NO137095B - METHYLCOBALAMIN PROCEDURES. - Google Patents

METHYLCOBALAMIN PROCEDURES. Download PDF

Info

Publication number
NO137095B
NO137095B NO3443/72A NO344372A NO137095B NO 137095 B NO137095 B NO 137095B NO 3443/72 A NO3443/72 A NO 3443/72A NO 344372 A NO344372 A NO 344372A NO 137095 B NO137095 B NO 137095B
Authority
NO
Norway
Prior art keywords
methylcobalamin
solution
hydroxocobalamin
cobalamin
reduction
Prior art date
Application number
NO3443/72A
Other languages
Norwegian (no)
Other versions
NO137095C (en
Inventor
Jean Boige
Original Assignee
Opochimie Immeuble Ind L Hercu
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
Application filed by Opochimie Immeuble Ind L Hercu filed Critical Opochimie Immeuble Ind L Hercu
Publication of NO137095B publication Critical patent/NO137095B/en
Publication of NO137095C publication Critical patent/NO137095C/en

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)
  • Catalysts (AREA)

Description

Oppfinnelsen angår en fremgangsmåte ved fremstilling av methylcobalamin fra hydroxocobalamin eller cyanocobolamin. The invention relates to a process for the production of methylcobalamin from hydroxocobalamin or cyanocobalamin.

Methylcobalamin er en kjent forbindelse, og det er også Methylcobalamin is a known compound and it is also

kjent at denne forbindelse er avledet fra cyanocobalamin eller hydroxocobalamin ved å erstatte cyangruppen (CN) eller hydroxyl-gruppen (OH) med en methylgruppe (CH3). Det er videre kjent at disse cobalaminer kan anvendes for terapeutiske formål som be-rettiger administrering av vitamin B 12. known that this compound is derived from cyanocobalamin or hydroxocobalamin by replacing the cyano group (CN) or the hydroxyl group (OH) with a methyl group (CH3). It is also known that these cobalamins can be used for therapeutic purposes that justify the administration of vitamin B 12.

En fremgangsmåte ved fremstilling av methylcobalamin er dessuten kjent. Ifolge denne fremgangsmåte reduseres cyanocobalamin (vitamin B 12) eller hydroxocobalamin (vitamin B 12b) A method for the production of methylcobalamin is also known. According to this procedure, cyanocobalamin (vitamin B 12) or hydroxocobalamin (vitamin B 12b) is reduced

for framstilling av det tilsvarende reduserte cobalamin (B 12s). Denne reduksjon utfores ved hjelp av natriumborhydrid i oxygenfri atmosfære, hvorefter det reduserte cobalamin (B 12s) omsettes med methyloxalat eller methyljodid for binding av methylgruppen til koboltatomet i det reduserte cobalamin B 12s. for the production of the correspondingly reduced cobalamin (B 12s). This reduction is carried out using sodium borohydride in an oxygen-free atmosphere, after which the reduced cobalamin (B 12s) is reacted with methyl oxalate or methyl iodide to bind the methyl group to the cobalt atom in the reduced cobalamin B 12s.

Det er kjent at det reduserte cobalamins B I2s stabilitet It is known that it reduced the stability of cobalamin B I2

er dårlig, og under reduksjonen og spesielt for methylgruppen bindes til koboltatomet, overfores cobalaminet B 12s delvis til cobalaminet B 12r som er et mindre redusert cobalamin enn cobalaminet B 12s og som ikke er istand til å inngå binding med en methylgruppe. is poor, and during the reduction and especially for the methyl group attached to the cobalt atom, the cobalamin B 12s is partially transferred to the cobalamin B 12r which is a less reduced cobalamin than the cobalamin B 12s and which is not capable of forming a bond with a methyl group.

