Process for preparing antifungal V-28-3M

Details Process for preparing antifungal V-28-3M Process for preparing antifungal V-28-3M

1999-12-03

2002-02-12

Peselev, Elli (Department: 1623)

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

Organic compounds

Carbohydrates or derivatives

C536S018500

Reexamination Certificate

active

06346610

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a process for preparing V-28-3M useful as an antimycotic agent, and to an intermediate thereof.
BACKGROUND ART
In recent years, mycotic opportunistic infectious disease and deep mycosis are apt to increase due to the improvement of longevity with the progress in advanced medical care and the like. Most of the heptaene antimycotic agents generally used for these mycoses have strong toxicity for animal cells in addition to their antimycotic activities. Accordingly, an antimycotic agent having low cytotoxicity has been expected.
A novel heptaene antimycotic agent, V-28-3M, having high antimycotic activity and low toxicity for animal cells has been found (JP-A-63-218686 and JP-A-3-81225). V-28-3M is obtained by subjecting V-28-3 which is also a heptaene antimycotic agent (JP-A-61-189224 and JP-A-2-300134) to methyl esterification.
Previously, this methyl esterification was carried out using diazomethane or trimethylsilyldiazomethane. However, diazomethane is explosive and has a markedly strong toxicity. On the other hand, trimethylsilyldiazomethane as its substituent agent is expensive, so that the use of each of these reagents is not suitable for an industrially appropriate method as methyl esterification.
As an agent for methyl esterification other than diazomethane and trimethylsilyldiazomethane, methyl iodide can be exemplified which has been reported in relation to the methyl esterification of amphotericin B. However, when V-28-3 is directly subjected to methyl esterification with methyl iodide, a compound in which the amino group of the amino sugar is multiply methylated is formed as the main product, so that the yield of V-28-3M as the objective product becomes extremely low.
Furthermore, when an N-protected form of the amino group of the amino sugar of V-28-3 (hereinafter referred to as “N-protected V-28-3”) is subjected to methyl esterification with methyl iodide, the formation ratio of an N-protected form of by-product D (a side reaction product which gives a retention time of 20 minutes under the analyzing conditions shown in Examples, a mono-methylation product of the aromatic amino group of V-28-3M) is considerably increased. This N-protected by-product D is converted into by-product D via a deprotection step of the protecting group. The by-product D is hardly reduced by the purification step. Thus, when methyl iodide is used as the methyl esterification agent in methyl esterification of the N-protected V-28-3, contamination of impurity (by-product D) in the medicinal material is increased, so that such a method is not suitable as a production process of medicaments.
DISCLOSURE OF THE INVENTION
An object to be solved by the present invention is to develop an industrially suitable method for preparing V-28-3M by subjecting V-28-3 to methyl esterification efficiently. At the same time, development of its production process with low by-production of impurities is expected.
With the aim of attaining the above-described object, the present inventors have conducted intensive studies and found, as a result of the efforts, a method which can inhibit by-production of the by-product D and efficiently convert V-28-3 into V-28-3M, by protecting the amino group of the amino sugar of V-28-3 with an appropriate protecting group, subjecting the carboxyl group of the N-protected V-28-3 to methyl esterification with methyl methanesulfonate or methyl p-toluenesulfonate in the presence of a base, and deprotecting the N-protected intermediate.
On the other hand, when unprotected V-28-3 is directly treated with methyl iodide, methyl methanesulfonate or methyl p-toluenesulfonate in the presence of a base, the yield of the objective product is low and a compound in which the amino group of the amino sugar moiety is multiply methylated is formed as the main product in addition to the objective product.
Also, when methyl esterification is carried out with methyl iodide under basic conditions using the N-protected intermediate of an appropriate amino sugar, N-protected by-product D is formed in an amount of approximately 5 to 10 area % (per N-protected V-28-3M, HPLC analysis) in addition to the objective N-protected V-28-3M. The N-protected by-product D formed under the reaction conditions remains in the final product in an amount of 6 to 8 area % (per V-28-3M, HPLC analysis) as the by-product D after the subsequent deprotection step and purification step.
On the other hand, when the N-protected intermediate is subjected to methyl esterification using methyl methanesulfonate or methyl p-toluenesulfonate as the methyl esterification agent, formation of the N-protected by-product D can be reduced to about 1 area % or less (per N-protected V-28-3M, HPLC analysis). The N-protected by-product D is reduced to its detection limit or less as the by-product D in the final product after the subsequent deprotection step and purification step.
Accordingly, the present invention relates to a process for preparing V-28-3M represented by formula (4), comprising reacting an N-protected form of V-28-3 represented by formula (1) (wherein R
1
represents a hydrogen atom, and X represents formula (2) or (3)) with methyl methanesulfonate or methyl p-toluenesulfonate in the presence of a base for methyl esterification of the carboxyl group of the N-protected compound to produce a methyl ester of N-protected V-28-3 represented by formula (1) (wherein R
1
represents a methyl group, and X represents formula (2) or formula (3)), and releasing the N-protecting group from the protected intermediate, and to a methyl ester of the N-protected V-28-3 represented by formula (1) (wherein R
1
represents a methyl group, and X represents formula (2) or formula (3)).
Formula (1):
Formula (2):
(R
2
represents a 9-fluorenylmethoxycarbonyl group or a trifluoroacetyl group)
Formula (3):
(R
3
represents a benzylidene group)
Formula (4):


REFERENCES:
patent: 4235993 (1980-11-01), Sipos et al.
patent: 285805 (1988-10-01), None
patent: 50-129531 (1975-10-01), None
patent: 1-56683 (1989-03-01), None
patent: 4-145066 (1992-05-01), None
patent: WO 88/00201 (1988-01-01), None
patent: WO 88/02004 (1988-03-01), None

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