Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
2000-02-01
2001-05-22
Kifle, Bruck (Department: 1611)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C549S313000
Reexamination Certificate
active
06235899
ABSTRACT:
The present invention relates to a novel process for preparing alkoxyfuranoneamine derivatives, to the compounds obtained by this process, and to the use of these compounds in the synthesis of inhibitors of interleukin-1beta converting enzyme.
Patent Applications WO 95/35308, WO 97/22619, WO 97/22618, EP 519 748 and WO 96/33209 describe compounds which inhibit interleukin-1beta converting enzyme.
The process for preparing some of the compounds described in the patent applications mentioned above uses the compounds of the formula (I) below:
in which R
1
represents an ethyl radical and R
2
represents a —CH═CH
2
radical.
The compounds of the formula (I) are prepared from protected L-aspartic acid and require 4 synthetic steps: 1) acylation, 2) reduction, 3) oxidation, 4) cyclization, (Chapman K. T. et al., Bioorg. Med. Chem. Lett. 2(6), 613-8 (1992)).
This process has major drawbacks, in particular when it is desired to obtain chiral compounds of the formula (I). More specifically, an expensive chiral starting reagent, &bgr;-tert-butyl L-aspartate, has to be used, and above all chromatographic methods have to be used to isolate and/or purify the various diastereoisomers.
One object of the present invention is thus to find another route for the synthesis of the compounds of the formula (I) which avoids the use of this starting material and which does not require chromatographic separations.
The Applicant thus proposes a novel synthetic route starting with the alkoxyfuranone of the formula (II) in racemic form, giving access to the novel compounds of the formulae (IVa), (IVb), (IVc) and (IVd) as defined below, in salified or non-salified form, which are then protected, where necessary, in order in particular to obtain the compounds of the formula (I)
This process has the advantage of being able to be carried out on large scale, starting with a readily accessible and inexpensive compound of the formula (II), with the separation and/or purification steps being carried out by crystallization rather than by chromatography. Each diastereoisomer of the formula (III), (IV) or (I) can thus be isolated.
The present invention thus relates, on the one hand, to the compounds of the formula (IVa), (IVb), (IVc) or (IVd) below:
in which R
1
is an alkyl group containing from 1 to 4 carbon atoms or a phenylalkyl group containing from 7 to 11 carbon atoms, as well as the addition salts thereof with acids.
The invention naturally extends to the salts of the compounds of the formula (IVa), (IVb), (IVc) or (IVd), such as, for example, the salts formed with inorganic or organic acids on the amine. The acids may thus be hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic or aspartic acid, alkanesulphonic acids such as methanesulphonic or ethanesulphonic acid, arylsulphonic acids, such as benzenesulphonic or paratoluenesulphonic acid, and arylcarboxylic acids.
They may also be chloroacetic or trichloroacetic acid. Most particularly, they are salts formed with hydrochloric acid.
When R
1
is an alkyl group containing from 1 to 4 carbon atoms, it can be, in particular, methyl, ethyl, butyl or propyl, and most particularly ethyl.
The term “phenylalkyl” preferably refers to the benzyl group.
The invention more particularly relates to the compound of the formula (IVd) as defined above, as well as the addition salts thereof with acids.
The invention most particularly relates to the compounds of the formula (IVd) in which R
1
is an ethyl group, as well as the addition salts thereof with acids.
