NO742545L - - Google Patents
Info
- Publication number
- NO742545L NO742545L NO742545A NO742545A NO742545L NO 742545 L NO742545 L NO 742545L NO 742545 A NO742545 A NO 742545A NO 742545 A NO742545 A NO 742545A NO 742545 L NO742545 L NO 742545L
- Authority
- NO
- Norway
- Prior art keywords
- cyanocobalamin
- methylcobalamin
- solution
- water
- oxalic acid
- Prior art date
Links
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 claims description 77
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- 235000000639 cyanocobalamin Nutrition 0.000 claims description 38
- 239000011666 cyanocobalamin Substances 0.000 claims description 38
- 229960002104 cyanocobalamin Drugs 0.000 claims description 38
- 235000007672 methylcobalamin Nutrition 0.000 claims description 34
- 239000011585 methylcobalamin Substances 0.000 claims description 34
- JEWJRMKHSMTXPP-BYFNXCQMSA-M methylcobalamin Chemical compound C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O JEWJRMKHSMTXPP-BYFNXCQMSA-M 0.000 claims description 34
- ASARMUCNOOHMLO-WLORSUFZSA-L cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2s)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@H](C)OP([O-])(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O ASARMUCNOOHMLO-WLORSUFZSA-L 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 18
- CPKISUMKCULUNR-UHFFFAOYSA-N 2-methoxy-2-oxoacetic acid Chemical compound COC(=O)C(O)=O CPKISUMKCULUNR-UHFFFAOYSA-N 0.000 claims description 15
- 238000007069 methylation reaction Methods 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 13
- 239000002184 metal Substances 0.000 claims description 11
- 229910052751 metal Inorganic materials 0.000 claims description 11
- 239000000843 powder Substances 0.000 claims description 11
- 239000012429 reaction media Substances 0.000 claims description 10
- 230000011987 methylation Effects 0.000 claims description 9
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 4
- 229910017052 cobalt Inorganic materials 0.000 claims description 4
- 239000010941 cobalt Substances 0.000 claims description 4
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 150000001868 cobalt Chemical class 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- 229910002651 NO3 Inorganic materials 0.000 claims 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims 1
- 238000006722 reduction reaction Methods 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 229920005989 resin Polymers 0.000 description 8
- 239000011347 resin Substances 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- YZCKVEUIGOORGS-UHFFFAOYSA-N Hydrogen atom Chemical compound [H] YZCKVEUIGOORGS-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 150000001768 cations Chemical class 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- 241001070941 Castanea Species 0.000 description 2
- 235000014036 Castanea Nutrition 0.000 description 2
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 229920001429 chelating resin Polymers 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 229940010007 cobalamins Drugs 0.000 description 2
- 150000001867 cobalamins Chemical class 0.000 description 2
- UFMZWBIQTDUYBN-UHFFFAOYSA-N cobalt dinitrate Chemical compound [Co+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O UFMZWBIQTDUYBN-UHFFFAOYSA-N 0.000 description 2
- 229910001429 cobalt ion Inorganic materials 0.000 description 2
- 229910001981 cobalt nitrate Inorganic materials 0.000 description 2
- XLJKHNWPARRRJB-UHFFFAOYSA-N cobalt(2+) Chemical compound [Co+2] XLJKHNWPARRRJB-UHFFFAOYSA-N 0.000 description 2
- MULYSYXKGICWJF-UHFFFAOYSA-L cobalt(2+);oxalate Chemical compound [Co+2].[O-]C(=O)C([O-])=O MULYSYXKGICWJF-UHFFFAOYSA-L 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- YOZNUFWCRFCGIH-BYFNXCQMSA-L hydroxocobalamin Chemical compound O[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O YOZNUFWCRFCGIH-BYFNXCQMSA-L 0.000 description 2
- -1 methyl- Chemical group 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 150000003751 zinc Chemical class 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 description 1
- 229930003270 Vitamin B Natural products 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 235000004867 hydroxocobalamin Nutrition 0.000 description 1
- 239000011704 hydroxocobalamin Substances 0.000 description 1
- 229960001103 hydroxocobalamin Drugs 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
Description
Fremgangsmåte ved fremstilling av methyl-Procedure for the production of methyl-
cobalamin fra cyanocobalamincobalamin from cyanocobalamin
Foreliggende oppfinnelse angår en fremgangsmåte for fremstilling av methylcobalamin i industriell målestokk ut fra cyano-coba lamin. Methylcobalamin er en kjent forbindelse, og det er kjent at dette produkt avledes fra cyanocobalamin ved erstatning av cyano-gruppen (CN) med en methylgruppe (CH3). Methylcobalamin og cyanocobalamin anvendes innen medisinen ved behandlinger hvor der admini-streres vitamin B^^. The present invention relates to a method for the production of methylcobalamin on an industrial scale from cyanocobalamin. Methylcobalamin is a known compound, and it is known that this product is derived from cyanocobalamin by replacing the cyano group (CN) with a methyl group (CH3). Methylcobalamin and cyanocobalamin are used in medicine in treatments where vitamin B is administered.
