HU183192B - Improved process for preparing corrinoide derivatives bearing a substituent in position co-aeta - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to an improved process for the preparation of Co-R-corinoids of the formula I wherein R is a β-linked organic group attached to the cobalt atom of the corinoid, preferably a C1-C4 alkyl group, a p-methylbenzaldehyde group, optionally halogenated at two end positions. or a 2-haloethylamino-substituted C5-C6 sugar or deoxy-sugar alcohol, naturally occurring pyrimidine-based nucleosides, preferably adenosine and guanosine, or an inorganic anion, preferably hydroxyl, bisulfite or nitrite, and Z represents the 5,6-dimethylbenzimidazolyl, [5-hydroxybenzimidazolyl], aden-7-yl and 2-methyladen-7-yl group attached to the cobalt atom of the corinoid at the α position may correspond to a general formula I, but R group X-Co-X-corinoid X - where X is a cobalt atom to produce the final product R anion, other than cyanide, nitrite, bisulphite or thiocyanate, other than anion, is reduced under oxygen and light conditions, and the resulting reduced corrinoid is reacted with a suitable reagent, i.e., an alkylating agent, to introduce the desired group R; with a reactive derivative of a pyrimidine-based nicoside, CH3--1-

Description

The present invention relates to an improved process for the preparation of the Co-R-corrinoids of formula I wherein R is an organic group attached to the cobalt atom of the corrinoid via a carbon atom having from 1 to 4 carbon atoms, p-methylbenzaldehyde optionally substituted by -haloethylamino

The C 5 -C 6 sugar alcohol or the deoxy sugar alcohol radical, the naturally occurring pyrimidine-based nucleosides, such as adenosine and guanosine, may have hydroxyl, bisulfite or nitration as the inorganic anion, and Z is the benzyl-imidazole of 5,6 5-hydroxybenzimidazolyl, aden-7-yl and 2-methyladen-7-yl.

The chrominase compounds, of which Vitamin B1, Coa- [α- (5,6-dimethylbenzimidazolyl)] - C0- 6 -cyanocobamide, are the first isolated members, are known compounds and are now known in their three-dimensional structure. For a common interpretation of both complete nucleotide-containing and incomplete nucleotide-free corinoids, the names given in The Nomenclature of Corrinoids, 1973 Recommendations, Biochemistry 13, 1555-1560 (1974).

As is known in the literature (E. Lester Smith, Vitamin Biz [1965], London; F. Enke, J.M. Babior: Cobalamin, Biochem and Pathophysiology (1975), British Patent No. 963,373), the corrinoids Co / 3. the substituent may be an inorganic anion or an organic group, a carbanion, which in the latter case is an organocorrinoid.

The inorganic anions attached to the cobalt atom at the β-position may be cyanide, thiocyanato, bisulfite, nitration, hydroxyl, or may be attached to a halide such as chloride, bromide or iodide.

Co-R-corrinoids formed with an organic group, carbanion, are formed by direct cobalt-carbon bonding, and are therefore highly sensitive to light, under conditions of rapid degradation.

Organic R substituents include alkyl, hydroxyalkyl, aralkyl, acyl, sugar alcohol derivatives, and derivatives of naturally occurring and synthetic nucleosides. Naturally occurring nucleosides include adenosine, cytidine, inosine, guanosine.

The reactive groups present in the nucleosides, with the exception of the group attached to the carbon atom to which the cobalt atom is attached, must be protected during the reaction.

Conventional protecting groups can be used for this purpose, which are removed after the reaction is carried out in a known manner.

A sugar alcohol derivative is, for example, the residue of a mannitol derivative such as 1,6-bis [(2-chloroethyl) amino] -1,6-didedoxy-D-mannitol (Degranol) or 1,6-dibromo-1. , 6-didedoxy-D-mannitol (Myelohromol) can be the root.

The compounds of formula I are known and exhibit valuable pharmacological properties, such as vitamin B1 and modified vitamin B1 activity, as well as remarkable enzyme activity.

