Macrolide production

Details Macrolide production Macrolide production

2000-11-07

2002-07-16

Peselev, Elli (Department: 1623)

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

Organic compounds

Carbohydrates or derivatives

C536S018500

Reexamination Certificate

active

06420537

ABSTRACT:

This present invention relates to azithromycins, e.g. a compound of formula
Azithromycin (9-deoxo-9a-aza-9a-methyl-9a-homoerithromycin A) is a well-known antibacterial agent described e.g. in The Merck Index, 12th Edition (1996), page 157 (946).
An azithromycin or azithromycins as used herein includes azithromycin of formula I and a compound of formula I, wherein
one or more free hydroxyl groups are substituted, e.g. by protecting groups; e.g. conventional hydroxy protecting groups; and/or
a methoxy group is replaced by a free hydroxyl group or by a hydroxyl group which is substituted excluding methoxy, e.g. by protecting groups, e.g. conventional hydroxy protecting groups; and/or
a dimethylamino group is replaced by a substituted amino group excluding dimethylarnino, e.g. by a protected amino group, e.g. a conventional protected amino group.
Azithromycins, e.g. azithromycin of formula I, may e.g. be produced by methylation e.g. by a method as conventional, of 9-deoxo-9a-aza-9a-homoerythromycins, e.g. 9-deoxo-9a-aza-9a-homoerythromycin, e.g. a compound of formula
e.g. via an Eschweiler-Clarke reaction, e.g. in the presence of formaldehyde and in the presence of a reducing agent, e.g. formaldehyde/formic acid, in halogenated solvent,
A 9-deoxo-9a-aza-9a-homoerythromycin or 9-deoxo-9a-aza-9a-homoerythromycins as used herein include a compound of formula II and a compound of formula II, wherein
one or more free hydroxyl groups are substituted, e.g. by protecting groups; e.g. conventional hydroxy protecting groups; and/or
a methoxy group is replaced by a free hydroxyl group or by a hydroxyl group which is substituted excluding methoxy, e.g. by protecting groups, e.g. conventional hydroxy protecting groups; and/or
a dimethylamino group is replaced by a substituted amino group excluding dimethylamino, e.g. by a protected amino group, e.g. conventional protected amino group.
9-deoxo-9a-aza-9a-homoerythromycins are known and obtainable e.g. by a method as conventional.
It was now surprisingly found, that an Eschweiler-Clarke reaction in the production of azithromycins starting from 9deoxo-9a-aza-9a-homoerythromycins including methylation and isolation of azithromycins, e.g. a compound of formula I, may be carried out avoiding halogenated solvent.
In one aspect the present invention provides a process for the production of azithromycins, e.g. azithromycin, e.g. of formula I, by methylation of the nitrogen atom in position 9 of the ring structure in 9-deoxo-9a-aza-9a-homoerythromycins, e.g. a compound of formula II, in the presence of formaldehyde and in the presence of a reducing agent, e.g. formic acid or hydrogen, comprising that methylation, e.g. and isolation of azithromycins, is carried out in non-halogenated solvent, e.g. selected from water, alcohols, ketones, alkyl esters and ethers.
A process according to the present invention may be carried out as follows: The nitrogen atom in position 9 of the ring structure in 9-deoxo-9a-aza-9a-homoerythromycins may be methylated in the presence of formaldehyde and in the presence of a reducing agent in non-halogenated solvent.
A hydroxyl protecting group in 9-deoxo-9a-aza-9a-homoerythromycins includes e.g. conventional hydroxyl protecting groups, including e.g. protecting groups for the diol function present in positions 11 and 12 of a compound of formula II , such as protecting groups which form a cyclic group together with two hydroxy groups, e.g. a hydrogenorthoborate group.
Non-halogenated solvent includes e.g. water and an organic solvent, the chemical formula of which does not contain halogen atoms. In contrast to that, halogenated solvent includes organic solvent, the chemical formula of which contains at least one halogen atom.
Non-halogenated solvent as used herein includes solvent which is miscible with water and solvent which is able to form a two phase system with water, including, e.g. a solvent of a low dielectric constant, e.g. appropriate ketones, such as dialkyl ketones, e.g. for example di(C