For å unngå denne betydelige ulempe som påvirker utbyttet To avoid this significant disadvantage that affects the yield

av methylcobalamin, er det nodvendig å anvende overskudd av re-duksjonsmidler, men dette innebærer også en ulempe fordi det da er fare.for at cobalaminmolekylet angripes irreversibelt under of methylcobalamin, it is necessary to use an excess of reducing agents, but this also entails a disadvantage because there is then a danger that the cobalamin molecule is irreversibly attacked under

dannelse av nedbrytningsprodukter som er uheldige for renheten eller utbyttet av det onskede produkt. formation of decomposition products which are detrimental to the purity or yield of the desired product.

Ved hjelp av den foreliggende fremgangsmåte unngås de ovennevnte ulemper samtidig som overforingen av cyanocobalamin eller hydroxocobalamin til methylcobalamin utfores under optimale be-tingelser og med betraktelig nedsatt risiko for dannelse av reduserte cobalaminforbindelser som ikke er istand til å "inngå binding med en methylgruppe, eller for dannelse av nedbrytningsprodukter av cobalamin. By means of the present method, the above-mentioned disadvantages are avoided at the same time that the conversion of cyanocobalamin or hydroxocobalamin to methylcobalamin is carried out under optimal conditions and with a considerably reduced risk of the formation of reduced cobalamin compounds which are unable to "bond with a methyl group, or for formation of breakdown products of cobalamin.

Oppfinnelsen angår således en fremgangsmåte ved fremstilling av methylcobalamin ved samtidig reduksjon og methylering av hydroxocobalamin eller cyanocobalamin i en vandig, methanolisk opplosning i nærvær av sinkpulver og en methylester, og fremgangsmåten er særpreget ved at hydroxocobalaminet eller cyanocobalaminet opploses i en methanolopplosning som inneholder 5-20 volum- vann, og monomethyloxalat, et coboltsalt og sinkpulver tilsettes til opp-løsningen og-omsetningen får finne sted mens blandingen er utsatt for luft^ inntil reduksjonen og methyleringen er avsluttet. The invention thus relates to a method for the production of methylcobalamin by simultaneous reduction and methylation of hydroxocobalamin or cyanocobalamin in an aqueous, methanolic solution in the presence of zinc powder and a methyl ester, and the method is characterized by the fact that the hydroxocobalamin or cyanocobalamin is dissolved in a methanol solution containing 5-20 volume of water, and monomethyloxalate, a cobalt salt, and zinc powder are added to the solution, and the reaction is allowed to take place while the mixture is exposed to air^ until the reduction and methylation are completed.

Ved hjelp av denne fremgangsmåte er det mulig samtidig og Using this procedure, it is possible at the same time and

i den samme opplosning å gjennomfore en reduksjon og methylering. Derved nedsettes betraktelig varigheten av det reduserte cobalamin da dette methyleres efter hvert som det dannes. in the same solution to carry out a reduction and methylation. Thereby, the duration of the reduced cobalamin is considerably reduced as this is methylated as it is formed.

Den foreliggende fremgangsmåte kan representeres ved hjelp av detfolgende reaksjonsskjerna: The present method can be represented by means of the following reaction core:

hvori (1) representerer hydroxocobalamin, (2) det nascerende hydrogen dannet ved innvirkning av monomethyloxalatet på sinkpulveret, og (3) det reduserte cobalamin som straks methyleres med gruppen CH^ (<*>+) fra monomethyloxalatet med dannelse av methylcobalaminet (5). Det fremgår av det nedenstående at det reduserte cobalamin (3) ikke kan identifiseres i reaksjons-mediumet, og dets varighet er derfor meget kort. in which (1) represents hydroxocobalamin, (2) the nascent hydrogen formed by the action of the monomethyloxalate on the zinc powder, and (3) the reduced cobalamin which is immediately methylated with the group CH^ (<*>+) from the monomethyloxalate to form the methylcobalamin (5) . It appears from the following that the reduced cobalamin (3) cannot be identified in the reaction medium, and its duration is therefore very short.

Den i det sure methyloxalat frie syre forer til dannelse The free acid in the acidic methyloxalate leads to formation

av nascerende hydrogen ved omsetning med sinkpulveret, og methyl-oxalatets methylgruppe frigjores lettere under reduserende be-tingelser. of nascent hydrogen by reaction with the zinc powder, and the methyl oxalate's methyl group is released more easily under reducing conditions.

