Method of producing oxazolidinones, the use thereof and...

Details Method of producing oxazolidinones, the use thereof and... Method of producing oxazolidinones, the use thereof and...

2000-04-04

2002-08-20

Coleman, Brenda (Department: 1624)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S228000

Reexamination Certificate

active

06437145

ABSTRACT:

The invention is relative to methods of producing oxazolidinones of general formula I
in which
R
1
signifies hydrogen; (C
1
-C
12
)-alkyl; (C
2
-C
10
)-alkenyl; (C
2
-C
10
)-alkinyl; (C
1
-C
6
)-alkyl which is substituted singly or multiply by equal or different groups from the group of halogen, (C
1
-C
4
)-alkoxy, (C
1
-C
4
)-alkylthio, —CN, (C
2
-C
5
)-alkoxycarbonyl and (C
2
-C
6
)-alkenyl; (C
3
-C
8
)-cycloalkyl which is unsubstituted or substituted by one or more groups from the group (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy, (C
1
-C
4
)-alkylthio and halogen; (C
5
-C
8
)-cycloalkenyl; aryl or aryl-(C
1
-C
4
)-alkyl which are unsubstituted or substituted in the aryl group; —OR
6
; NR
7
R
8
; or stands in conjunction with the adjacent carbonyl group for a protective group, especially boc, Z, TFA, alloc, teoc, formyl, tosyl, mesyl, fmoc, moc, suitable for protecting the amino group of an amino acid;
R
2
and R
3
signify, independently of one another and equally or differently hydrogen, (C
1
-C
8
)-alkyl or (C
3
-C
8
)-alkenyl, (C
3
-C
8
)-alkinyl or (C
3
-C
8
)-cycloallyl,
which above C-containing groups can be unsubstituted or substituted singly or multiply, preferably up to three times, by equal or different groups from the group containing halogen, hydroxy, (C
1
-C
8
)-alkoxy, (C
1
-C
8
)-alkylmercapto, (C
2
-C
8
)-alkenylmercapto, (C
2
-C
8
)-alkinylmercapto, (C
2
-C
8
)-alkenyloxy, (C
2
-C
8
)-alkinyloxy, (C
3
-C
7
)-cycloalkyl, (C
3
-C
7
)-cycloalkoxy, cyano, mono- and di-(C
1
-C
4
-alkyl)-amino, aryl, aryl-(C
1
-C
6
)-alkoxy, which last two groups cited in the aryl ring can be unsubstituted or substituted singly or multiply, preferably up to three times, by equal or different groups from the group of halogen, (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy, (C
1
-C
4
)-halogen alkyl, (C
1
-C
4
)-halogen alkoxy; and
which groups R
2
and R
3
can be connected together to a 3-10-member ring which can also be N, O, S-heterosubstituted itself in addition to the cited substituents;
R
4
can be hydrogen, (C
1
-C
6
)-alkyl, (C
2
-C
6
)-alkenyl, (C
2
-C
6
)-alkinyl, aryl, alkaryl, aryl alkyl or cycloalkyl and the linear as well as the branched alkyl groups can contain halogen- and/or heteroatom substitution (N, O, S) either singly or multiply, just as the aliphatic or aromatic cycles;
R
5
signifies a (C
1
-C
2
)-alkane diyl chain which can be substituted with up to four (C
1
-C
4
)-alkyl groups, (C
3
-C
4
)-alkenyl groups, (C
3
-C
4
)-alkinyl groups, (C
3
-C
8
)-cycloalkyl groups and/or aryl groups, which alkane diyl chain itself as well as its substituents can be N, O, S-heterosubstituted
and two of the substituents of the alkane diyl chain can be connected to one another or one of the substituents of the alkane diyl chain with R
4
even to a ring;
R
6
signifies hydrogen, (C
1
-C
8
)-alkyl, (C
3
-C
12
)-cycloalkyl, (C
2
-C
8
)-alkenyl or (C
2
-C
8
)-alkinyl, which above C-containing groups are unsubstituted or substituted singly or multiply, preferably up to three times, by equal or different groups from the group containing halogen, hydroxy, (C
1
-C
8
)-alkoxy, (C
1
-C
8
)-alkylmercapto, (C
2
-C
8
)-alkenylmercapto, (C
2
-C
8
)-alkinylmercapto, (C
2
-C
8
)-alkenyloxy, (C
2
-C
8
)-alkinyloxy, (C
3
-C
7
)-cyClOalkyl, (C
3
-C
7
)-cycloalkoxy, cyano, mono-and di-(C
1
-C
4
-alkyl)-amino, carboxy, (C
1
-C
8
)-alkoxycarbonyl, (C
2
-C
8
)-alkenyloxycarbonyl, (C
1
-C
8
)-alkylmercaptocarbonyl, (C
2
-C
8
)-alkinyloxycarbonyl, (C
1
-C
8
)-alkylcarbonyl, (C
2
-C
8
) alkenylcarbonyl, (C
2
-C
8
)-alkinylcarbonyl, 1-(hydroxy imino)-(C
1
-C
6
)-alkyl, 1-[(C
1
-C
4
)-alkylimino]-(C
1
-C
4
) -alkyl, 1-[(C
1
-C
4
)-alkoxyimino]-(C
1
-C
6
)-alkyl, (C
1
-C
8
)-alkylcarbonyl amino, (C
2
-C
8
)-alkenylcarbonyl amino, (C
2
-C
8
)-alkinylcarbonyl amino, amino carbonyl, (C
1
-C
8