Among the organocorrinoids of the formula I, methylcobalamin containing R at the ε β position, Co - [α- (5,6-dimethylbenzimidazolyl)] - Co / 3-methylcobamide, is known as the coenzyme of methionine synthetase, while R Bi, containing 5'-dedoxyadenosine; coenzyme, Coo- [α- (5,6-dimethylbenzimidazolyl)] - Co / 3-adenosylcobamide has numerous isomerase activities.

A number of processes are known for preparing Co / 3-R comnoids. It is known that the cyanide group binds most strongly to the central cobalt atom of the corrinoids. Thus, a small amount of cyanide contamination can convert any Co / 3-substituted derivative to a more stable cyanide compound. In order to avoid this, the processes mainly start from a cyano-free derivative, which in turn has to be prepared from the cyanol obalamine by expensive conversion and isolation.

Co-R-cobamides containing an unsubstituted or substituted aliphatic hydrocarbon group, an acyl, an alkyl, an aralkyl or an arylsulfonyl group, are prepared according to the process described in British Patent 963 373 and German Patent Specification 1 213 842. a cobamide in which an anion, in particular a cyano group or a water molecule, is attached to the cobalt atom, and then the reduced cobamide in which the initially trivalent cobalt is reduced to a monovalent, is reacted with a suitable alkylating, acylating or sulfonylating agent. When hydroxocobalamin is used as a starting material, it is preconditioned on an ion exchange column. During the reaction, unconverted hydroxocobalamin contaminates the product. When cyanides start from obalamin, the cyanide group which is cleaved during the reduction is partially removed and partially bound to the zinc used for the reduction. In the weakly acidic medium, the cyanide is slowly released and converts part of the reaction product into cyanocobalamin. Thus, the crude product contaminates cyanocobalamin and hydroxocobalamin together. Their separation is made difficult by the fact that they crystallize under similar conditions with the product and are not easily separated by cyanocobalamin column chromatography as they pass close to the final product on the column. Other cobamide cleavage products are formed as intermediates in the reaction and must be removed.

Belgian Patent 759,614 discloses the removal of cyanide ions from solutions of Co ^t- cobamides produced by reduction of cyanocobalamin. For this purpose, they are described as different

-2183 192 metal salts are used which, due to the reducing agent used, sodium borohydride, precipitates in a highly alkaline medium in the form of metal hydroxide and binds the cyanide ions liberated in complex form. The disadvantage of the process is that the reaction proceeds slowly and thus the amount of impurity hydroxocobalamin is increased, the resulting ferrocyanide forms a stable precipitate with the hydroxocobalamin, thus reducing the yield, acidifying the alkaline solution and liberating the crude product by chromatography.

The manufacture of the pharmaceutically important methyl cobalamin is also the subject of several patents.

Thus, according to Belgian Patent No. 773,144, hydroxocobalamin is reduced under nitrogen with stannous chloride under high light, and the reduced cobamide is then alkylated in the dark. On the other hand, it is known that other methyl groups of the corrine skeleton are demethylated as a side reaction in the presence of strong light and contaminate the final product.

According to Japanese Patent Publication No. 7,036,911, hydroxocobalamin is reduced with semicarbazide hydrochloride and the product is chromatographed on several ion exchange columns with different properties.

According to German Patent Nos. 2,255,203 and Belgian Patent No. 817,937, hydroxo and cyanocobalamin are simultaneously reduced and methylated with a metal salt and oxalic acid monomethyl ester, and the crude product is purified by chromatography. The process requires large ion exchange columns, 65% yield after purification.

Substantially better yields of alkyl cobalamines according to Japanese Patent Publication No. 7,234,720 are obtained by adding Grignard reagent to the reduced hydroxocobalamin in an ethereal medium and then purifying the product by column chromatography.

