Process for production of methylcobalamin

Details Process for production of methylcobalamin Process for production of methylcobalamin

2002-05-23

2003-12-02

Ford, John M. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C536S117000, C536S017100, C536S026410

Reexamination Certificate

active

06657057

ABSTRACT:

FIELD OF THE INVENTION
Methylcobalamin is a coenzyme-type vitamin B
12
existing in blood and cerebrospinal fluid and is excellent in migrating ability to nervous tissues as compared with other B
12
homologs. Biochemically, it exhibits a pharmacological action of accelerating metabolism of nucleic acids, proteins and lipids by methyl group rearrangement and thereby restoring damaged nervous tissues. Based on these properties, it has been clinically employed for preventing, treating or improving peripheral neuropathy such as diabetic neuropathy and polyneuritis, particularly numbness, pain and paralysis, and is also effective in megaloblastic anemia owing to vitamin B
12
deficiency, and thus, it is an important vitamin.
Accordingly, the present invention relates to an industrially excellent and novel process for producing methylcobalamin useful as medicines.
PRIOR ART
Methylcobalamin has been hitherto produced mainly by the following synthetic methods:
(1) a method of reacting hydroxocobalamin with a dicarboxylic acid monomethyl ester in the presence of a metal powder (JP-A 49-47899);
(2) a method of reacting cyanocobalamin with monomethyl oxalate in the presence of a metal powder in hydrous methanol (JP-A 50-41900);
(3) a method of reacting hydroxocobalamin with methylmercury iodide or ammonium methylhexafluorosilicate (JP-B 50-38120); and
(4) a method of reacting cyanocobalamin with methyl iodide in the presence of sodium borohydride (JP-B 45-38059).
However, dicarboxylic acid monomethyl esters such as monomethyl oxalate to be used in the methods (1) and (2) are not commercially available and hence are necessary to prepare in use, so that it is impossible to utilize them industrially. Furthermore, zinc powder to be used as the metal powder is a heavy metal and hence it is inevitable to take measures for preventing its contamination into products and for protecting the environment, so that the powder is industrially not preferable.
Moreover, methylmercury iodide to be used in (3) is a pollutant and hence cannot be employed industrially. Furthermore, ammonium methylhexafluorosilicate is also not commercially available and hence is necessary to prepare in use, so that it is impossible to utilize it industrially.
On the other hand, the synthetic method (4) is a very excellent method in view of yield and product purity, but is not satisfactory as an industrial process because methyl iodide has an extremely low boiling point (41 to 43° C.) and is difficult to handle. Furthermore, from the viewpoint of protecting working environment or natural environment, the use of methyl iodide assigned as a specified chemical substance and having toxicity such as possibility of carcinogenicity is by no means preferable in view of industrial health of factory workers. Moreover, in order to obtain highly pure methylcobalamin by the method of using methyl iodide, operation for purification by one or more kinds of column chromatography is usually necessary, which is a serious problem from operational viewpoint and viewpoint of production cost. In addition, the quantity of organic solvents for use in the column purification is large and also waste liquid quantity tends to be enormous.
Thus, an industrially excellent process for producing methylcobalamin is not completely established yet and hence a novel excellent method has been desired.
DISCLOSURE OF THE INVENTION
The present inventors have extensively studied for the purpose of improving the above problems. As a result, surprisingly, they have found that aimed methylcobalamin can be conveniently, safely, and inexpensively obtained in high yields by the below-mentioned method, and thus accomplished the present invention.
Accordingly, the present invention provides an industrially excellent process for producing methylcobalamin, particularly a novel process using no methyl iodide and no purification by column chromatography.