Tilpasning av methylcobalamin i form av injiserbare am-puller er imidlertid betydelig mere fordelaktig enn cyanocobalamin på grunn av methylcobalaminets méget storre opploselighet i vann. Adaptation of methylcobalamin in the form of injectable ampoules is, however, significantly more advantageous than cyanocobalamin due to methylcobalamin's much greater solubility in water.
Der er kjent en fremgangsmåte ved fremstilling av methylcobalamin. Ved den kjente fremgangsmåte reduseres cyanocobalamin (vitamin B12) under dannelse av redusert cobalamin (Bi2s)« Denne reduksjon utfores med natriurnborhydrid (NaBH^) i en atmosfære som ikke<i>nneholder oxygen, hvorefter dette réduserte cobalamin (B12s) omsettes med methyloxalat eller methyljodid for å feste methylgruppen til cobolt i det reduserte cobalamin v (B1, 2s)'. A method for the production of methylcobalamin is known. In the known method, cyanocobalamin (vitamin B12) is reduced to form reduced cobalamin (Bi2s)" This reduction is carried out with sodium borohydride (NaBH^) in an atmosphere that does not contain oxygen, after which this reduced cobalamin (B12s) is reacted with methyl oxalate or methyl iodide to attach the methyl group to cobalt in the reduced cobalamin v (B1, 2s)'.
På grunn av den dårlige stabilitet er det reduserte cobalamin B12stilboyelig til under reduksjonen, og særlig for festing av methylgruppen, å overfores delvis til cobalaminB12r, som er et mindre redusert cobalamin enn cobala<min>B s, og som er mindre istand ti 1 å feste methylgruppen. Due to its poor stability, the reduced cobalamin B12 is liable to be partially transferred during the reduction, and especially for the attachment of the methyl group, to cobalamin B12r, which is a less reduced cobalamin than cobalamin B s, and which is less able to 1 attach the methyl group.
For å unngå denne alvorlige ulempe som påvirker utbyttet av methylcobalamin, er det nddvendig å anvende overskudd av reduksjons-midlet. Dette forer til en annen ulempe, da man risikerer å angripe cobalaminmolekylet irreversibelt under dannelse av spaltningsprodukter som er til skade for enheten og utbyttet av methylcobalamin. To avoid this serious disadvantage affecting the yield of methylcobalamin, it is necessary to use an excess of the reducing agent. This leads to another disadvantage, as there is a risk of irreversibly attacking the cobalamin molecule with the formation of cleavage products which are detrimental to the unit and the yield of methylcobalamin.
For å unngå overforing av cobalamin B^2g er der likeledes foreslått å utfore reaksjonen i nærvær av en inert gass, slik som argon. Imidlertid vil anvendelse av en slik gass komplisere betydelig operasjonene og oke prisen kraftig. In order to avoid excess transfer of cobalamin B^2g, it is also proposed to carry out the reaction in the presence of an inert gas, such as argon. However, the use of such a gas will significantly complicate the operations and increase the price considerably.
Foreliggende fremgangsmåte er ikke beheftet med disse ulem-per og gjor det mulig å overfore cyanocobalamin til methylcobalamin under betingelser slik at man betydelig begrenser risikoen for dannelse av redusert cobalamin som ikke er istand til å feste methylgruppen, eller for spaltningsprOdukter-av cobalamin. The present method is not affected by these disadvantages and makes it possible to transfer cyanocobalamin to methylcobalamin under conditions so as to significantly limit the risk of formation of reduced cobalamin which is unable to attach the methyl group, or of cleavage products of cobalamin.