According to Hungarian Patent No. 163,770, iodocobalamin, hydroxocobalamin or Biocoenzyme are reacted with methylmercury halide or ammonium methylhexafluorosilicate. However, the selective methylation in this step is not free of fission products, which are formed by heating or drying to dryness for 6 hours at 65 ° C in the presence of large amounts of iodine. In addition, the reagent used in the process reduces the number of derivatives that can be produced, and the difficulty in producing the reagent limits the scope for higher volume production.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a process for the preparation of Co-R-corrinoids which is readily commercially available.

The present invention is based on the discovery that when the Co-X-corrinoid used as a starting material, in which X represents an anion attached to a cobalt atom, the X anion is covalently bonded, the β-substitution of the cobalt atom can be easily accomplished by removing the interfering anion. .

The present invention therefore relates to an improved process for the preparation of the Co-R-corrinoids of formula I - wherein the R group is in the β position and the organic group attached to the cobalt atom of the corrinoid is C 1-4 alkyl, p-methylbenzaldehyde, optionally halogen or a C 5 -C 6 sugar alcohol or deoxy sugar alcohol substituted with 2-haloethylamino, a naturally occurring pyrimidine-based nucleoside such as adenosine and guanosine, and the inorganic anion may be hydroxyl, bisulfite or nitration; 5,6-dimethylbenzimidazolyl, 5-hydroxybenzimidazolyl, aden-7-yl and 2-methyladen-7-yl attached to the cobalt atom of the position - of formula I but X at the R group carrier Co-X-corrinoids - where X is different from the R substituent of the final product to be bonded to the cobalt atom anion as a bisulfite, cyanide, nitrite or thiocyanate ion - under oxygen and light-free conditions, and the resulting reduced corrinoid with a reagent such as an alkylating agent, a reactive derivative of p-methylbenzaldehyde, a pyrimidine-based nucleoside with a reactive derivative, a sugar alcohol or a deoxy sugar alcohol derivative, or with an inorganic salt of the inorganic anion of the R group, such as sodium metabisulfite or sodium nitrite, or by bubbling air at the meaning of the hydroxy group of R, The process is characterized in that the reduction of the Co-X-corinoids is carried out in the presence of at least one compound that covalently binds the X group. This compound binds the X group liberated during the reduction and any primary amine impurities that may be present and is removed from the reaction mixture. Thus, the product is not contaminated with unreacted or reconstituted starting material, nor is it possible to form antimetabolites.

Any organic compound with which it is covalently attached to form an addition compound is capable of binding the X group.

When the X group is a cyanide or thiocyanato ion, an aliphatic or aromatic aldehyde, an aliphatic or aromatic ketone, or an aldose or ketone is used. These compounds form addition compounds with said groups.

Suitable aliphatic aldehydes are, for example, formaldehyde or acetaldehyde, while aromatic aldehydes are, for example, benzaldehyde or p-dimethylaminobenzaldehyde.

Examples of aliphatic ketones are acetone or methyl ethyl ketone and aromatic ketones include phenylethyl ketone.

Suitable aldoses are, for example, D-ribose, arabinose, glucose, mannose, galactose, for example, fructose or sorbose.

When X is a bisulfite anion, it can also be bonded to an aldehyde which binds the bisulfite anion in the form of aldehyde bisulfite.

When X represents a nitrite anion, it is bound to phenol or a phenol derivative which forms a nitrophenol with the nitrite anion. The phenol derivative may be, for example, cresol or thymol.

An advantage of the process of the invention, as mentioned above, is that it is relatively pure

The final product is -3183,192 and only a small amount of leaching is obtained without the need for chromatography on ion exchange columns or pre-activated diethylaminoethyl or carboxymethylcellulose columns.

The process of the invention is illustrated by the following embodiments.

Example 1

5.0 g of crystalline cyanocobalamin are weighed into a 500 ml four-necked round-bottomed flask, then 100 ml of distilled water and 2 ml of 40% aqueous formaldehyde solution are added. The flasks are fitted with a drip funnel and two screw plugs, one of which is fitted with a long, one with a short stem and the fourth with a small rubber cylinder.

After the magnetic stirring is started, the system is suctioned off with vacuum and then charged with argon gas through the long connector. This operation is repeated two more times and the short-end connector is connected to a gas washer bottle filled with distilled water.

