Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-01-04
2003-01-07
Peselev, Elli (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
Reexamination Certificate
active
06504017
ABSTRACT:
The present invention relates to the synthesis of antibacterial macrolides, such as of the erythromycin, for example erythromycin A, type, e.g. roxithromycin, dirithromycin, clarithromycin, azithromycin and similar compounds.
A compound useful in the production of antibacterial macrolides, such as of the erythromycin type is, e.g. described in U.S. Pat. No. 3,478,014, namely a compound of formula
hereinafter designated as erythromycin A oxime. Erythomycin A is a well known, e.g. antibacterial agent. Isolated erythromycin A oxime, e.g. in free-base form obtained according to known processes may be obtained in unstable form, e.g. it may be hygroscopic. We have now found erythromycin A oxime in free-base form in stable, e.g. non hygroscopic form, e.g. a compound according to the present invention may keep a constant water content under normal, e.g. normal air humidity, environmental conditions for at least 24 hours.
In one aspect, the present invention provides a compound of formula I
in anhydrous and stable form, or
in the form of a solvate with non-halogenated organic solvent; or
in the form of a hemihydrate.
Non-halogenated organic solvent as used herein is able to form a solvate with a compound of formula I and is able to form a two-phase system with water. Non-halogenated solvent includes e.g. acetic acid alkyl esters, preferably with alkyl of more than 1 C-atom, e.g. C
2-8
, such as C
2-6
, such as ethyl, propyl and butyl acetates, e.g. isopropyl acetate and n-butylacetate; and alkyl ketones, e.g. dialkyl ketones, e.g. methyl-butyl ketones, such as methyl-isobutylketone. Mixtures of individual solvents, e.g. as described above are included. Non-halogenated organic solvent as used herein means that the chemical formula of that organic solvent does not contain halogen atoms. In contrast to that a halogenated organic solvent means that the chemical formula thereof contains at least one halogen atom. If not otherwise defined herein alkyl includes (C
1-12
)alkyl, e.g. (C
1-8
)alkyl, such as (C
1-6
)alkyl, e.g. (C
1-4
)alkyl. In erythromycin A oxime, e.g. of formula I, in the form of a hemihydrate, according to the present invention there may be determined
a water content (Karl Fischer) of about 1.6% (theory: 1.19%; monohydrate: 2.35%) which may remain below 2.35%, e.g. 2%, e.g. after several, e.g. 24 hours and more, e.g. several days, under normal, e.g normal air humidity, environmental conditions
an endotherm at 136° C. in differential scanning calorimetry (heating rate 10° C./min)
a loss of 1.15% of weight between 100° C. and 200° C. in thermal gravimetric analysis (theory:1.19%)
a high content of the E isomer and a low content of the Z isomer.
A compound of the present invention including e.g. a compound of formula I in anhydrous and stable form, and a compound of formula I in the form of a solvate with non-halogenated solvent and a compound of formula I in the form of a hemihydrate may be obtained as follows:
Erythromycin A oxime, e.g. of formula I
may be treated in a mixture of water and aromatic solvent; or,
may be extracted I into a non-halogenated solvent which is able to form a solvate with a compound of formula I and which is able to form a two phase system with water;
and a compound of the present invention may be isolated; and
an isolated compound of the present invention treated with aromatic solvent may be dried at temperatures at 50° C. or above.
In another aspect the present invention provides a process for the production of a compound of formula I in the form of a solvate, comprising
treating a compound of formula I in a mixture of water and aromatic solvent and isolating a compound of formula I in the form of a hemihydrate; or
extracting a compound of formula I, into non-halogenated solvent and isolating a compound of formula I in the form of a solvate with non-halogenated organic solvent; and
a process for the production of a compound of formula I in anhydrous and stable form, comprising drying a compound of formula I in the form of a solvate with non-halogenated solvent at temperatures of 50° C. or above.
In the process of the present invention a compound of formula I in free base form, or in the form of a salt, e.g. a hydrochloride, and/or in the form of a solvate, such as a hydrate, preferably in the form of a salt may be brought into contact with a mixture containing water and an aromatic solvent in the production of a hemihydrate of formula I, or in non-halogenated solvent, e.g. as defined above for the production of a compound of formula I in the form of a solvate with non-halogenated solvent; e.g. a compound of formula I may be dissolved or suspended in a mixture containing water and an aromatic solvent or non-halogenated solvent. The pH of a mixture obtained may be at an pH where a compound of formula I is present in free base form, including e.g. a pH of 7.5 to 10.5, for example 9.0 to 10.0. Adjustment of the pH to e.g. 7.5 to 10, e.g. if a compound of formula I is in the form of a salt, may be carried out e.g. by use of an appropriate base, e.g. addition to a suspension or a solution of a compound of formula I in a solvent. An appropriate base includes a base which is able to set free a compound of formula I in the form of a salt; including, for example, an inorganic base, such as an alkali-, e.g. sodium-, potassium-; earth alkali-, e.g. calcium-, magnesium-; and ammonium-; -hydroxide, -carbonate, -bicarbonate; and an organic base, such as ammonia and an amine, e.g. alkyl amine, such as triethylamine or diisopropylamine. A base may be preferably a hydroxide, e.g. sodium and ammonia; preferably in aqueous solution; e.g. in about 10% to 35%, such as 15% to 30% aqueous solution. The base may, e.g. be combined with a solution or suspension of a compound of formula I in salt form in water, e.g. in mixture with an aromatic or non-halogenated solvent.
An aromatic solvent as used herein includes aromatic organic solvent such as benzene, toluene, xylene, e.g. o-xylene, m-xylene, p-xylene; preferably toluene or xylene; and an aromatic solvent system, e.g. mixtures of individual aromatic solvent, e.g. as described above; preferably a mixture of o-xylene and/or m-xylene and/or p-xylene; and a mixture of aromatic solvent with one or more other organic solvents, e.g. organic solvent which may be useful in organic chemistry. Preferably in the suspension or solution of a compound of formula I the non-halogenated solvent is present without any further non-halogenated organic solvent; optionally one or more, e.g. non-halogenated organic solvents miscible or immiscible with water may be present; provided that a two phase system with water is formed in a mixture of solvents; and provided that a compound of formula I in free base form is obtained from the mixture in the form of a solvate with non-halogenated solvent. Preferably the aromatic solvent is present without any further organic solvent; optionally an organic solvent, e.g. such as an organic solvent useful in organic chemistry, preferably a solvent the chemical formula of which does not contain a halogen atom, may be present; provided that a compound of formula I in free base form is obtained in the form of a hemihydrate after combination with a base; e.g. in an isolation step. The non-halogenated solvent may be used in an amount sufficient to dissolve a compound of formula I, e.g. during an extraction of a compound of formula I into the organic phase which may be dependent on the solubilizing characteristics of the solvent. Per gram of a compound of formula I, e.g. 2 ml to 20 ml and more, for example 3 ml to 15 ml, such as 5 to 12 ml of the non-halogenated organic solvent may be used. The amount of non-halogenated organic solvent in respect with the amount of water may be dependent on the chemical nature of the organic solvent and on the miscibility characteristics of the organic solvent with water. The range of water and non-halogenated organic solvent used may be such that a two phase system is formed. The appropriate amount of water and the amount of non-halogenated organic solvent can be easily determined.
Bosch Immaculada
Centellas Victor
Diago Jose
Biochemie S.A.
Peselev Elli
Pfeiffer Hesna J.
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