Fremgangsmåten ifolge oppfinnelsen ved fremstilling av methylcobalamin ved hvilken, man utforer methylering av redusert cobalamin er kjennetegnet ved at man anvender en oppldsning inneholdende minst 40 g pr. liter cyanocobalamin i en blanding av methanol og vann, og at der til denne blanding tilsettes oxalsyremonomethylester og et metallpulver som ér istand til å frigi hydrogen ved innvirkning på oxalsyre-monomethylestere i den hensikt å samtidig utfore en reduksjon av cyanocobalamin og methylering av det reduserte cobalamin-ethyImethylcobalamin. The method according to the invention for the production of methylcobalamin in which methylation of reduced cobalamin is carried out is characterized by using a solution containing at least 40 g per liters of cyanocobalamin in a mixture of methanol and water, and that to this mixture is added oxalic acid monomethyl ester and a metal powder which is able to release hydrogen by impact on oxalic acid monomethyl esters with the intention of simultaneously carrying out a reduction of cyanocobalamin and methylation of the reduced cobalamin -ethylImethylcobalamin.
Den kjennsgjerning at reduksjon og methylering av cyanoco-ba lamin utfores samtidig ved hjelp av oxalsyre-monomethylester begrenser betydelig eksistensvarigheten av det reduserte cobalamin (B-^^s) som erholdes ved innvirkning av nascerende hydrogen som dannes ved reaksjonen mellom oxalsyre-monomethylesteren og metallpulveret, fordi det reduserte cobalamin methyleres efterhvert som det dannes. Fremgangsmåten kan utfores i nærvær av luft. The fact that reduction and methylation of cyanocobalamin are carried out simultaneously by means of oxalic acid monomethyl ester significantly limits the duration of existence of the reduced cobalamin (B-^^s) obtained by the action of nascent hydrogen formed by the reaction between the oxalic acid monomethyl ester and the metal powder , because the reduced cobalamin is methylated as it is formed. The procedure can be carried out in the presence of air.
Reduksjons- og methyleringsreaksjonen kan illustreres ved folgende skjema: The reduction and methylation reaction can be illustrated by the following scheme:
hvor (1) betegner cyanocobalamin, (2) nascerende hydrogen dannet ved reaksjon av den frie syregruppe i oxalsyre-monomethylesteren og meta llpulveret, (3) betegner redusert cobalamin (B^g) sora straks methyleres av CH^-gruppen, (4) som stammer fra oxalsyre-monomethy1-esteren, under dannelse av methylcobalamin (5). where (1) denotes cyanocobalamin, (2) nascent hydrogen formed by reaction of the free acid group in the oxalic acid monomethyl ester and the metal powder, (3) denotes reduced cobalamin (B^g) which is immediately methylated by the CH^ group, (4) which originates from the oxalic acid monomethyl ester, forming methylcobalamin (5).
Samtidig med de ovenfor angitte reaksjoner hydrogeneresAt the same time as the above-mentioned reactions, hydrogenation is carried out
CN gruppen fra cyanocobalamin (1) til methylamin ved folgende reaks j on: The CN group from cyanocobalamin (1) to methylamine by the following reaction:
Det fremgår efter skjemaet for denne reaksjon at det teo-retisk er tilstrekkelig ved reaksjonen mellom oxalsyre-monomethy1-esteren og metallpulveret å frigi 5 gramatomer nascerende hydrogen pr. grammolekyl cyanocobalamin. Imidlertid foretrekkes der å anvende overskudd av oxalsyre-monomethylester og metallpuIver. It appears from the scheme for this reaction that it is theoretically sufficient in the reaction between the oxalic acid monomethyl ester and the metal powder to release 5 gram atoms of nascent hydrogen per gram molecule cyanocobalamin. However, it is preferred to use an excess of oxalic acid monomethyl ester and metal powders.
Det under reduksjonen dannede methylamin forblir i reak-sjonsmi1joet, og dets methylgruppe innvirker overhodet ikke på methyleringsreaksjonen. The methylamine formed during the reduction remains in the reaction medium, and its methyl group does not affect the methylation reaction at all.
