydroxid och vattenfritt kalciumsulf at under 24 timmar och darefter under 5 timmar yid 115° Cf0,5 mm Hg-yakuum. Produkten innehaller folsyra, som enligt kemisk bestamning fir 97,8 %-ig. The magnesium hydroxide precipitated by ammonia from 30 g of AlgSO1, 7 H2 O in 1 liter of water is collected on a filter, washed with water and mixed with 10 g of folic acid (86% according to chemical evaluation and containing 7.1% of water) in 400 cm3 of water. Then additional magnesium hydroxide, which precipitated from 30 g of MgSO 4, 7 H 2 O in 1000 cm 3 of water by means of sodium hydroxide, was added, filtered and quenched with water. The liquid is then heated to 85 ° C. It leaves a sewn red-colored flake on phenolphthalein paper. The hot mixture is filtered and the straw-dried filtrate is cooled. The yellow mass which precipitates is dissolved in 200 cm3 of water at 85 ° C. After cooling, a yellow formation forms, which accumulates on the filter and dissolves at 1100 cm3 of water at 8 ° C. The cooling is carried out slowly and the liquid is allowed to stand. for about 16 hours. Then an orange precipitate appears on the man's bat with a light yellow smooth aro-yen. The light yellow substance is isolated and collected on the filter, dissolved in 100 cm 3 of hot water and to this solution is added 50 cm 3% acetic acid at 85 ° C dried in a vacuum desiccator over solid sodium hydroxide and anhydrous calcium sulfate for 24 hours and then for 5 hours at 115 ° Cf0.5 mm Hg-vacuum. The product contains folic acid, which according to chemical assessment fir 97.8% -ig.

Exempel 6. Example 6.

En Issuing av 2 g folsyra (86 %-ig) i 100 cm3 vatten behandlas med 1 g kalciumhydroxid yid 85° C. Darvid loses huvuddelen av den fasta gula bestandsdelen. De icke lbsliga delarna avlagsnas genom varm filtrering. Efter kylning till omkring 60° C behandlas filtratet med en losning av I g MgSO4, 7 H20 i en ringa mangd vatten. Den ringa fallningen avlagsnas genom filtrering och filtratet utspades med en lika stor volym etanol. En voluminos gul fallning uppkommer, som samlas pa filtret. Detta material kan omkristalliseras ur vatten; enligt foreliggande exempel loses det emellertid i varmt vatten, varefter losningen gores klar och 50 cm' 50 %-ig attiksyra vid omkring 80° C tillsattas. Efter kylning samlas det utfallda materialet pa filtret och torkas vid 60° C. Det erhalles 1,127 g material, som innehaller 86,0 % folsyra och 8,1 % vatten. An Issuing of 2 g of folic acid (86%) in 100 cm 3 of water is treated with 1 g of calcium hydroxide at 85 ° C. This dissolves the bulk of the solid yellow component. The non-liquid parts are removed by hot filtration. After cooling to about 60 ° C, the filtrate is treated with a solution of 1 g of MgSO 4, 7 H 2 O in a small amount of water. The slight precipitate is removed by filtration and the filtrate is diluted with an equal volume of ethanol. A yellow drop of a volume occurs, which accumulates on the filter. This material can be recrystallized from water; according to the present example, however, it is dissolved in hot water, after which the solution is cleared and 50 cm 3 of 50% acetic acid at about 80 ° C are added. After cooling, the precipitated material is collected on the filter and dried at 60 ° C. 1.127 g of material are obtained, which contain 86.0% folic acid and 8.1% water.

Exempel 7. Example 7.

En lOsning av 1 g folsyra (86 % folsyra och 7,1 % vatten) i 50 cm' vatten behandlas med 1 g kaleiumhydroxid vid 80-85° C. Efter varm filtrering behandlas filtratet med 0,8 g magnesiumsulfatheptahydrat, lost i en ringa mangd vatten. A solution of 1 g of folic acid (86% folic acid and 7.1% of water) in 50 cm 3 of water is treated with 1 g of potassium hydroxide at 80-85 ° C. After hot filtration, the filtrate is treated with 0.8 g of magnesium sulfate heptahydrate, dissolved in a ring. plenty of water.

Det utfallda materialet avlagsnas och filtratet sates till ett overskott av varm, utspadd attiksyra (50 cm3, 50 °,'„-ig). Efter kylning samlas den gula fallningen pa filtret, tyattas med vatten och aceton samt torkas vid 60° C. Det erhallna materialet innehaller 90 % folsyra och 7,7 °A; vatten. The precipitated material is removed and the filtrate is added to an excess of hot, dilute acetic acid (50 cm 3, 50 °, 50 g). After cooling, the yellow precipitate collects on the filter, is washed with water and acetone and dried at 60 ° C. The resulting material contains 90% folic acid and 7.7 ° A; water.

Claims

Patent claim:

1. A method of recovering folic acid from a mixture of folic acid and pterins related thereto, which adheres to the folic acid, is characterized in that this mixture is treated with a magnesium compound to effect an aqueous solution of the resulting magnesium folate and that non-soluble substances are separated therefrom. soluble magnesium folate and that the solution is then treated so that either magnesium folate or folic acid precipitates.

2. A kit according to claim 1, characterized in that said mixture is first treated in and for the formation of some other salt, which is then reacted with a magnesium compound, to produce magnesium folate by double reaction.

3. A claim according to claim 2, characterized in that said mixture is first treated with calcium hydroxide and then with magnesium sulphate.

4. A stand according to claims 1, 2 or 3, characterized in that a hot, concentrated surface solution of magnesium folate is prepared, that this solution after the removal of non-soluble substances therefrom is cooled in and for the effect of a precipitation of magnesium folate, that the precipitate is isolated. clay and, if desired, again dissolved in hot water, and finally the solution is acidified to obtain a formation of folic acid.

5. A kit according to claim 4, characterized in that the temperature of the hot solution is between 75 and 100 ° C.

6. A set according to any one of claims 1-5, characterized in that the filling of folic acid is effected by the acidification of the solution to a pH value of about 3.

7. R.-ft according to any one of the patent claims, characterized in that said magnesium compound produces magnesium oxide. Stockholm 1949. Kung, l. Boktr. P. A. Norstmlt & Miler 490089