Ved den foreliggende fremgangsmåte utfores reduksjonen In the present method, the reduction is carried out

og methyleringen i nærvær av organiske eller uorganiske koboltsalter, som koboltklorid, koboltnitrat og koboltoxalat. and the methylation in the presence of organic or inorganic cobalt salts, such as cobalt chloride, cobalt nitrate and cobalt oxalate.

Disse koboltsalter påskynder omsetningen og regulerer spesielt reaksjonsmediumets Rh. Derved reguleres også reduksjonen. These cobalt salts speed up the turnover and in particular regulate the Rh of the reaction medium. This also regulates the reduction.

Hydroxocobalaminet er opplost I en opplosning av vann og methanol inneholdende 5-20 volum- vann. Tilstedeværelsen av vann letter den i methyloxalatet frie syres angrep på sinkpulveret. The hydroxocobalamin is dissolved in a solution of water and methanol containing 5-20 volumes of water. The presence of water facilitates the attack of the free acid in the methyl oxalate on the zinc powder.

Ved hjelp av den foreliggende fremgangsmåte hvor det anvendes opplesninger inneholdende ca. 50 g hydroxocobalamin pr. liter methanol, overfores hydroxocobalaminet praktisk talt kvantitativt til methylcobalamin på under 20 minutter. Reaksjons-forlopet kan folges ved hjelp av et spektrofotometer. By means of the present method where readings containing approx. 50 g of hydroxocobalamin per liter of methanol, the hydroxocobalamin is practically quantitatively transferred to methylcobalamin in less than 20 minutes. The course of the reaction can be followed using a spectrophotometer.

Dersom reaksjonen får fortsette utover 20 minutter, f.eks. If the reaction is allowed to continue beyond 20 minutes, e.g.

i inntil 1,5 time, viser de spektrofotometriske registreringer ikke noen vesentlig forandring av det dannede methylcobalamin. Det forekommer derfor ingen risiko for at methylcobalaminmolekylet skal odelegges når reduksjonen finner sted. for up to 1.5 hours, the spectrophotometric records do not show any significant change in the formed methylcobalamin. There is therefore no risk of the methylcobalamin molecule being broken down when the reduction takes place.

Reaksjonsforlbpet kan dessuten folges visuelt ved reduksjonen av hydrox'ocobalaminet og methyleringen av dette. Opplosningen som til å begynne med er rod, blir fiolett og derefter kastanje-brun og stabiliserer seg med denne farve. The course of the reaction can also be followed visually by the reduction of the hydroxocobalamin and its methylation. The solution, which is initially red, turns violet and then chestnut-brown and stabilizes with this color.

Den'iakttatte blågrbnne farve ved den kjente fremstilling av methylcobalamin som tilskrives dannelsen av det reduserte cobalamin B 12s, forekommer ikke, og dette utgjor et bevis for at denne forbindelse har en meget kort levetid ved den foreliggende fremgangsmåte og methyleres efter hvert som den dannes. The observed blue-green color in the known preparation of methylcobalamin which is attributed to the formation of the reduced cobalamin B 12s does not occur, and this constitutes evidence that this compound has a very short life in the present process and is methylated as it is formed.

Ifblge en fordelaktig utforelsesform av den foreliggende fremgangsmåte utfelles det dannede methylcobalamin ved tilsetning av 3~5 volumdeler aceton. According to an advantageous embodiment of the present method, the formed methylcobalamin is precipitated by the addition of 3~5 parts by volume of acetone.

Det utfelte og utvundne methylcobalamin opploses fortrinns-vis i en meget liten mengde vann, hvorefter en sterk base tilsettes inntil det fås en pH av ca. 9, blandingen filtreres, 6-8 volumdeler aceton settes til det erholdte filtrat og den erholdte opplosning får henstå for utkrystallisering. The precipitated and extracted methylcobalamin is preferably dissolved in a very small amount of water, after which a strong base is added until a pH of approx. 9, the mixture is filtered, 6-8 parts by volume of acetone are added to the resulting filtrate and the resulting solution is left for crystallization.