Thereafter, 2 g of sodium borohydride dissolved in 10 ml of distilled water are added to the mixture via a dropping funnel. After a quick foaming and sparkling, the ruby red color of the crystalline mixture changes to brown and then to greenish blue. From now on, all operations are performed in dim light only.

After stirring for one hour, taking care that no air enters the system, another 0.5 g of sodium borohydride dissolved in 5 ml of distilled water is added to the crystalline solution. After stirring for a further 15 minutes, methanol (10 ml, 1 ml) was added. At this point, the solution suddenly changes from greenish-blue to red. After 20 minutes, an additional 3 mL of methanol containing 0.5 mL of methyl iodide was added to complete the reaction.

After stirring for 1 minute, 12-15 ml of 10% aqueous hydrochloric acid solution is slowly added dropwise to pH 6. After the evolution of hydrogen has ceased, the pH is checked and the contents of the flask are washed with distilled water in a shaking funnel.

The resulting solution (about 200 ml) was dissolved in crystalline phenol (10 g) and extracted successively with phenols (75, 50 and 25 ml) of phenol-chloroform (v / v). The combined organic phases are washed with an equal volume of distilled water and the phases are separated.

To the organic phase was added 150 ml of acetone, 60 ml of distilled water and 500 ml of chloroform, and the separated organic layer was extracted with 25 ml of distilled water.

A 10-fold volume of acetone was added to the combined aqueous phase and allowed to crystallize at room temperature overnight.

The needle crystals are then punctured on a sintered glass filter and dried at 60 ° C to 10% moisture. 4.92 g of crude methyl cobalamin are obtained, which is recrystallized as follows.

Dissolve 20.0 g of crude methyl cobalamin in 500 ml of distilled water containing 40% by volume of ethanol at 40-50 ° C. Pre-activated and neutralized diethylaminoethylcellulose (10 g dry weight) was added to the solution. After stirring for 15-20 minutes, the mixture at about 45 ° C is filtered through a porcelain filter and a paper filter under vacuum with a water jet pump. The cellulose remaining on the filter is washed with distilled water containing about 20% v / v ethanol at about 45 ° C until the washings are colorless. Pre-activated and neutralized carboxymethylcellulose (10g dry weight) was added to the filtrate and treated as after addition of diethylaminoethylcellulose and finally the resulting clear solution was rotary evaporated at 40 ° C. at a temperature not greater than about 300 ml, and then allowed to crystallize overnight at 17-22 ° C.

The crystals are then filtered through a sintered glass filter, washed with acetone and dried first in air and then at 60 ° C in an oven to a moisture content of 10%. Evaporation of the mother liquor (15.2 g) yielded another 4.12 g of crystalline methylcobalamin having an extinction content of 99.4%. Impurities (determined by the methods of the BP 73 Pharmacopoeia): cyanocobalamin content: 0%, acidic impurity 0.3%, free hydroxocobalamin content: 0.6%. K yield: 98.6%.

Example 2

5.0 g of crystalline cyanocobalamin are weighed into a 500 ml four-necked ground-glass flask, then 100 ml of a 1: 1 mixture of methanol and distilled water and 2 ml of a 40% aqueous formaldehyde solution are added. The reduction was carried out as described in Example 1 by adding 2 g of sodium borohydride dissolved in 10 ml of distilled water, followed by addition of 0.5 g of sodium borohydride dissolved in 5 ml of distilled water.

After the addition of the second amount of sodium borohydride, the mixture was stirred for 15 minutes and the reagent prepared as follows was added.

