Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-01-18
2002-03-05
Peselev, Elli (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S018500
Reexamination Certificate
active
06353096
ABSTRACT:
The subject-matter of the present invention is a process of use in converting the 4″ (S)-OH functional group of the cladinose unit of an azamacrolide to 4″ (R)—NH2.
The present invention relates more particularly to the field of macrolide antibiotics of erythromycin type and more particularly their azamacrolide derivatives which form the subject-matter of Patent EP 508,699 and which correspond to the following general formula:
in which R is a hydrogen atom or a C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
6
-C
12
arylsulphonyl group, which are, if appropriate, substituted.
These compounds are obtained from erythromycin and their synthesis involves two major stages:
the creation of the 8a-azalide macrocycle starting from the (Z) oxime, which is subjected to a stereospecific Beckmann rearrangement, and
the modification of the cladinose group at the 4″ position, which consists of the conversion of the 4″ (S)-OH to 4″ (R)-NH
2
, that is to say with inversion of configuration, which can be illustrated as follows:
In fact, the route currently used to provide for this conversion of the 4″ (S)-OH to 4″ (R)-NH
2
is not completely suitable for production on an industrial scale.
It involves, successively, an oxidation of the hydroxyl functional group at the 4″ position to a ketone functional group and then the conversion of this ketone to an oxime, which, by reduction, results in an approximately 1 to 1 mixture of the expected amino derivative and of its 4″ epimer.
This synthetic route consequently has the major disadvantage of requiring the formation of sp
2
C-4″ intermediates and thus of losing the stereochemical information initially present at the sp
3
C-4″ of the cladinose unit. This result is all the more of a nuisance since the isomers, acquired on conclusion of this synthetic route, are obtained with a low yield of about 20% and are in addition difficult to separate. Thus, for a crude reaction yield of about 20%, only approximately 7% of the amino derivative with inversion of configuration is obtained.
The object of the present invention is specifically to provide a new access route to these derivatives, aminated at the 4″ position, which advantageously makes it possible to retain a significant stereoselectivity and provides a satisfactory yield.
More specifically, a first subject-matter of hi the present invention is a process for the preparation of a compound of general formula I
in which:
R is a hydrogen atom or a C
1
-C
10
alkyl, C
2
-C
10
. alkenyl or C
6
-C
12
arylsulphonyl group, which are, if appropriate, substituted, and
A, which are identical or different, are
a hydrogen atom,
a nitrogen atom, if appropriate substituted,
a C
1
-C
4
alkyl group, which is optionally substituted by one or more aryl groups, which are, if appropriate, substituted,
an R
2
CO or R
2
SO
2
group, with R
2
being a hydrogen atom, a C
1
-C
18
alkyl group or an aryl group, which are, if appropriate, substituted,
∇ means that the C in the 4″ position has undergone an inversion of configuration with respect to the formula II, from a compound of general formula II
with:
R as defined in general formula I and
P
1
being a protective group for the hydroxyl functional group at the 2′ position, characterized in that it comprises at least the stages consisting in:
activating the hydroxyl functional group at the 4″ position in the compound of general formula II, in order to obtain a compound of general formula III
in which:
R and P
1
are as defined in general formulae I and II and
OR
1
is a leaving group,
bringing the said compound of general formula III thus obtained into contact with a nitrogenous nucleophilic derivative under conditions which are sufficient to allow the stereoselective displacement of the hydroxyl functional group activated by the said nitrogenous nucleophile, and
deprotecting the hydroxyl functional group at the 2′ position, in order to result in the expected compound of general formula I.
The claimed process thus has the significant advantage of not requiring the formation of the sp
2
C-4″ intermediate necessarily generated in the prior synthetic route discussed above. It involves only an inversion of configuration at the 4″ position and this inversion is obtained efficiently by displacement by a nitrogenous nucleophile of the activated alcohol functional group present at this 4″ position.
Consequently, the claimed process proves to be particularly advantageous for preparing with a very satisfactory yield, a 4″ (R)-NA
2
derivative of general formula I′
with A and R as defined above from a 4″ (S)-OH azamacrolide derivative of general formula II′
with R and P
1
as defined above.
As regards the leaving group represented by OR
1
in general formula III, it is preferably selected from C
1
-C
20
alkyl sulphonates, C
5
-C
6
aryl or heteroaryl sulphonates or C
6
to C
26
alkylaryl sulphonates, which are substituted, if appropriate, by one or more halogen atoms, preferably fluorine, and/or a nitro, cyano or trifluoromethyl group.
The leaving group represented by OR
1
in general formula III is preferably a group selected from mesylate, triflate and tosylate and is more preferably a triflate group.
Use may in particular be made according to the invention, as nitrogenous nucleophilic compound, of compounds of the following types: ammonia, amines which may or may not be substituted by deprotectable groups, such as a benzyl group or one of its derivatives, amides, imides, sulphonamides, sulphonimides, hydrazines or azides.
According to a preferred alternative form of the claimed process, it is more preferably an organic organosoluble azide which can be generated in situ.
The leaving groups deriving from the activation of the hydroxyl functional group at the 4″ position in the general formula II by a compound of formula IVA or IVB
with:
X being a halogen atom or a nitrogenous heterocycle, preferably an imidazole ring, and
B being a C
1
-C
20
alkyl, C
5
-C
6
aryl or heteroaryl or C
6
-C
26
alkylaryl group, which are or are not substituted by one or more halogen atoms, preferably fluorine, and/or a nitro, cyano or trifluoromethyl group, are very particularly suitable for the invention.
The compound of general formula III thus obtained is preferably brought into contact with an organosoluble azide in order to result, by stereoselective nucleophilic displacement, in a compound of general formula V
in which R and P
1
are as defined in general formula I and ∇ means that the C in the 4″ position has undergone an inversion of configuration with respect to the formula II,
The C-4″ carbon of the compound II preferably has a S configuration and the C-4″ carbon of the compound V a R configuration.
According to this alternative form of the claimed process, a reduction of the said compound of formula V can additionally be carried out, prior or otherwise to the deprotection of the hydroxyl functional group at the 2′ position, so as to obtain a compound of general formula I in which A is a hydrogen atom. This reduction of the azide functional group can be carried out by any conventional method, such as those described by E. F. V. Scriven et al., Chem. Rev. (1988), 88, 297-368. A catalytic reduction with hydrogen or hydrazine in the presence of palladium-on-charcoal, for example, or of Raney nickel can in particular be carried out.
On conclusion of this reduction, the expected 4″ (R)-NH
2
amino derivative, that is to say with inversion of configuration, is thus recovered with a satisfactory yield.
Consequently, this alternative form of the claimed process is very particularly of use in the preparation of the compounds of general formula I″
in which:
R is a hydrogen atom or a C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
6
-C
12
arylsulphonyl group, which are, if appropriate, substituted, from a compound of general formula II as defined above.
Mention may very particularly be made, as illustra
Garel Laurent
Guevel Ronan
Leon Patrick
Lhermitte Frederic
Oddon Gilles
Frommer William S.
Frommer & Lawrence & Haug LLP
Kowalski Thomas J.
Merial
Peselev Elli
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