Man vil imidlertid på den annen side kunne frykte at CN-gruppen som frigis under reduksjonen,, skulle innvirke på methy ler-ingsreaks jonen. However, on the other hand, one might fear that the CN group released during the reduction would affect the methylation reaction.
Blant de metallpulvere som er istand til å frigi hydrogen ved innvirkning på oxalsyre-monomethyles ter foretrekkes der å anvende zinkpulver. Among the metal powders which are capable of liberating hydrogen when acting on oxalic acid monomethyl esters, it is preferred to use zinc powder.
Man har konstatert at for å utfore reduksjonen og methyleringen av cyanocobalamin er det nodvendig at konsentrasjonen av cyanocobalamin i reaksjonsmediet må være over 40 g/l. En slik konsentrasjon er det umulig å oppnå i ren methanol eller vann, da opploseligheten av cyanocobalamin i de to opplosningsmidler er hen-holdsvis 20 og 13 g/l. Man har ikke desto mindre konstatert den overraskende effekt at opploseligheten av cyanocobalamin oker i en blanding av methanol og vann og når et maksimum når mengden av vann i methanol er lik 8 volum% og når opp til 160 g/l for denne mengde. It has been established that in order to carry out the reduction and methylation of cyanocobalamin, it is necessary that the concentration of cyanocobalamin in the reaction medium must be above 40 g/l. Such a concentration is impossible to achieve in pure methanol or water, as the solubility of cyanocobalamin in the two solvents is 20 and 13 g/l, respectively. Nevertheless, the surprising effect that the solubility of cyanocobalamin increases in a mixture of methanol and water has been established and reaches a maximum when the amount of water in methanol is equal to 8% by volume and reaches up to 160 g/l for this amount.
Det er imidlertid uhensiktsmessig å operere med en slik konsentrasjon av cyanocobalamin, idet de gunstige betingelser for opp løseligheten, reduksjonen og methyleringen oppfylles når den an-vendte blanding av methanol og vann inneholder mellom 7 og 15 % vann. However, it is inappropriate to operate with such a concentration of cyanocobalamin, as the favorable conditions for solubility, reduction and methylation are met when the mixture of methanol and water used contains between 7 and 15% water.
Ifolge en foretrukken utforelsesform av fremgangsmåten opprettholdes reaksjonsmiljoet ved en temperatur mellom 28 og 32°C. According to a preferred embodiment of the method, the reaction environment is maintained at a temperature between 28 and 32°C.
Det er et foretrukket trekk å holde reaksjonsmi1joet mellom de angitte temperaturgrenser. Hvis temperaturen er over 32°C, vil reduksjonsreaksjonen være tilboyelig til å forlope for fort, slik at man risikerer å spalte cobalaminmolekylet. It is a preferred feature to keep the reaction medium between the specified temperature limits. If the temperature is above 32°C, the reduction reaction will tend to proceed too quickly, so that there is a risk of splitting the cobalamin molecule.
Hvis på den annen side temperaturen er lavere enn 28°C, forloper reduksjonen og methyleringen for sakte*og ufullstendig, hvilket er uheldig for utbyttet av sluttproduktet. If, on the other hand, the temperature is lower than 28°C, the reduction and methylation proceed too slowly* and incompletely, which is unfavorable for the yield of the final product.
Ifolge et annet foretrukket trekk ved fremgangsmåten til-, settes reaksjonsmiljoet coboltsalter. According to another preferred feature of the method, cobalt salts are added to the reaction medium.
Slike coboltsalter kan f.eks. være coboltklorid, ■ cobolt ni-trat eller coboltoxalat, som katalyserer reduksjonsreaksjonen og re-gulerer pH i reaksjonsmiljoet. Such cobalt salts can e.g. be cobalt chloride, ■ cobalt nitrate or cobalt oxalate, which catalyzes the reduction reaction and regulates the pH in the reaction environment.