Freshly prepared 5'-O-mesyl-2 ', 3'-isopropylidene-adenosine from 2.5 g of adenosine having a moisture content of less than 0.1% was concentrated in a round-bottom flask to 65 ml of 1: 1 by volume methanol-0.3 n. hydrochloric acid solution and the reaction mixture was refluxed for 30 minutes. It was then cooled rapidly to room temperature with 2N sodium hydroxide solution

7.2 to 8.2 and slowly add dropwise to the greenish-blue bridocobalamin-containing mixture prepared as above. Upon addition, the mixture suddenly turns red. After stirring for an additional 45 minutes, the reaction mixture was adjusted to pH 6.0 with 10% aqueous hydrochloric acid and the methanol was distilled off under vacuum at 40 ° C. The residue is extracted with phenol-chloroform (1: 1), the organic phase is washed with distilled water and desalted, and the product is recrystallized from the aqueous phase by continuous addition of acetone and left to stand at 0-5 ° C overnight. 5.4 g of crude Bi are thus obtained; Vitamin Coenzyme 4183 was obtained, which was recrystallized as described in Example 1. Yield: 5.10 g of crystalline Biocoenzyme, Coa- [α- (5,6-dimethylbenzimidazolyl)] - Co / 3-adenosylcobamide, having an active ingredient content of 96.1%; Yield: 87.5%. Impurities as determined by the BP 73 Pharmacopoeia: cyanocobalamin: 0%, acidic impurity: 0.3%, free hydroxocobalamin: 0.5%.

Example 3

5.0 g of crystalline vitamin B-factor ΠΙ {Coa [α- (5-hydroxybenzimidazolyl)] - Co-3-cyanocobamide} in 100 ml of a 1: 1 methanol-distilled water mixture in Example 1 is reduced to hydrococobalamin as described.

Then, 1 ml of acetaldehyde and 0.5 g of glucose and 2.5 g of 5'-O-tosyladenosine, prepared as 2.8 g of 5'-O-tosyl-2, are added as the cyano-addition compound. ', 3'-Isopropylidene adenosine was heated at reflux for 30 minutes at 80 ° C with 65 ml of a 1: 1 mixture of ethanol-0.3N hydrochloric acid and the pH of the alcoholic solution was adjusted to 2N with sodium hydroxide solution 8.0. .

Desalting, concentration, and recrystallization yielded 5.06 g (86.8%) of coenzyme B1-vitamin Factor III coa [5'-hydroxybenzimidazolyl] -co-3-adenosylcobamide.

Example 4

5.0 g of cyanocobalamin are reduced to hydrococobalamin as described in Example 1. The procedure of Example 1 was followed, but using 1 ml of benzaldehyde and 0.5 g of arabinose as the cyano-addition compound, 1.5 ml of ethyl bromide was added in two portions to give 4.46 g of ethyl cobalamin in a yield of:

88.9%.

Example 5

5.0 g of cyanocobalamin are reduced to hydrococobalamin as described in Example 1. The same procedure as in Example 1 was followed, however, using 1 ml of methyl ethyl ketone and 0.5 g of fructose as the cyano-addition compound and 1.5 g of sodium metabisulphite dissolved in 10 ml of distilled water for Co-β substitution. 5.12 g of crystalline sulfitocobalamine, Coa- [α-5,6-dimethylbenzimidazolyl] -Co / 3-sulfitocobamide, are obtained; yield:

98.4%.

Example 6

The crystalline cyanocobalamin (5.0 g) was reduced to hydrococobalamin as described in Example 1 except that 0.8 g of p-dimethylaminobenzaldehyde and 0.5 g of D in 10 ml of a 1: 1 water-methanol solution were added as the cyanoating agent. ribose, and 1.5 g of sodium nitrite dissolved in 10 ml of distilled water for Co / 3 substitution. After stirring for 10 minutes, approx. It is washed with 100 ml of distilled water in a shaking funnel and then concentrated by phenol-chloroform extraction as in Example 1 and recrystallized from acetone. This gives 4.85 g of crystalline nitrite cobalamin, Coa- [α- (5,6-dimethylbenzimidazolyl)] - Co / 3-nitritocobamide. Yield: 95.6%.

Example 7

To 5.0 g of crystalline nitritocobalamin is added 100 ml of distilled water and 6 ml of liquefied phenol, followed by the procedure of Example 1 below. 4.7 g of crystalline methylcobalamin, Coa - [- (5,6-dimethylbenzimidazolyl)] - Co / 1-methylcobamide, are obtained. Yield: 96.1%.