Moreover, the present invention relates to a process for preparing compounds of (IVa), (IVb), (IVc) or (IVd) as described above, characterized in that it comprises at least one of the following steps:
a) action of an arylamine of the formula R
3
R
4
CHNH
2
, in which R
3
is a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms and R
4
is an optionally substituted aryl, on the racemic alkoxyfuranone of the formula (II):
in which R
1
is an alkyl group containing from 1 to 4 carbon atoms or a phenylalkyl group containing from 7 to 11 carbon atoms,
and production of the trans isomer compounds (4R,5R) and (4S,5S) of the formulae (IIIa) and (IIIb) respectively:
which subsequently
are separated by crystallization, carrying out, if necessary, one or more salification reactions,
or, when R
3
is a hydrogen atom, are resolved by the action of an optically active acid,
b) where appropriate, epimerization reaction on the compound of the formula (IIIa) or (IIIb), in salified or non-salified form, in the presence of an acid, in order to obtain the cis isomer compounds (4R,5S) or (4S,5R) of the formula (IIIc) or (IIId), which are salified if necessary,
c) hydrogenolysis reaction,
either on the trans isomer (4R,5R) or (4S,5S) of the formula (IIIa) or (IIIb), in salified or non-salified form, in order to obtain the compound of the formula (IVa) or (IVb) in the form of the trans isomer (4R,5R) or (4S,5S) as defined above, which is then, if necessary, salified and/or protected,
or on the cis isomer (4R,5S) or (4S,5R) of the formula (IIIc) or (IIId), in salified or non-salified form, in order to obtain the compound of the formula (IVc) or (IVd) in the form of the cis isomer (4R,5S) or (4S,5R), as defined above, which is, if necessary, salified and/or protected.
In particular, the reaction for protecting the amines of the formula (IVa), (IVb), (IVc) or (IVd), in salified or non-salified form, is carried out by the action of the chloroformate of the formula Cl—CO—O—CH
2
—R
2
, R
2
representing a tert-butyl, (C
2
-C
4
)-alkenyl, (C
2
-C
4
)-alkynyl or phenyl radical, which may be substituted or unsubstituted, in order to obtain the compounds of the formula (Ia), (Ib), (Ic) or (Id) respectively, in the form of the trans diastereoisomers (4R,5R) and (4S,5S) or the cis diastereoisomers (4R,5S) and (4S,5R), which, if necessary, are salified,
The action of the arylamine R
3
R
4
CHNH
2
on the racemic alkoxyfuranone of the formula (II) is carried out according to the standard methods required for the Michael reaction, that is to say, in particular, in a dipolar aprotic solvent, such as dimethylformamide, at room temperature. The process can also be performed with the R or S phenylethylamine or in aqueous isopropanol.
The separation of the two trans isomers (4R,5R) and (4S,5S), i.e. the compounds of the formulae (IIIa) and (IIIb) respectively, by crystallization is carried out according to the methods known to those skilled in the art concerning the separation of isomers. As a preferred example, the separation is carried out by the action of trichloroacetic acid in a solvent such as tert-butyl methyl ether or aqueous isopropanol. The trans isomer (4R,5R) (IIIa) is crystallized in the form of the trichloroacetic acid salt, while the trans isomer (4S,5S) (IIIb) is recovered in the form of the monochloroacetic acid salt by treatment of the mother liquors in the presence of monochloroacetic acid.
When R
3
is a hydrogen atom (non-chiral amine), the separation (resolution) is then carried out by means of a chiral acid, such as tartaric acid, camphorsulphonic acid, salicylic acid, dibenzoyltartaric acid or R
+
2,4-hydroxyphenoxypropionic acid.
The epimerization reaction on one of the isomers (4R,5R) or (4S,5S) of the formula (IIIa) or (IIIb) is carried out in the presence of a Lewis acid, such as ferric chloride or titanium tetrachloride, optionally complexed with tetrahydrofuran, boron trichloride, boron trifluoride etherate and tin tetrachloride, or of an organic acid, such as methanesulphonic acid, trifluoroacetic acid or para-toluenesulphonic acid. It is preferably tin tetrachloride, in the presence of a relatively non-polar solvent, such as dichloromethane, or methanesulphonic acid in a solvent, such as toluene.
The hydrogenolysis reaction on the cis or trans diastereoisomers of the formula (IIIa), (IIIb), (IIIc) or (IIId) is carried out according to the standard methods known to those skilled in the art, for
Bouchet Raphael
Brion Francis
Colladant Colette
Lagouardat Jacques
Biermann, Muserlian and Lucas
Hoechst Marion Roussel
Kifle Bruck
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