Process which is useful for converting the carbonyl function...

Details Process which is useful for converting the carbonyl function... Process which is useful for converting the carbonyl function...

2001-05-16

2003-05-13

Peselev, Elli (Department: 1623)

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

Organic compounds

Carbohydrates or derivatives

C536S018500

Reexamination Certificate

active

06562953

ABSTRACT:

The present invention relates to a process which is useful in particular for converting the carbonyl function in position 4″of the cladinose unit of an aza-macrolide into an amine derivative.
The present invention relates more particularly to the field of erythromycin-type macrolide antibiotics and more particularly to the aza-macrolide derivatives thereof which form the subject of patent EP 508 699 and which correspond to the following general formula:
in which R represents a hydrogen atom or a C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
6
-C
12
arylsulphonyl group, which may be substituted.
These compounds are obtained from erythromycin and their synthesis involves two major steps:
the creation of the 8a-azalide macrocycle from the (Z) oxime which undergoes a stereospecific Beckmann rearrangement, and
the modification of the cladinose group in position 4″which consists in converting the 4″(S)—OH into 4″(R)—NH
2
, i.e. with inversion of configuration, which may be illustrated as follows:
In point of fact, the route actually selected to carry out this conversion of the 4″(S)—OH function into 4″(R)—NH
2
is not entirely suitable for industrial-scale production.
It involves, successively, an oxidation of the hydroxyl function in position 4″ into a ketone function and then conversion of this ketone into an oxime, which, on reduction, gives an approximately 1 to 1 mixture of the expected amine derivative and its 4″ epimer. The isomers obtained after this synthetic route are obtained in a low yield of about 20% and in addition are difficult to separate by chromatography. Thus, for a crude reaction yield of about 20%, only about 7% of the amine derivative with inversion of configuration is obtained.
The subject of the present invention is, precisely, to propose a novel route of access to these derivatives aminated in position 4″, in satisfactory yield.
More specifically, a subject of the present invention is described in the following numbered paragraphs:
1. Process for preparing a compound of general formula I
in which:
R is a hydrogen atom or an optionally substituted C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
6
-C
12
arylsulphonyl group, and
R
1
and R
2
, which may be identical or different, represent
a hydrogen atom,
a C
1
-C
10
alkyl group optionally substituted with one or more optionally substituted aryl groups, or an optionally substituted C
6
-C
12
aryl group, by reductive amination of a compound of general formula II:
in which:
R is as defined in the general formula I, and
P represents a hydrogen atom or a protecting group,
characterized in that it comprises:
placing the said compound of general formula II in contact with at least one nitrogenous reagent and a Lewis acid under conditions that are favourable for converting the 4″ carbonyl function,
reducing the resulting mixture using a reducing agent, and
optionally deprotecting the hydroxyl function in position 2′, to give the expected compound of general formula I.
2. Process according to paragraph 1, characterized in that the compound of general formula I is obtained in the form of a mixture of its 2 isomers 4″R and 4″S.
3. Process according to paragraphs 1 or 2, characterized in that the 4″R isomer is obtained as the major product.
4. Process according to one of the preceding paragraphs, characterized in that the nitrogenous reagent is chosen from ammonia, ammonium salts, for instance ammonium acetate or ammonium hydrochloride, primary amines NH
2
R
A
, secondary amines NH(R
A
)
2
with the radicals R
A
, which may be identical or different, representing a C
1
to C
10
alkyl or C
6
to C
12
aryl group or a silyl group of the type SiR
B
R
C
R
D
in which the groups R
B
, R
C
and R
D
, which may be identical or different, can be an alkyl or aryl group.
5. Process according to paragraph 4, characterized in that the nitrogenous reagent is chosen from benzylamine, hexamethyldisilazane and ammonia.
6. Process according to one of the preceding paragraphs, characterized in that the nitrogenous reagent is introduced in a proportion of from 1 to 30 equivalents relative to the compound of general formula II and preferably in a proportion of from 1 to 10 equivalents.
7. Process according to one of the preceding paragraphs, characterized in that the Lewis acid is aprotic.
8. Process according to one of the preceding paragraphs, characterized in that the Lewis acid is introduced in a proportion of from 1 to 30 equivalents relative to the compound of general formula II.
9. Process according to one of the preceding paragraphs, characterized in that the Lewis acid is chosen from organometallic complexes of the elements from column IVB, IIIA or IIB of the Periodic Table of the Elements.
10. Process according to paragraph 9, characterized in that the said complex is chosen from titanium(IV) isopropoxide, aluminium(III) isopropoxide, titanium(IV) isopropoxide bis(acetylacetonate) and zinc(II) trifluoroacetate.
11. Process according to one of the preceding paragraphs, characterized in that the reducing agent is a metal hydride.
12. Process according to paragraph 11, characterized in that it is a boron or aluminium hydride.
13. Process according to paragraph 11 or 12, characterized in that it is sodium, lithium or zinc borohydride.
14. Process according to any one of the preceding paragraphs, characterized in that it is used in the presence of an organic solvent chosen from aromatic hydrocarbons, in particular toluene, halogenated solvents such as dichloromethane, alcohols such as methanol, nitrites such as acetonitrile, ethers such as THF or sulphoxides such as DMSO.
15. Process according to any one of the preceding paragraphs, characterized in that the Lewis acid is titanium isopropoxide or aluminium isopropoxide, the nitrogenous reagent is ammonia, hexamethyldisilazane or benzylamine, and the solvent is dichloromethane, tetrahydrofuran or toluene.
16. Process according to paragraph 15, characterized in that the reducing agent is sodium borohydride or lithium borohydride.
17. Process according to any one of the preceding paragraphs, characterized in that the compound of formula II dissolved in an organic solvent is added to the mixture of the Lewis acid and the nitrogenous reagent.
18. Process according to any one of paragraphs 1 to 16, characterized in that the compound of formula II and the Lewis acid are mixed together in an organic solvent and the nitrogenous reagent is added slowly to this mixture.
19. Process according to any one of paragraphs 1 to 16, characterized in that the compound of formula II is mixed with the nitrogenous reagent in an organic solvent and the Lewis acid is then added.
After the said process, the two isomeric forms R and Z of the expected 4″ amine derivative are obtained. However, the diastereoselectivity is such that the 4″R form is generally obtained predominantly. As emerges from the examples given below, the process claimed can advantageously give a 4″R/4″S mixture with a molar ratio from 60/40 and which may be up to 90/10.
Consequently, the process claimed is found to be particularly advantageous for obtaining this (4″R)-amino derivative, whose separation from the (4″S)-amino form obtained as the minor product can then be carried out by the techniques known to those skilled in the art.
In the context of the present invention, a compound of general formula II is thus reacted with a nitrogenous agent and a Lewis acid under conditions that are sufficient to allow the conversion of the carbonyl function in position 4″. When this conversion is complete, the resulting mixture is reduced directly to give the compound of general formula I.
The process claimed advantageously does not require an intermediate step and allows the two reactions to be carried out in sequence in the same reaction medium.
Nitrogenous reagents which can be used in particular include a compound chosen from ammonia, ammonium salts such as ammonium acetate, ammonium hydrochloride, primary amines NH
2
R
A
a

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