Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1998-04-09
1999-09-28
Peselev, Elli
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 185, C07H 100, C07H 1708
Patent
active
059590882
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to a process for producing erythromycin derivatives and fumarate crystals of erythromycin derivatives produced by the process.
BACKGROUND ART
Compounds represented by the general formula (II): ##STR1## (where R.sub.1 is a lower alkyl group and R.sub.2 is a lower alkyl group) are described in Japanese Patent Public Disclosure No. 56873/1994, etc. and are known to have a capability for promoting the movement of digestive tracts.
Process for producing these compounds are described in Japanese Patent Public Disclosure No. 56873/1994, Bioorg. & Med. Chem. Lett., Vol. 4, No. 11, p. 1347, 1994, etc.
However, the processes described in these references have several drawbacks that make them unsuitable for commercial operations, such as the multitude of the steps involved, much use of column chromatography for purification and the use of reagents (e.g., iodine) that are unsuitable for large-scale production. Further, the compounds are required to have high quality in such terms as stability, uniformity and compliance with standards if they are to be used for supplying pharmaceuticals or starting materials therefor of the kind that is to be produced by the process of the invention.
DISCLOSURE OF INVENTION
The present inventors conducted intensive studies in order to deal with this situation and found an efficient process for producing and purifying fumarates of compounds represented by the general formula (II): ##STR2## (where R.sub.1 is a lower alkyl group and R.sub.2 is a lower alkyl group); the inventors also found that the fumarate crystals purified by the process had better quality as pharmaceuticals or starting materials therefor than the heretofore obtained crystals. The present invention has been accomplished on the basis of these findings.
Thus, the present invention relates to a process for producing a fumarate of a compound of the general formula (II): ##STR3## (where R.sub.1 is a lower alkyl group and R.sub.2 is a lower alkyl group) ##STR4## comprising the steps of acetylating the hydroxyl group in position 2' of erythromycin A, formylating the hydroxyl group in position 4" and thereafter performing a reaction for the formation of hemiketal, thereby producing a compound of the formula (III): ##STR5## oxidizing the hydroxyl group in position 11 of the compound (III) to produce a compound of the formula (IV): ##STR6## alkylating the hydroxyl group in position 12 of the compound (IV), removing the acetyl group in position 2' and the formyl group in position 4" to produce a compound of the general formula (V): ##STR7## (where R.sub.2 is a lower alkyl group), reacting the compound (V) with benzyloxycarbonyl chloride under basic conditions, thereafter removing the introduced benzyloxycarbonyl group, subsequently alkylating the nitrogen atom in position 3', thereafter converting the compound to a fumarate in a crude crystal form, then recrystallizing the crude crystal from an alcoholic solvent and thereafter effecting another recrystallization from hydrous ethyl acetate.
The invention also relates to a process for producing a fumarate of a compound of the general formula (II): ##STR8## (where R.sub.1 is a lower alkyl group and R.sub.2 is a lower alkyl group) ##STR9## comprising the steps of acetylating the hydroxyl group in position 2' of erythromycin A, formylating the hydroxyl group in position 4" and thereafter performing a reaction for the formation of hemiketal, thereby producing a compound of the formula (III): ##STR10## oxidizing the hydroxyl group in position 11 of the compound (III) to produce a compound of the formula (IV): ##STR11## alkylating the hydroxyl group in position 12 of the compound (IV), removing the acetyl group in position 2' and the formyl group in position 4" to produce a compound of the general formula (V): ##STR12## (where R.sub.2 is a lower alkyl group), reacting the compound (V) with benzyloxycarbonyl chloride under basic conditions, thereafter removing the introduced benzyloxycarbonyl group, subsequently alkylating the nitrogen atom in
REFERENCES:
patent: 4672056 (1987-06-01), Fernandes et al.
patent: 5008249 (1991-04-01), Omura et al.
Kawasaki Yasushige
Miura Yutaka
Oishi Kazuhiro
Chugai Seiyaku Kabushiki Kaisha
Peselev Elli
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