Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-13
2001-05-22
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S415000
Reexamination Certificate
active
06235775
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to an intermediate for V-28-3M useful as a fungicide, a process for producing it and a process for purifying V-28-3M through the intermediate.
V-28-3M has a high fungicidal activity and a low toxicity. In a previously known method for the purification of V-28-3M in the form of a crude precipitate thereof, after an acid amide or urea is added to an aqueous solution thereof or a solution thereof in a water containing solvent, an insoluble material is removed and an alkali is added to the supernatant to precipitate V-28-3M [Japanese Patent Unexamined Published Application No.5-59084](hereinafter referred to as JP-Kokai 5-59084). However, although the purity of V-28-3M was increased, the crystallization thereof was difficult in this method, and for the further purification, only reversed phase HPLC or counter current distribution method could be employed [Japanese Patent Publication for Opposition Purpose No.4-53878 (hereinafter referred to as JP-Kokai 4-53878)].
In the reversed phase HPLC or counter current distribution method for the high purification, the cost of the purification of the intended product is high because an extremely large amount of the solvent is required for the purification and the quantity of the crude product to be treated each time is only small. Further, the increase in the scale of the laboratory is difficult. Thus, this method is industrially not preferred.
V-28-3M is easily soluble in dimethyl sulfoxide or dimethylformamide, but it is generally difficult to crystallize it from such a polar solvent in which it is highly soluble. Also, although V-28-3M is easily soluble in a water containing solvent such as an aqueous methanol solution, the crystallization thereof from such a solvent is difficult. Methods of recovering V-28-3M from a solution thereof in such a polar solvent in the prior art include a method wherein an extremely large amount of water, for example, 20 parts by volume per part by volume of the solution, is added to the solution, taking advantage of the fact that V-28-3M is practically insoluble in water, or a method wherein an alkali is added to the solution to precipitate V-28-3M at a pH of 12 or above (JP-Kokai 5-59084). However, the precipitate thus obtained could not be crystallized and, therefore, the purity thereof did not reach to the level of that obatined by the HPLC purification method.
SUMMARY OF THE INVENTION
The object of the present invention is to provide an acetone adduct of V-28-3M from which highly pure V-28-3M can be obtained in a high yield.
Another object of the present invention is to provide a process for producing the acetone adduct of V-28-3M.
Still another object of the present invention is to provide a process for purifying V-28-3M by the crystallization to obtain highly pure V-28-3M in a large scale, thereby to make up for the low productivity thereof.
After intensive investigations on the crystallization of V-28-3M, the inventors have found that although V-28-3M is scarcely soluble in ordinary organic solvents, it is slightly soluble in some solvents such as acetone and methanol, particularly in acetone, the crystallization rate of V-28-3M can be remarkably improved and, therefore, the purity thereof can be remarkably increased because the amino sugar moiety of V-28-3M is dehydration-condensed with acetone to form the acetone adduct. The inventors have also found that since the obtained acetone adduct is easily hydrolyzed in an aqueous solution to release acetone, purified V-28-3M can be easily obtained.
In some cases, crude precipitates containing V-28-3M are contaminated with high-molecular substances formed in the course of the culture, which substances inhibit the dissolution of V-28-3M in acetone to lower the recovery rate and also to inhibit the crystallization of the acetone adduct. It has been found that the crystallization of the acetone adduct can be facilitated if V-28-3M precipitate which may be obtained by dissolving the crude precipitate in dimethyl sulfoxide or dimethylformamide and adding an organic solvent to the resulting solution to precipitate only the high-molecular substances, and removing the precipitate, prior to the precipitation of V-28-3M by adding a solvent having lower polarity is used as a starting material for the aceton adduct, because high-molecular substances are removed from the crude precipitate.
The present invention has been established on the basis of these findings.
Namely, the present invention provides a new acetone adduct of V-28-3M represented by following formula (1):
The present invention also provides a process for producing the new acetone adduct of V-28-3M represented by above formula (1), comprising the steps of dissolving a material containing V-28-3M represented by following formula (2) in acetone, concentrating and/or cooling the obtained solution to precipitate and separate impurities from the solution, and concentrating and/or cooling the mother liquor to precipitate the crystals of new acetone adduct of V-28-3M:
The present invention also provides a process for purifying V-28-3M, comprising the steps of dissolving the crystals of the acetone adduct of V-28-3M obtained by the precipitation in the above-described production process, dissolving the obtained crystals in a water containing organic solvent to hydrolyze the acetone adduct crystals and thereby obtaining V-28-3M.
REFERENCES:
patent: 4177265 (1979-12-01), Michel et al.
patent: 5023079 (1991-06-01), Komoda et al.
patent: 4-12199 (1992-04-01), None
patent: 4-53878 (1992-08-01), None
patent: 5-59084 (1993-03-01), None
Aoki Yuuichi
Sato Yutaka
Ajinomoto Co. Inc.
Lambkin Deborah C.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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