Organic compounds -- part of the class 532-570 series – Organic compounds – Base salt formation of 3-position -cooh group
Patent
1998-08-03
2000-08-15
Berch, Mark L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Base salt formation of 3-position -cooh group
540335, C07D49916
Patent
active
061038970
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a process for the production of the salt, e.g. the sodium salt, of the penicillin antibiotic amoxicillin. Sodium amoxicillin is a well known penicillin widely used for parenteral preparations.
When sodium amoxicillin is made by spray-drying or freeze-drying of an aqueous solution the content of degradation products may be extremely high and therefore the assay of the product low. Normally commercially available sodium amoxicillin obtained by spray-drying may be very unstable and may have a high content of by-products.
Crystalline sodium amoxicillin is a preferred form of sodium amoxicillin. A process for its production in a mixture of solvents via a solvate of sodium amoxicillin and removing the solvating solvent therefrom is disclosed, for example, in EP-B-0 131 147. The mixture of solvents required results in the use of large amount of solvents and in a complicated and expensive recovery system requiring generally the incineration of several kilograms of solvents per kilogram of sodium amoxicillin. For example, according to example 22 of EP-B-0 131 147, wherein the highest yields are disclosed, per kilogram of sodium amoxicillin about 80 1 of a solvent mixture (methanol, methyl acetate, methylene chloride) has to be used. Efficient solvent recovery is difficult since methanol forms azeotropes with methylene chloride and methyl acetate. Probably for this reason practically all commercially available sodium amoxicillin has been obtained by spray-drying despite the previously mentioned quality problems.
EP-B-0 596 262 describes a further sodium amoxicillin production process. However, the solvent mixture used is even more complex than according to EP-B-0 131 147 in that, apart from methanol and methyl acetate, still a further C.sub.2-5 alcohol is used.
Surprisingly we have now found a new process for the production of a salt, e.g. sodium, of amoxicillin which overcomes the deficiencies of prior art processes, i.e. an industrially applicable, simple process, using only low volumes of a simple solvent system, even essentially one single solvent, wherein the salt, e.g. sodium, of amoxicillin crystallizes giving surprisingly excellent yields and quality of the product.
In one aspect the present invention provides therefore a process for the production of a crystalline salt of amoxicillin in ethanol as solvent, e.g. crystallising said salt from an essentially ethanolic solution. The crystalline salt may be produced, e.g. as disclosed with reference to step (ii) below.
In a further aspect the present invention provides a process for the production of a crystalline salt of amoxicillin which is characterized by the steps compound.
Step (i) may be carried out as follows:
Amoxicillin, e.g. trihydrate or partially anhydrified, preferably trihydrate, may be dissolved, e.g. in ethanol, e.g. in the presence of a solubilizing agent, for example a base, including a suitable amine. As used herein the term amine includes a mixture of amines. Amoxicillin may react with the base to give a salt of amoxicillin; for example in case of an amine, to give an amine salt, or in case of a mixture of amines to give a mixture of amine salts of amoxicillin. A further solvent, for example methyl acetate, may be present.
In a further aspect the present invention provides a process for the production of a crystalline salt of amoxicillin which is characterized by the steps compound.
An amine salt of amoxicillin may be produced by contacting amoxicillin with an amine or a mixture of amines. Preferred amines include C.sub.1-4 trialkyl or dialkyl amines. Preferably the alkyl groups in each of the di- or trialkylamines are identical. Especially preferred are triethylamine, diethylamine and diisopropylamine. A mixture of amines is preferred. Preferably the amine mixture contains two different amines, in, for example, a ratio of about 1.5:1 to 5:1, e.g. of about 2:1 to 3:1. It is especially preferred to use a mixture of trialkylamines and dialkylamines, for example of triethylamine and diisopropylamine. e.g. in a ratio as
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Sykulski Chemical Abstracts, vol. 104, No. 16, Apr. 21, 1986 Abstract No. 135958.
Cabre Joan
Diago Jose
Esteve Asuncion
Ludescher Johannes
Berch Mark L.
Biochemie Gesellschaft m.b.H.
Dohmann George R.
McNally Lydia T.
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