Tilsetningen av den sterke base bevirker at saltene av sink eller kobolt utfelles som ellers ville ha holdt seg i opplosning. The addition of the strong base causes the salts of zinc or cobalt to precipitate which would otherwise have remained in solution.

Det således erholdte methylcobalamin kan gjenopploses og ledes over en harpiksionebytter for å fjerne eventuelle spor av hydroxocobalamin, hydratisert cobalaminklorid eller cobalaminoxa-lat. The methylcobalamin thus obtained can be redissolved and passed over a resin ion exchanger to remove any traces of hydroxocobalamin, hydrated cobalamin chloride or cobalamin oxalate.

Efter denne rensing kan methylcobalaminet rekrystalliseres i aceton. After this purification, the methylcobalamin can be recrystallized in acetone.

Det ved hjelp av den foreliggende fremgangsmåte fremstilte That by means of the present method produced

methylcobalamin kan karakteriseres ved sammenligning av den spesifikke elektriske motstand til en konsentrert opplosning av methylcobalamin i avionisert vann med den spesifikke elektriske motstand til avionisert vann som sådant, hvorved innholdet av ioner i det methylcobalamin can be characterized by comparing the specific electrical resistance of a concentrated solution of methylcobalamin in deionized water with the specific electrical resistance of deionized water as such, whereby the content of ions in it

fremstilte methylcobalamin kan bedommes. produced methylcobalamin can be assessed.

Methylcobalaminet kan også identifiseres ved spektrofoto-metri. Absorpsjonsspektrumet fo.r en noytral eller basisk opplosning av methylcobalamin viser topper ved de folgende bølge-lengder: 267, 3^3 og 525 nm. The methylcobalamin can also be identified by spectrophotometry. The absorption spectrum for a neutral or basic solution of methylcobalamin shows peaks at the following wavelengths: 267, 3^3 and 525 nm.

Forholdet mellom absorpsjonen ved 267 nm og 525 nm til absorpsjonen ved 3^3 nm er hhv. 1,'+ og 0,65, og absorpsjonen for en opplosning inneholdende 100 y methylcobalamin pr. cm^ til- The ratio between the absorption at 267 nm and 525 nm to the absorption at 3^3 nm is respectively 1.'+ and 0.65, and the absorption for a solution containing 100 μg of methylcobalamin per cm^ to-

• svarer 1^-6-267 nm. • corresponds to 1^-6-267 nm.

Absorpsjons spektrumet for en sur opplosning av methylcobalamin er annerledes. Den maksimale absorpsjon forekommer ved 300 og !+70 nm. Dessuten er noytrale eller basiske oppløsninger av methylcobalamin rosa mens de sure oppløsninger er gule. The absorption spectrum for an acidic solution of methylcobalamin is different. The maximum absorption occurs at 300 and !+70 nm. Also, neutral or basic solutions of methylcobalamin are pink while the acidic solutions are yellow.

Eksempel 1 Example 1

1 g hydroxocobalamin ble opplost i 20 cn<H> methanol og 2 cm<J >vann. 5 g surt methyloxalat ble satt til denne opplosning, og blandingen ble omrort inntil opplosningen var fullstendig, hvorefter 0,5 g koboltklorid og h g findelt sinkpulver ble tilsatt. 1 g of hydroxocobalamin was dissolved in 20 cn<H> of methanol and 2 cm<J> of water. 5 g of acidic methyl oxalate was added to this solution, and the mixture was stirred until the solution was complete, after which 0.5 g of cobalt chloride and 1 g of finely divided zinc powder were added.

Omrøringen ble fortsatt i 1 time, hvorefter opplosningen ble filtrert for å fjerne sink eller uoppløselige sinksalter fra reaks jonsblandingen. Stirring was continued for 1 hour, after which the solution was filtered to remove zinc or insoluble zinc salts from the reaction mixture.