Example 8

The procedure described in Example 1 was followed, but starting from 2.0 g of crystalline thiocyanato-cobalamin, Coa- [α- (5,6-dimethylbenzimidazolyl)] -thiocyanato-cobamide, 0.9 g of sodium was added in two portions as a reducing agent. borohydride, 0.3 ml of methyl iodide was used as alkylating agent to give 1.86 g of methyl cobalamin, Coa- [α- (5,6-dimethylbenzimidazolyl)] - Co-methyl-cobamide. Yield: 95.8%.

Example 9

The procedure is as in Example 2, except that 1.0 g of crystalline pseudo-vitamin B, Coa- [α- (aden-7-yl)] -Co / 3-cyanocobamide, 0.45 g of sodium borohydride as reducing agent and nucleoside reagent are used as starting material. 0.4 g of 5'-O-mesyladenosine was used. 0.86 g of crystalline pseudo Bi coenzyme, Coa- [α- (aden-7-yl)] - Co / 3-adenosyl cobamide are obtained.

Example 10

1.0 g of crystalline Bi; vitamin Vitamin monocarboxylic acid at position "e", Coa- [α- (5,6-dimethylbenzimidazolyl)] - Co / 3-cyanocobamic acid (a, b, c, d, g) pentamide; In 40 ml of distilled water, in the presence of 0.4 ml of a 40% aqueous formaldehyde solution, as described in Example 1, 0.45 g of sodium borohydride was reduced in two portions to a hydrococobalamin. Then, 0.5 g of Degranol, 1,6-bis [(2-chloroethyl) amino] -1,6-dideoxy-D-mannitol, dissolved in 10 ml of ethanol, are added to the reaction mixture. After stirring for 45 minutes, the pH was adjusted to 5.5 to 6.0 with 10% aqueous hydrochloric acid. It is then de-alcoholized by brief vacuum distillation, concentrated and desalted with a mixture of phenol and chloroform, the organic solvent is removed from the aqueous solution and the active compound is bound on an activated diethylaminoethylcellulose column. Dissolved distilled water containing 2% sodium chloride, adjusted to pH 8.0 with 2N sodium hydroxide5

-5183 192 gel. The pH of the effluent solution was adjusted to 5.5 with 10% aqueous hydrochloric acid, and the solution desalted and bound on a carboxymethylcellulose column. Wash the column with 0.05 M acetic acid until the effluent is colorless, then dissolve the product in the column with 0.8 M aqueous acetic acid. After concentration and concentration with a mixture of phenol and chloroform, 9 to 10 volumes of acetone are added to the aqueous solution (about 20 ml) and the temperature is kept below 5 ° C for 6-8 days. 0.76 g of crystalline product is obtained, which is a derivative of vitamin B8 monocarboxylic acid (position e) -Degranol, i.e. Coo - [? - (5,6-dimethylbenzimidazolyl)] - C0-3-1-ethylamino-6 -chloroethylamino-1,6-didedoxy-D-mannitcobamic acid (a, b, c, d, g) pentamide.

Example 11

The procedure described in Example 10 was followed, however, using Delanol instead of Myelobromol, 1,6-dibromo-1,6-dideoxy-D-mannitol. 0.70 g of crystalline product is obtained, which is a derivative of vitamin B-monocarboxylic acid (position e) -Myelobromol, i.e., Coafe-prime dimethylbenzimidazolyl-N-Co / l-o-bromo-1,6-dideoxy-D. -manniticobamic acid (a, b, c, d, g) pentamide.

Example 12

The procedure described in Example 10 was followed, however, using 0.5 g of p-chloromethylbenzaldehyde instead of Degranol. 0.55 g of product is obtained which is a p-methylbenzaldehyde derivative of vitamin B6 monocarboxylic acid (position e), Coa- [α- (5,6-dimethylbenzimidazolyl)] - C0- 3 - p -methylbenzaldehyde cobam. acid (a, b, c, d, g) pentamide.