1-5
)alkylketones, e.g. methyl-(C
1-5
)alkyl ketones, e.g. acetone and methylisobutyl ketone; di-(C
2-5
) alkyl ketones, such as diethylketone and diisopropylketone; esters, such as alkanoic acid esters, e.g. (C
1-6
)alkanoic acid, e.g. acetic acid alkyl, e.g. (C
1-8
) alkyl, such as (C
1-6
)alkyl, e.g. (C
1-4
)alkyl esters, for example n-butyl acetate, isopropyl acetate and ethyl acetate; ethers such as cyclic ethers, e.g. tetrahydrofuran and non-cyclic, e.g. dialkyl ethers, such as di(C
1-8
)alkyl, e.g. di(C
1-4
)alkyl ethers, such as methyl(C
1-4
)alkyl ethers, e.g. t-butyl methyl ether; and aromatic hydrocarbons, such as xylene or toluene; and solvents of higher dielectric constant, e.g. alcohols, such as alkyl alcohols, e.g.(C
1-5
)alkyl alcohols, for example methanol, ethanol and isopropanol; and amides, e.g. derived from a carboxylic acid, such as an alkanoic acid, , e.g. (C
1-3
)alkanoic acid, and including monoalkyl- and dialkylamides; e.g. mono(C
1-4
)alkyl and di(C
1-4
)alkylamides, such as N-methylformamide, dimethylacetamide and dimethylformamide.
Preferred non-halogenated solvents includes solvents, with low toxicity, e.g. pharmaceutically acceptable solvents, for example water; and alcohols such as ethanol, isopropanol and butanols; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; alkyl esters such as formic acid and acetic acid esters, e.g. ethyl acetate, isopropyl acetate and butyl acetate and ethers such as tert-butyl methyl ether and tetrahydrofuran, more preferably alcohols, esters, e.g. acetates, ketones and water. Non-halogenated solvent includes a solvent system, e.g. mixtures of individual solvents, e.g. as described above.
A solution of 9-deoxo-9a-aza-9a-homoerythromycins in a non-halogenated organic solvent as used as starting material according to the present invention may contain, e.g. a small amount of, water, e.g. to facilitate dissolution of 9-deoxo-9a-aza-9a-homoerythromycins, e.g. in case that 9-deoxo-9a-aza-9a-homoerythromycins in the form of a salt are used as a starting material.
If not otherwise defined herein alkyl includes (C
1-12
)alkyl, such as (C
1-6
)alky, for example (C
1-4
)alkyl. Lower alkyl includes e.g.(C
1-4
)alkyl. Formaldehyde according to the present invention as used herein includes formaldehyde, e.g. in the form of a gas, formaldehyde in aqueous and in non-halogenated solvent, e.g. as described above, solution and a formaldehyde precursor. A formaldehyde precursor includes a compound which may set free formaldehyde in an reaction medium, such as paraformaldehyde or s-trioxane. If a non-halogenated solvent is water, formaldehyde in a molar excess (in respect with a 9-deoxo-9a-aza-9a-homoerythromycins A used as a starting material) in form of an aqueous solution may be used, e.g. without use of further water.
A reducing agent according to the present invention as used herein includes conventional reducing agents useful in a reductive alkylation process, such as formic acid, zinc/HCI, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, BH
3
-pyridine, formic acid and hydrogen, e.g. in the presence of a, e.g. conventional, hydrogenation catalyst. A preferred reducing agent includes e.g. formic acid and hydrogen in the presence of a hydrogenation catalyst.
The amounts of formaldehyde and of the reducing agent present in the methylation reaction according to the present invention are not critical; e.g. a stoechiometric amount or more relating to a 9-deoxo-9a- aza-9a-homoerythromycin A starting compound may conveniently be present. An appropriate amount includes e.g. 1 to 30, such as 1 to 5, e.g. 1 to 3 equivalents of formaldehyde and of a reducing agent. Appropriate reaction conditions for the methylation reaction according to the present invention include e.g.
a temperature range of ca −10° C. up to the reflux temperature of the solvent or solvent system present, such as from 30° C. to 80° C., e.g. more than 50C.;
an appropriate pressure, e.g. atmospheric pressure, and a pressure which is above or below atmospheric pressure; and
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