80 cm^ aceton ble tilsatt for å utfelle methylcobalaminet, 80 cm^ of acetone was added to precipitate the methylcobalamin,

og utfellingen ble utfort kaldt i 12 timer. and the precipitate was kept cold for 12 hours.

Blandingen ble derefter filtrert gjennom et sintret glass-filter, og det utvundne bunnfall ble gjenopplost i 25 cm^ vann, hvorefter 200 cm^ aceton ble tilsatt. Opplosningen ble utkrystallisert kaldt i lopet av 12 timer. De utvundne krystaller ble efter filtrering vasket'med aceton og derefter torket under vakuum ved omgivelsestemperatur. The mixture was then filtered through a sintered glass filter, and the precipitate recovered was redissolved in 25 cc of water, after which 200 cc of acetone was added. The solution was crystallized cold over the course of 12 hours. After filtration, the recovered crystals were washed with acetone and then dried under vacuum at ambient temperature.

Det ble erholdt 0,7 g methylcobalam: n som i en noytral eller basisk opplosning bevirket at denne fikk en rosa farve og i en sur opplosning at denne fikk en gul farve. 0.7 g of methylcobalam was obtained, which in a neutral or basic solution gave it a pink color and in an acidic solution gave it a yellow color.

På tegningen er vist de erholdte spektrofotometriske avles-ninger, og på tegningen representerer kurven 1 det i noytralt eller basisk miljo erholdte absorpsjonsspektrum og kurven 2 det i surt miljo erholdte absorpsjonsspektrum. De høyeste absorpsjonsverdier forekommer ved bølgelengder av ca. 520, 3<1>+3 og 267 nm for en noytral eller basisk opplosning av methylcobalamin. The drawing shows the obtained spectrophotometric readings, and in the drawing curve 1 represents the absorption spectrum obtained in a neutral or basic environment and curve 2 the absorption spectrum obtained in an acidic environment. The highest absorption values occur at wavelengths of approx. 520, 3<1>+3 and 267 nm for a neutral or basic solution of methylcobalamin.

Det fremgår også av tegningen at absorpsjonsverdiene ved It also appears from the drawing that the absorption values at

267 og 525 nm i forhold til absorpsjonsverdien ved 3^-3 nm er hhv. 1,^3 og'0,63. 267 and 525 nm in relation to the absorption value at 3^-3 nm are respectively 1.^3 and'0.63.

Det kan dessuten av kurvene utledes at hydroxocobalamin ikke er tilstede i opplosningen av methylcobalamin da det mellom pH k- og pH 9 ikke forekommer de trinn som er særpregede for en opplosning av It can also be deduced from the curves that hydroxocobalamin is not present in the solution of methylcobalamin, as between pH k- and pH 9 the steps that are characteristic for a solution of

hydroxocobalamin. hydroxocobalamin.

Eksempel 2 Example 2

cmJ 3 van1n0 .g hydroxocobalamin ble opplost i 200 cmJ ■3 methanol og 15 cmJ 3 van1n0 .g hydroxocobalamin was dissolved in 200 cmJ ■3 methanol and 15

^5 g surt methyloxalat ble satt til opplosningen som ble omrort inntil opplosningen var fullstendig, og derefter ble h g kobolt - klorid og 35 g findelt sinkpulver tilsatt. ^5 g of acid methyl oxalate was added to the solution which was stirred until the solution was complete, and then 1 g of cobalt chloride and 35 g of finely divided zinc powder were added.

Omroringen ble fortsatt i 1 time, hvorefter opplosningen ble filtrert for å fjerne sink eller uoppløselige sinksalter fra reaks jonsblandingen. Stirring was continued for 1 hour, after which the solution was filtered to remove zinc or insoluble zinc salts from the reaction mixture.

h volumdeler aceton ble satt til filtratet under omroring fc å utfelle methylcobalaminet og utfellingen ble foretatt kaldt i lbpet av h timer. .Blandingen ble filtrert på en Buchner-trakt, og det utvundne bunnfall ble gjenopplost i en meget liten mengde vann. h parts by volume of acetone were added to the filtrate with stirring to precipitate the methylcobalamin and the precipitation was carried out cold for a period of h hours. .The mixture was filtered on a Buchner funnel and the precipitate recovered was redissolved in a very small amount of water.