Ved å anvende de angitte betingelser kan man nesten kvanti-tativt overfore cyanocobalamin til methylcobalamin. Man kan folge By applying the specified conditions, cyanocobalamin can be almost quantitatively converted to methylcobalamin. You can follow
reaksjonsforlopet visuelt ved hjelp av et spektrofotometer. Oppløs-ningen av cyanocobalamin som i begynnelsen er rod, går over til fio-lett og derefter til kastanjebrun eftersom cyanocobalamin overfores til methylcobalamin. the course of the reaction visually using a spectrophotometer. The solution of cyanocobalamin, which is initially red, changes to violet and then to chestnut brown since cyanocobalamin is transferred to methylcobalamin.
Den blå-gronne farve som er beskrevet i litteraturen, og som tilskrives dannelse av redusert cobalamin Bn12„ s fremkom ikke, hvilket utgjor et bevis på at denne forbindelse ved foreliggende fremgangsmåte har ,en meget kort levetid på grunn av at den methyleres umiddelbart efter sin dannelse. The blue-green color described in the literature, which is attributed to the formation of reduced cobalamin Bn12„s, did not appear, which constitutes proof that this compound has a very short lifetime in the present method due to the fact that it is methylated immediately after its formation.
Når reaksjonen er avsluttet, filtreres reaksjonsmiljoet for å fjerne overskudd av zink og dannede uopploselige zinksalter. When the reaction is finished, the reaction medium is filtered to remove excess zinc and formed insoluble zinc salts.
Man utfeller derefter methylcobalamin i filtratet med fire volum aceton, filtrerer og opploser det utfeldte methylcobalamin på-nytt i en blanding av like mengder aceton og vann. Methylcobalamin is then precipitated in the filtrate with four volumes of acetone, filtered and the precipitated methylcobalamin is re-dissolved in a mixture of equal amounts of acetone and water.
Den erholdte opplosning kan derefter krystalliseres direkte, men renses forst fortrinnsvis ved passering gjennom hensikts-messige kromatigrafiske kolonner. The solution obtained can then be crystallized directly, but preferably purified first by passing through suitable chromatographic columns.
Ifolge en variant av fremgangsmåten fores oppløsningen av cyanocobalamin, vann, methanol og oxalxyre-monomethylester gjennom en kolonne inneholdende metallpulver,og hydroxocobalamin separeres fra oppløsningen som gjenvinnes ved utlopet av kolonnen. According to a variant of the method, the solution of cyanocobalamin, water, methanol and oxalxyre monomethyl ester is passed through a column containing metal powder, and hydroxocobalamin is separated from the solution which is recovered at the outlet of the column.
Omdannelsen av cyanocobalamin til methylcobalamin utfores således kontinuerlig i kolonnen i kontakt med metallpulveret som frigir nascerende hydrogen, idet det reagerer med oxalsyre-monomethylesteren. The conversion of cyanocobalamin to methylcobalamin is thus carried out continuously in the column in contact with the metal powder which releases nascent hydrogen, as it reacts with the oxalic acid monomethyl ester.
Denne kontinuerlige operasjonsmetode gjor det mulig å hoyne utbyttet av methylcobalamin, og tillater likeledes anvendelse av en stdrre mengde cyanocobalamin i hver operasjon. This continuous operation method makes it possible to increase the yield of methylcobalamin, and also allows the use of a greater amount of cyanocobalamin in each operation.
Ved endt reaksjon er det ikke nødvendig å filtrere oppløs-ningen som gjenvinnes ved utlopet av kolonnen.. Denne kan direkte anvendes ved separasjonsoperasjonene og rensningen av methylcobalamin. At the end of the reaction, it is not necessary to filter the solution that is recovered at the outlet of the column. This can be directly used in the separation operations and the purification of methylcobalamin.
Som ved den fdrste utforelsesform inneholder blandingen av methanol og vann fortrinnsvis mellom 7 og 15 % vann, idet opplosningen av cyanocobalamin tilsettes salter av cobolt, slik som coboltklorid, coboltnitrat eller coboltoxalat. As in the first embodiment, the mixture of methanol and water preferably contains between 7 and 15% water, the solution of cyanocobalamin being added to salts of cobalt, such as cobalt chloride, cobalt nitrate or cobalt oxalate.
De efterfolgende to eksempler illustrerer fremgangsmåten ved fremstilling av methylcobalamin ut fra cyanocobalamin. The following two examples illustrate the procedure for producing methylcobalamin from cyanocobalamin.