Example 13

5.0 g of crystalline sulfitocobalamin crystal are dissolved in 100 ml of distilled water under light protection. In the following, the procedure described in Example 1 is followed except that all operations are strictly protected from light. 4.56 g of crystalline methylcobalamin, Coa- [α- (5,6-dimethylbenzimidazolyl)] - Co / 3-methylcobamide, are obtained.

Example 14

In the same manner as in Example 2, however, starting material, 1.0 g of factor A, Coa- [α- (2-methyladen-7-yl)] - Co / 3-cyanocobamide, was added in two portions with a total reduction of 0. , 45 g of sodium borohydride, 0.5 ml of phenylethyl ketone and 0.1 g of sorbose and 0.4 g of 5'-O-mesyladenosine as nucleoside reagent, giving 0.81 g of crystalline coenzyme F, Coa- [α- (2-methyladen-7-yl)] - C0 5 -adenosylcobamide is obtained.

Example 75

5.0 g of crystalline cyanocobalamin are reduced to hydrococobalamin as described in Example 1. At the end of the reduction, air was bubbled through the solution in a gentle stream for 10 minutes. The apparatus was opened and the pH was adjusted to 4.5-5.5 with 10% formic acid with further stirring. The reaction mixture was washed with 100 ml of distilled water in a shaking funnel and concentrated by extraction with phenol-chloroform as in Example 1, followed by recrystallization from acetone. This gives 4.92 g of crystalline hydroxocobalamin formate, Coa- [α- (5,6-dimethylbenzimidazolyl)] - Co / 3-aquacobamide formate. Yield: 95.79%.

Claims (5)

1. A process for the preparation of the Co-R-corrinoids of the formula I wherein R is in the form of an organic group attached to the cobalt atom of the corrinoid via a carbon atom C 1 -C 4 alkyl, p-methylbenzaldehyde, C 5 -C 6 sugar or deoxy sugar alcohol optionally substituted with two terminal halo or 2-haloethylamino groups, naturally occurring pyrimidine-based nucleosides, preferably adenosine and , or as inorganic anion hydroxy, bisulfite or nitrite, And Z is a 5,6-dimethylbenzimidazolyl, 5-hydroxybenzimidazolyl, aden-7-yl, and 2-methyladen-7-yl group attached to the cobalt atom of the corinoid according to formula I, but reduction of the Co-X corrinoid bearing X at the R group, where X represents a cyanide, nitrite, bisulfite or thiocyanate anion other than the R substituent of the final product to be prepared, and the resulting reduced reacting a corrinoid with a reagent such as an alkylating agent, a reactive derivative of p-methylbenzaldehyde, a reactive derivative of a pyridine-based nucleoside, an alcohol or a deoxy sugar alcohol of a sugar, a bisulfite salt or a nitrite salt, or the meaning of the hydroxyl group of the R group is by bubbling air, leaving Co-X reduction in the presence of at least one organic compound covalently bonding the group X, (a) when X is a cyanide or thiocyanate ion, an aliphatic or aromatic aldehyde, an aliphatic or a'omatic ketone, and optionally an aldose or ketone, to bind it; (b) when X is a bisulfite, an aliphatic or aromatic aldehyde, c) when X is a nitration, phenol or a phenol derivative is used for its bonding. Process for carrying out process a) and b) according to claim 1, characterized in that formaldehyde or benzaldehyde are used as aliphatic aldehyde-6183 192 sulfur or aromatic aldehyde. 3. The process of claim 1, wherein the aliphatic ketone is acetone or methyl ethyl ketone. 4. The process of claim 1, wherein the aldose is glucose, arabinose or D-ribose, and the ketose is fructose or sorbose. 5. Process according to any one of claims 1 to 3, characterized in that the cyanocobamides Co-X5 are complex cyanocobamides, preferably vitamin B1, vitamin B1, pseudo vitamin B1 or any vitamin Bn monocarboxylic acid derivative. .