Til denne opplosning ble langsomt og i overensstemmelse med opplosningens pH tilsatt en 5 N natriumhydroxydopplosning inntil c ble oppnådd en pH av 9,2 for å utfelle sinkhydroxyd eller kobolt-hydroxyd som ellers ville ha holdt .seg i opplosning. To this solution, a 5 N sodium hydroxide solution was added slowly and in accordance with the pH of the solution until a pH of 9.2 was achieved in order to precipitate zinc hydroxide or cobalt hydroxide which would otherwise have remained in solution.

Blandingen fikk henstå kald i 2 timer og ble derefter filtre på en Buchner-trakt. 2 1 aceton ble satt til filtratet, og opplosningen ble'utkrystallisert kaldt i lbpet av h timer. The mixture was allowed to stand cold for 2 hours and then filtered on a Buchner funnel. 2 1 of acetone was added to the filtrate, and the solution was crystallized cold over the course of h hours.

De utvundne krystaller ble efter filtrering vasket i aceton The recovered crystals were washed in acetone after filtration

i ether og derefter tbrket under vakuum ved omgivelsestemperatur. in ether and then dried under vacuum at ambient temperature.

Det ble erholdt 8,5 g methylcobalamin inneholdende 17% fukl 8.5 g of methylcobalamin containing 17% fucl were obtained

het. hot.

Det erholdte produkt ble kontrollert ved måling av den spes: fikke elektriske motstand til en opplosning av 5000 y methylcobalamin pr. cm^ avionisert vann. The product obtained was checked by measuring the specific electrical resistance to a solution of 5000 μl of methylcobalamin per cm^ deionized water.

Den målte spesifikke elektriske motstand var hbyere enn 100( ohm/cm. Dette resultat viser at det i opplosningen ikke forekomme ioner som kunne ha skrevet seg fra den sink eller kobolt som ble : The measured specific electrical resistance was higher than 100 (ohm/cm. This result shows that there are no ions in the solution that could have formed from the zinc or cobalt that became:

fort.i reaksjonsblandingen. fast.in the reaction mixture.

Den ovennevnte opplosning efter fortynning til 50 Y methylcobalamin pr. cm 3 viste ved spektrofotometriske malinger de hby-este absorpsjonsverdier ved en bblgelengde av 267, 3^3 og 520 nm, tilsvarende de resultater som ble oppnådd med rent methylcobalamin. The above solution after dilution to 50 Y methylcobalamin per cm 3 showed by spectrophotometric paints the highest absorption values at a wavelength of 267, 3^3 and 520 nm, corresponding to the results obtained with pure methylcobalamin.

Det fremgår av de ovenstående eksempler at den foreliggende fremgangsmåte ved fremstilling av methylcobalamin er meget enkel å gjennomfore. It appears from the above examples that the present method for the production of methylcobalamin is very simple to carry out.

Det erholdes et rent methylcobalamin takket være en fullstendig regulert reduksjon av hydroxocobalaminet idet det anvendes et reagens bestående av surt methyloxalat som ved den foreliggende fremgangsmåte spiller en dobbeltrolle ved at det på den ene side utgjor en syre som er istand til å bevirke dannelse av nascerende hydrogen ved omsetning med sinkpulveret, og ved at det på den annen side av-gir frie methylgrupper som kan inngå binding med det reduserte cobalamin. A pure methylcobalamin is obtained thanks to a completely regulated reduction of the hydroxocobalamin using a reagent consisting of acidic methyl oxalate which, in the present method, plays a double role in that, on the one hand, it forms an acid which is capable of causing the formation of nascent hydrogen by reaction with the zinc powder, and by the fact that, on the other hand, it gives off free methyl groups which can form a bond with the reduced cobalamin.