)-alkylamino carbonyl, di-(C
1
-C
6
)-alkylamino carbonyl, (C
2
-C
6
)-alkenylamino carbonyl, (C
2
-C
6
)-alkinylamino carbonyl, (C
1
-C
8
)-alkoxycarbonyl amino, (C
1
-C
8
)-alkylamino carbonyl amino, (C
1
-C
6
)-alkylcarbonyloxy, which is unsubstituted or substituted by halogen, nitro, (C
1
-C
4
)-alkoxy or optionally substituted phenyl, (C
2
-C
6
)-alkenylcarbonyloxy, (C
2
-C
6
)-alkinylcarbonyloxy, (C
1
-C
8
)-alkylsulfonyl, phenyl, phenyl-(C
1
-C
6
)-alkoxy, phenyl-(C
1
-C
6
)-alkoxycarbonyl, phenoxy, phenoxy-(C
1
-C
6
)-alkoxy, phenoxy-(C
1
-C
6
)-alkoxycarbonyl, phenylcarbonyloxy, phenylcarbonyl amino, phenyl-(C
1
-C
6
)-alkylcarbonyl amino, which last-named 9 groups in the phenyl ring are unsubstituted or substituted simply or multiply, preferably up to three times, by equal or different groups from the group of halogen, (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy, (C
1
-C
4
)-halogen alkyl, (C
1
-C
4
)-halogen alkoxy and nitro, and [containing] groups of the formulas —SiR′
3
, —O—SiR′
3
, R′
3
Si—(C
1
-C
8
)-alkoxy, —CO—O—NR′
2
, —O—N═CR′
2
, —N═CR′
2
, —O—NR′
2
, CH(OR′)
2
and —O—(CH
2
)
m
—CH(OR′)
2
in which the R′s in the cited formulas signify independently of each other hydrogen, (C
1
-C
4
)-alkyl, phenyl, which is unsubstituted or substituted singly or multiply, preferably up to three times, by equal or different groups from the group of halogen, (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy, (C
1
-C
4
)-halogen alkyl, (C
1
-C
4
)-halogen alkoxy and nitro, or signify in pairs a (C
2
-C
6
)-alkane diyl chain and m=0 to 6, and [containing] a substituted alkoxy group of the formula R″O—CHR′″(OR″)—(C
1
-C
6
)-alkoxy in which the R″ signify independently of each other (C
1
-C
4
)-alkyl or together (C
1
-C
6
)-alkane diyl and R″″ signifies hydrogen or (C
1
-C
4
)-alkyl, and
R
7
and R
8
have a significance, independently of one another and equally or differently, indicated for R
6
and R
7
and R
8
can also be connected among themselves to a ring;
as well as is relative, e.g., to novel oxazolidinones obtainable according to the method of the invention and to the use of oxazolidinones.
1,3-oxazolidin-5-ones are especially significant as activated intermediates in the &agr;-selective reaction of &agr;-amino dicarboxylic acids with nucleophiles. Esters or amides can be produced from &agr;-amino dicarboxylic acids by reacting oxazolidinones with alcohols or amines in approximately 100% &agr;-regioselectivity under almost complete preservation of the optical activity of the initial product at the same time, that is, with decidedly high enantioselectivity.
&agr;-acid derivatives of aspartic acid and glutamic acid are used as pharmaceutical agents such as e.g. CCK antagonists (Drugs of the Future, 1993, 18, 919-31) and as sweeteners such as e.g. alitame (EP 34,876), aspartame (DE 21 07 411) and L-Asp-D-&agr;-amino alkanoyl-(S)-(&agr;-alkylbenzyl amides (WO 94/00028).
A protection of the &bgr;- and &ggr;-carboxyl function such, e.g., as ester is necessary for the &agr;-selective production of these substances. If this does not take place, mixtures of &agr;- and &bgr;- and/or &ggr;-substitution products result which must be purified in an expensive manner. This is the case if the readily producible inner anhydrides of general formula II are used for coupling (Houben-Weyl, volume 15/1, J. Chem. Soc. 1950, 1954, J. Chem. Soc. 1952, 24, DE 21 07 411, WO 87/03869).
The invention had the problem of developing a method permitting an &agr;-selective coupling of Asp and Glu using the relatively simply producible inner anhydrides. Furthermore, the invention had the problem of indicating novel N-acylated oxazolidinone derivatives which should permit as intermediate products the &agr;-selective coupling with amines or alcohols with the obtention of esters and amides from &agr;-amino dicarboxylic acids.
These and other problems not cited in detail are solved with a method by reacting cyclic anhydrides of general formula II
in which R
1
, R
4
and R
5
have the significance indicated for formula I with carbonyl compounds of general formula III
in which R
2
and R
3
have the significance indica

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