Ekse mpel 1Example 1
100 g cyanocobalamin oppløses i 2 liter methanol og 200 ml vann. Oppløsningen er fullstendig klar med en karakteristisk rod farve. 100 g of cyanocobalamin is dissolved in 2 liters of methanol and 200 ml of water. The solution is completely clear with a characteristic red color.
Til denne opplosning tilsettes 200 g oxalsyre-monomethylester, 30 g coboltklorid, hvorefter den erholdte blanding bringes til 28°C og holdes ved denne temperatur. Der tilsettes derefter 300 g zinkpulver. To this solution are added 200 g of oxalic acid monomethyl ester, 30 g of cobalt chloride, after which the resulting mixture is brought to 28°C and kept at this temperature. 300 g of zinc powder is then added.
Reduksjons- og methyleringsreaksjonene starter. Reaksjonene er eksoterme, og reaks jonsmi ljoet avkjoles .for å holde dette på The reduction and methylation reactions start. The reactions are exothermic, and the reaction mixture is cooled to keep this going
en temperatur under 32°C. Man lar reaksjonene forlope i 1 time,,a temperature below 32°C. The reactions are allowed to proceed for 1 hour,
mens reaksjonsmiljoet holdes under omroring. Dette reaksjonsmiljo får efter endt reaksjon en kastanjebrun farvNe. Den resulterende blanding filtreres for å fjerne zink eller dannede zinksalter som er uopploselige i reaksjonsmiljoet. Til filtratet tilsettes 4 volumer aceton for å utfelle methylcobalamin. Blandingen filtreres, og. det utfeldte methylcobalamin oppldses i. en blanding av like mengder vann og aceton. while the reaction medium is kept under agitation. After completion of the reaction, this reaction medium acquires a chestnut brown colour. The resulting mixture is filtered to remove zinc or formed zinc salts which are insoluble in the reaction medium. 4 volumes of acetone are added to the filtrate to precipitate methylcobalamin. The mixture is filtered, and. the precipitated methylcobalamin is dissolved in a mixture of equal amounts of water and acetone.
Den resulterende opplosning fores derefter gjennom en kolonne inneholdende en harpiks .sammensatt av kuleformige polymerperler inneholdende utvekslingsplasser for kationer og anioner, slik som harpiksen med varemerke "Retardion AG 11 A8" som markedsføres av-Bio-Rad,for å fjerne zinkionene, coboltionene etc. fra opplosningen, og derefter gjennom en kolonne med blandede skikt sammensatt av 3 volumer av en sterkt basisk [N^CH^) 3+ anionbytterharpiks, slik som harpiks IRA 400 fra Rohm & Haas, og T volum av en sulfonsyreharpiks, kationbytter, slik som '!Amberlite IRC 120"fra Rohm & Haas, for å fjerne ikke overfort cyanocobalamin eller- de for meget reduserte cobalaminer. The resulting solution is then passed through a column containing a resin composed of spherical polymer beads containing exchange sites for cations and anions, such as the trademarked resin "Retardion AG 11 A8" marketed by Bio-Rad, to remove the zinc ions, cobalt ions, etc. from the solution, and then through a mixed-bed column composed of 3 volumes of a strongly basic [N^CH^) 3+ anion exchange resin, such as resin IRA 400 from Rohm & Haas, and T volumes of a sulfonic acid resin, cation exchange, such as '!Amberlite IRC 120" from Rohm & Haas, to remove not too much cyanocobalamin or too much reduced cobalamins.
Efter rensning får opplosningen krystallisere efter til-setning av aceton. Der erholdes således 65 g methylcobalamin. After purification, the solution is allowed to crystallize after the addition of acetone. 65 g of methylcobalamin are thus obtained.
Absorpsjonsspektret til en fortynnet opplosning inneholdende methylcobalamin utviser maksima ved 267, 343 og 520 millimicron, tilsvarende det som erholdes med rent methylcobalamin. The absorption spectrum of a dilute solution containing methylcobalamin exhibits maxima at 267, 343 and 520 millimicrons, corresponding to that obtained with pure methylcobalamin.