Det reduserte cobalamin methyleres således efter hvert som det dannes, og derved unngås at dette blir for sterkt redusert eller at det tvertimot omdannes til et mindre redusert cobalamin som ikke er istand til å inngå binding med methylgruppen. The reduced cobalamin is thus methylated as it is formed, and thereby it is avoided that this is reduced too much or that, on the contrary, it is converted into a less reduced cobalamin which is not capable of forming a bond with the methyl group.

Den foreliggende fremgangsmåte utfores således i ett trinn og er derfor meget hurtig og gjor det mulig å oppnå et meget rent produkt. The present method is thus carried out in one step and is therefore very fast and makes it possible to obtain a very pure product.

Claims (1)

Fremgangsmåte ved fremstilling av methylcobalamin ved samtidig reduksjon og methylering av hydroxocobalamin eller cyanocobalamin i en vandig,methanolisk oppløsning i nærvær av sinkpulver og en methylester, karakterisert ved at hydroxocobalaminet eller cyanocobalaminet oppløses i en methanol-oppløsning som inneholder 5-20 volum% vann, og monomethyloxalat, et coboltsalt og sinkpulver tilsettes til oppløsningen og omsetningen får finne sted mens blandingen er utsatt for luft, inntil reduksjonen og methyleringen er avsluttet.Process for the production of methylcobalamin by simultaneous reduction and methylation of hydroxocobalamin or cyanocobalamin in an aqueous, methanolic solution in the presence of zinc powder and a methyl ester, characterized in that the hydroxocobalamin or cyanocobalamin is dissolved in a methanol solution containing 5-20% water by volume, and monomethyloxalate, a cobalt salt, and zinc powder are added to the solution and the reaction is allowed to take place while the mixture is exposed to air, until the reduction and methylation are completed.
NO3443/72A 1971-11-10 1972-09-26 METHYLCOBALAMIN PROCEDURES NO137095C (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR7140233A FR2159720A5 (en) 1971-11-10 1971-11-10

Publications (2)

Publication Number Publication Date
NO137095B true NO137095B (en) 1977-09-19
NO137095C NO137095C (en) 1977-12-28

Family

ID=9085580

Family Applications (1)

Application Number Title Priority Date Filing Date
NO3443/72A NO137095C (en) 1971-11-10 1972-09-26 METHYLCOBALAMIN PROCEDURES

Country Status (21)

Country Link
JP (1) JPS51120B2 (en)
AR (1) AR192677A1 (en)
AT (1) AT330374B (en)
AU (1) AU464986B2 (en)
BE (1) BE789252A (en)
BR (1) BR7207834D0 (en)
CA (1) CA972746A (en)
CH (1) CH545299A (en)
DE (1) DE2255203A1 (en)
DK (1) DK133381B (en)
ES (1) ES408279A1 (en)
FR (1) FR2159720A5 (en)
GB (1) GB1355899A (en)
IE (1) IE36822B1 (en)
IL (1) IL40762A (en)
LU (1) LU66165A1 (en)
NL (1) NL153548B (en)
NO (1) NO137095C (en)
OA (1) OA04191A (en)
SE (1) SE383350B (en)
ZA (1) ZA727831B (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NO742545L (en) * 1973-08-08 1975-03-10 Opochimie L
JPS583753Y2 (en) * 1978-08-25 1983-01-22 日立造船株式会社 Connection device for offshore structures
JPH0422432A (en) * 1990-05-18 1992-01-27 Maruyama Mfg Co Ltd Method and device for agitating spray liquid in spray liquid tank
KR100694688B1 (en) * 1999-12-09 2007-03-13 에자이 알앤드디 매니지먼트 가부시키가이샤 Process for production of methylcobalamin
EP1394174B1 (en) * 2001-06-05 2015-11-11 Eisai R&D Management Co., Ltd. Process for producing methylcobalamin