The following will explain the present invention in detail.
The present invention relates to a process for producing methylcobalamin (V), which is represented by the following chemical reaction formula:
Cobalamin-CN or Cobalamin-OH→Cobalamin-CH
3
Cyanocobalamin (I), hydroxocobalamin (II), and methylcobalamin (V) according to the present invention are known natural compounds and are represented by the following chemical formula:
Cyanocobalamin, CAS Res. No.: 68-19-9
Hydroxocobalamin, CAS Res. No.: 13422-51-0
Methylcobalamin, CAS Res. No.: 13422-55-4
R
2
═CN: Cyanocobalamin (I)
R
2
═OH: Hydroxocobalamin (II)
R
2
═CH
3
: Methylcobalamin (V)
The characteristic feature of the present invention is that a highly pure methylcobalamin equal to or superior to the product purified by column chromatography can be conveniently obtained in high yields only by methylating cyanocobalamin (I) or hydroxocobalamin (II) in the presence of a reducing agent (III) and a water-soluble methylating agent (IV) usually in an aqueous solution or a hydrous organic solvent, if necessary, precipitating the reaction product which is hardly soluble in water as crystals or precipitates, and then separating and treating it.
The water-soluble methylating agent (IV) in the present invention is not limited as far as it's solubility in water is 2% or more, and specifically includes trimethylsulfur derivatives (VI) represented by the following formula, for example.
wherein X represents a halogen atom or methoxysulfonyloxy group; and n represents 0 or 1.
Examples of the trimethylsulfur derivatives (VI) include the following compounds but they are not limited thereto.
(1) Trimethylsulfoxonium iodide, CAS Res. No.: 1774-47-6
(2) Trimethylsulfonium iodide, CAS Res. No.: 2181-42-2
(3) Trimethylsulfoxonium chloride, CAS Res. No.: 5034-06-0
(4) Trimethylsulfonium chloride, CAS Res. No.: 3086-29-1
(5) Trimethylsulfoxonium bromide, CAS Res. No.: 3084-53-5
(6) Trimethylsulfoxonium bromide, CAS Res. No.: 25596-24-1
(7) Trimethylsulfonium methyl sulfate, CAS Res. No.: 2181-44-4
All these compounds are known products and, in particular, trimethylsulfoxonium iodide, trimethylsulfonium iodide, trimethylsulfoxonium chloride, trimethylsulfoxonium bromide and trimethylsulfonium bromide are inexpensive and available as industrial starting materials. Moreover, trimethylsulfonium chloride can be easily synthesized and available by the method described in Tetrahedron Lett., 27, 1233 (1986) (B. Byrne et al.).
Among the trimethylsulfur derivatives (VI), trimethylsulfoxonium bromide, trimethylsulfonium bromide, trimethylsulfoxonium chloride and trimethylsulfonium chloride particularly exhibit a high solubility in water and have a characteristic that the use in a smaller amount affords highly pure methylcobalamin in high yields.
The amount of the trimethylsulfur derivative (VI) to be used is not particularly limited, but it is used in an amount of usually 1.0 to 5 equivalents, preferably 1.1 to 4.5 equivalents and more preferably 1.2 to 4 equivalents to cyanocobalamin (I) or hydroxocobalamin (II).
The reducing agent (III) according to the present invention is not particularly limited as far as it is a reducing agent employable in the synthesis of cyanocobalamin (I) or hydroxocobalamin (II). More specifically, examples thereof include sodium borohydride.
The amount of the reducing agent (III) to be used is not particularly limited, but it is used in an amount of usually 5 to 30 equivalents, preferably 8 to 25 equivalents and more preferably 10 to 20 equivalents to cyanocobalamin (I) or hydroxocobalamin (II).
The process according to the present invention enables the production of highly pure methylcobalamin in high yields using no metal ion or using only a small amount thereof as a cyan ion-trapping agent, and the process exhibits an extremely excellent effect in view that no problem arises at removal of metal ion products, which is difficult to filter, from the system.
Generally, when and methyl iodide is used as a methylating agent, ferrous sulfate is used as a cyan ion-trapping agent in combination with those agents in most cases, and it is necessary to use ferr

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