Den spesifikke motstand til en opplosning i demineralisert vann med en konsentrasjon på 5 microgram pr. cm 3 methylcobalami. n erholdt ifolge dette eksempel er over 10.000 ohm/cm, som viser at det erholdte methylcobalamin ikke bibeholder ioner som skriver seg fra det zink og cobolt som tilfores reaksjonsmiljoet. The specific resistance to a solution in demineralized water with a concentration of 5 microgram per cm 3 methylcobalamin. n obtained according to this example is over 10,000 ohm/cm, which shows that the methylcobalamin obtained does not retain ions that are written from the zinc and cobalt that are supplied to the reaction medium.
Som dette eksempel viser er fremgangsmåten ved fremstil-As this example shows, the procedure for manufacturing
ling av■methylcobalamin ut fra cyanocobalamin en meget bekvem frem-stillingsmåte. ling methylcobalamin from cyanocobalamin a very convenient method of preparation.
Der erholdes et methylcobalamin som er helt rent som folgeA methylcobalamin is obtained which is completely pure as a result
av en regulert reduksjon av cyanocobalamin ved hjelp av en forbindelse, oxalsyre- monomethylester, som spiller en dobbeltrolle, idet den på samme- tid er en. syre som er istand til å frigi nascerende of a regulated reduction of cyanocobalamin by means of a compound, oxalic acid monomethyl ester, which plays a dual role, being at the same time a. acid capable of releasing nascent
o o
hydrogen ved omsetning med zinkpulver, og et middel istand til å sikre methylering av redusert cobalamin. hydrogen by reaction with zinc powder, and a means capable of ensuring methylation of reduced cobalamin.
Det meget gode utbytte av methylcobalamin forklares på den annen side av det faktum at opplosningen inneholder ved starten en betydelig konsentrasjon av cyanocobalamin, hvilket muliggjores tak-ket være et klokt valg av opplosningsmidde1 som utgjores av en blanding av methanol og vann. The very good yield of methylcobalamin is explained, on the other hand, by the fact that the solution initially contains a significant concentration of cyanocobalamin, which is made possible thanks to a wise choice of solvent1 which is made up of a mixture of methanol and water.
Eksempel 2Example 2
200 g cyanocobalamin oppldses i 4 liter methanol og 400 cm 3 destillert vann. Når opplosningen er fullstendig, tilsettes 400 g oxalsyre-monomethyleiter og 100 g coboltklorid, og der omrores inntil der erholdes en klar opplosning." 200 g of cyanocobalamin are dissolved in 4 liters of methanol and 400 cm 3 of distilled water. When the solution is complete, 400 g of oxalic acid monomethyl ether and 100 g of cobalt chloride are added and stirred until a clear solution is obtained."
Man fyller en kolonne, anbragt vertikalt, med en hoyde påOne fills a column, arranged vertically, with a height on it
1 m og en diameter på 3 cm med zinkpulver til en hoyde på 80 cm. 1 m and a diameter of 3 cm with zinc powder to a height of 80 cm.
For å vaske og preparere kolonnen sirkuleres forst gjennom denne fra bunnen, mot topp 1 liter av en opplosning av methanol inneholdende 10 volum% vann. Derefter sirkuleres gjennom kolonnen fra bunnen mot topp opplosningen av cyanocobalamin med en hastighet på ca. 1 liter pr. time. To wash and prepare the column, first circulate through it from the bottom, towards the top, 1 liter of a solution of methanol containing 10% by volume of water. The solution of cyanocobalamin is then circulated through the column from the bottom towards the top at a rate of approx. 1 liter per hour.
Ved kolonnens utldp oppsamles opplosningen i en beholder-anbragt beskyttet mot lys. At the outlet of the column, the solution is collected in a container protected from light.
Hele den fremstillede opplosning fores gjennom kolonnen, og man kan gjenta operasjonen ved anvendelse av en opplosning iden-tisk med den foregående., The entire prepared solution is fed through the column, and the operation can be repeated using a solution identical to the previous one.
Spektrofotometriske analyser-utfort på den oppsamlede opplosning efter passasje gjennom kolonnen viser at man erholder 175 g methylcobalamin ut fra 200 g cyanocobalamin, hvilket er et utbytte lik 87,5 %. Spectrophotometric analysis carried out on the collected solution after passage through the column shows that 175 g of methylcobalamin is obtained from 200 g of cyanocobalamin, which is a yield equal to 87.5%.