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1178073B (en) * 1961-06-09 1964-09-17 Merck Ag E Process for the production of vitamin B and its stable solutions
FR1450375A (en) * 1961-12-11 1966-06-24 Glaxo Group Ltd Process for the preparation of a coenzyme of vitamin b12 and analogues thereof
DE1213842B (en) * 1962-04-27 1966-04-07 Hoffmann La Roche Process for the preparation of Co-R cobamides

Also Published As

Publication number Publication date
IL40762A0 (en) 1973-01-30
IE36822L (en) 1973-05-10
FR2159720A5 (en) 1973-06-22
NL7214368A (en) 1973-05-14
ES408279A1 (en) 1975-11-01
NO137095C (en) 1977-12-28
SE383350B (en) 1976-03-08
BE789252A (en) 1973-03-26
AR192677A1 (en) 1973-02-28
DE2255203A1 (en) 1973-05-17
ZA727831B (en) 1973-07-25
AT330374B (en) 1976-06-25
LU66165A1 (en) 1974-04-02
ATA945672A (en) 1975-09-15
IL40762A (en) 1975-07-28
CH545299A (en) 1973-12-15
AU4858272A (en) 1974-05-09
AU464986B2 (en) 1975-09-11
JPS51120B2 (en) 1976-01-05
IE36822B1 (en) 1977-03-02
DK133381C (en) 1976-10-04
BR7207834D0 (en) 1973-09-20
NL153548B (en) 1977-06-15
JPS4947399A (en) 1974-05-08
DK133381B (en) 1976-05-10
CA972746A (en) 1975-08-12
OA04191A (en) 1979-12-31
GB1355899A (en) 1974-06-05

Similar Documents

Publication Publication Date Title
CN109897070B (en) Preparation method of tetraamminepalladium acetate (II)
JP7267675B2 (en) 6&#39;-SIALYL LACTOSE SODIUM SALT CRYSTALS AND METHOD FOR PRODUCING SAME
EP3252065B1 (en) Crystal of ammonium n-acetylneuraminate anhydrate, and process for producing same
NO137095B (en) METHYLCOBALAMIN PROCEDURES.
AU2004319676B2 (en) Method for producing iron (III) gluconate complex
Snyder et al. The Insecticidal Principles of Haplophyton cimicidum. II. Haplophytine and Cimicidine1
JPS59102821A (en) Manufacture of chromium (iii) compound
Kaeding et al. Preparation of Salicylic Acids by the Hydroxylation of Benzoic Acids
CN111285788B (en) Preparation method of alliin
House et al. Transition metal complexes of tetraethylenepentamine. II. Some acidotetraethylenepentamine complexes of cobalt (III) and chromium (III)
US4153788A (en) Process of preparing mono-O-β-hydroxyethyl-7 rutoside
Scott-Moncrieff Natural anthocyanin pigments: The magenta flower pigment of Primula polyanthus
JPS60110825A (en) Separation of zirconium from hafnium
DE1493403A1 (en) Process for the resolution of racemates into their optical isomers
RU2230025C2 (en) Method for preparing elemental tellurium
Barger et al. XLVIII.—Blue adsorption compounds of iodine. Parts II and III. Derivatives of α-and of γ-pyrone
JP7201262B2 (en) Hydrate crystals of 3&#39;,3&#39;-cGAMP
JPS6114156B2 (en)
Krot et al. Synthesis of New Crystalline Pu (V) Compounds from Solutions: IV. Double Pu (V) Malonates of the Composition Co (NH 3) 6 [PuO 2 C 3 H 2 O 4] 2 A⋅ n H 2 O, A= NO 3, ClO 4, Cl, and Br
JP2000001491A (en) Purification of vitamin b12
Krot et al. Double Np (V) malonates with Co (NH 3) 6 3+ in the outer sphere
US4158616A (en) Uranium oxide production
KR890003843B1 (en) Process for producing the double sulfate of desoxyfructosyl serotonin and creatinine
Bessonov et al. Synthesis and study of complexes of Pu (V) and Np (V) propionates with α, α′-bipyridine
Baird et al. 18. Ascorbic acid and synthetic analogues