For å separere methylcobalaminet fra den oppsamlede opplosning og for å rense produktet går man frem som folger: Opplosningen fores gjennom en kolonne inneholdende en harpiks med betegnelsen<u>Retardion AG 11 AS", markedsfort av firmaet Bio-Rad, sammensatt av polymerperler inneholdende utvekslingsplasser for kationer og anioner for å fjerne zinkioner og coboltioner fra opplosningen. To separate the methylcobalamin from the collected solution and to purify the product, proceed as follows: The solution is passed through a column containing a resin with the designation<u>Retardion AG 11 AS", marketed by the company Bio-Rad, composed of polymer beads containing exchange sites for cations and anions to remove zinc ions and cobalt ions from the solution.
o o
Opplosningen fores derefter gjennom en kolonne med sammen-satte skikt bestående av 3 volumer av en sterkt basisk anionisk xonebytterharpiks inneholdende gruppene N(CH3) 3+, slik som harpiks IRA 400 fra firmaet Rohm & Haas, og 1:. volum av en sulfonsyreharpiks, kationbytter, slik som harpiksen "Amberlite IRC 120" fra firmaet Rohm & Haas, for å fjerne ikke omdannet cyanocobalamin eller de for sterkt reduserte cobalaminer. The solution is then passed through a column of composite layers consisting of 3 volumes of a strongly basic anionic xone exchange resin containing the groups N(CH 3 ) 3+ , such as resin IRA 400 from the company Rohm & Haas, and 1:. volume of a sulfonic acid resin, cation exchanger, such as the resin "Amberlite IRC 120" from the company Rohm & Haas, to remove unconverted cyanocobalamin or the too strongly reduced cobalamins.
Efter rensning får opplosningen krystallisere efter tilset-ning av aceton. After purification, the solution is allowed to crystallize after the addition of acetone.
Claims (6)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR7328998A FR2240232A1 (en) | 1973-08-08 | 1973-08-08 | Methylcobalamine prepn from cyanocobalamine - by reduction and methylation using methyl acid oxalate and a metal |
FR7346829A FR2256174A2 (en) | 1973-12-28 | 1973-12-28 | Methylcobalamine prepn from cyanocobalamine - by reduction and methylation using methyl acid oxalate and a metal |
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NO742545L true NO742545L (en) | 1975-03-10 |
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AR (1) | AR199756A1 (en) |
CA (1) | CA1019726A (en) |
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DE (1) | DE2434967A1 (en) |
DK (1) | DK136775B (en) |
ES (1) | ES428798A1 (en) |
GB (1) | GB1419933A (en) |
IE (1) | IE41823B1 (en) |
IL (1) | IL45384A (en) |
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US7220855B2 (en) | 2001-06-05 | 2007-05-22 | Eisai Co., Ltd. | Process for producing methylcobalamin |
CN102391340A (en) * | 2011-10-31 | 2012-03-28 | 河北玉星生物工程有限公司 | Preparation method of mecobalamin |
PL3481839T3 (en) | 2016-07-08 | 2023-10-02 | HealthTech Bio Actives, S.L.U. | Process for the purification of methylcobalamin |
CN114874276A (en) * | 2022-04-21 | 2022-08-09 | 南京工业大学 | Improved method for synthesizing mecobalamin |
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DK136775C (en) | 1978-05-08 |
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IN139935B (en) | 1976-08-21 |
JPS5041900A (en) | 1975-04-16 |
DK386274A (en) | 1975-04-01 |
LU70582A1 (en) | 1976-05-31 |
CH583744A5 (en) | 1977-01-14 |
OA04753A (en) | 1980-08-31 |
DE2434967A1 (en) | 1975-02-20 |
NL7410061A (en) | 1975-02-11 |
IE41823B1 (en) | 1980-04-09 |
SE7410005L (en) | 1975-02-10 |
GB1419933A (en) | 1975-12-31 |
DK136775B (en) | 1977-11-21 |
CA1019726A (en) | 1977-10-25 |
IL45384A (en) | 1976-09-30 |
SE412589B (en) | 1980-03-10 |
IL45384A0 (en) | 1974-11-29 |
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JPS5727119B2 (en) | 1982-06-08 |
ES428798A1 (en) | 1976-09-16 |
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