Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-02
2003-01-21
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S952000, C548S953000, C540S200000, C540S362000, C540S363000, C540S364000
Reexamination Certificate
active
06509463
ABSTRACT:
The present invention relates to isocyanoalkylcarbonic acid derivatives, to the reaction therof in isocyanide multi-component reactions to form sec-amidoalkylcarbonic acid derivatives, and to those sec-amidoalkylcarbonic acid derivatives.
Many commercially interesting, organic substances (e.g. pharmacological active ingredients and natural substances) contain structural features that are derived from &agr;-hydroxycarboxylic acid derivatives or &agr;-aminocarboxylic acid derivatives. The synthesis of those substances is often a complex procedure. Using isocyanide multicomponent reactions (isocyanide MCRs), such as the Passerini reaction (P-3CR) and the various variants of the Ugi reaction, it is possible to prepare those complicated structural features in a simple manner [I. Ugi et al. in:
Comprehensive Organic Synthesis: Selectivity for Synthetic Efficiency
, Vol. II, B. M. Trost, C. H. Heathcock, Pergamon Press, Oxford, 1991].
In multicomponent reactions, three or more starting materials (components) can be reacted with one another simultaneously or almost simultaneously in a one-pot reaction without the need to work up intermediates. The group of isocyanide MCRs (one component is an isocyanide) includes, for example, the Passerini 3-component reaction (P-3CR); the Ugi 4-component reaction (U-4CR) [I. Ugi,
Angew. Chem
. 1962, 74, 9]; and the Ugi 5-centre 4-component reaction (U-5C-4CR) [I. Ugi et al.,
Angew. Chem
. 1996, 108, 185] and the Ugi 4-component reaction with &bgr;-amino acids (U-4CR/&bgr;-AS) [I. Ugi et al.,
Tetrahedron
1995, 51, 139].
The products of those four types of reaction have secondary amide functions that are very difficult to convert into other derivatives, such as carboxylic acids and carboxylic acid esters, without the remainder of the molecule or any stereo-centres present being destroyed at the same time. The carbon atom of the secondary amide function that is formed originates from the isocyanide component used (R
Iso
-NC).
It is therefore a problem of the present invention to provide new isocyanide MCR products (sec-amidoalkylcarbonic acid derivatives), the secondary amide function of which can be converted into commercially interesting products (pharmacological sub-structures), such as &agr;-hydroxycarboxylic acid derivatives or &agr;-aminocarboxylic acid derivatives, under very mild reaction conditions.
A further problem of the present invention is to provide processes and intermediates for the preparation of the isocyanide MCR products.
The problem is solved by compounds (isocyanoalkylcarbonic acid derivatives) of the general formula I
The isocyanoalkylcarbonic acid derivatives I are at least bifunctional molecules in which an isocyanide function and a carbonic acid derivative function are bonded to one another via a bridge A having a chain length of 2 or 3 carbon atoms. It is particularly significant that the compound I contains only one isocyanide function: the cleavage of sec-amidoalkylcarbonic acid derivatives that would be obtained from isocyanide MCRs with diisocyanoalkylcarbonic acid derivatives would result in non-uniform products.
In formula I
A is a group of the formula
Z may be an O atom or a S atom, preferably an O atom.
The radicals R
1
to R
4
and, when present, R
6
and R
7
each have a maximum of 20 carbon atoms and are independently of one another H atoms, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alicyclic radicals, heteroalicyclic or heteroaryl radicals having up to 4 hetero atoms (hetero atoms are O, N, S); preferably those radicals each have a maximum of 15 carbon atoms, especially a maximum of 10 carbon atoms, and are independently of one another H atoms, substituted or unsubstituted alkyl, alkenyl, alkynyl, alicyclic or aryl radicals, more especially H atoms, substituted or unsubstituted methyl, ethyl, propyl, butyl, pentyl, hexyl, benzyl and cyclohexyl radicals, and most especially H atoms, methyl, ethyl, propyl, butyl, pentyl, hexyl, benzyl and cyclohexyl radicals.
Two of the radicals R
1
to R
4
and, when present, R
6
and R
7
that are separated from one another by up to two carbon atoms (such as, for example, the radicals R
1
and R
2
, R
3
and R
4
, R
1
and R
3
or R
6
and R
7
, but not, for example, R
1
and R6, since the latter are separated from one another by three carbon atoms) may be constituents of a common ring system, the ring system comprising a substituted or unsubstituted alicyclic monocycle (5 to 8 ring atoms), a heteroalicyclic monocycle (5 to 8 ring atoms with 0, 1 or 2 hetero atoms [O, N, S]), an alicyclic bicycle (7 to 14 ring atoms) or a heteroalicyclic bicycle (7 to 14 ring atoms with up to 4 hetero atoms [O, N, S]), preferably a substituted or unsubstituted alicyclic monocycle (5 to 8 ring atoms) or an alicyclic bicycle (7 to 14 ring atoms), more especially a cyclopentyl, cyclohexyl, norbornyl or bornyl ring.
The radical R
5
has a maximum of 20 carbon atoms, preferably 15 carbon atoms, especially 10 carbon atoms, and is a substituted or unsubstituted alkyl, alkenyl, alkynyl, allyl, alkaryl, aryl, alicyclic radical, heteroalicyclic or heteroaryl radical having up to 4 hetero atoms (hetero atoms are O, N, S), preferably an allyl, benzyl, 2-bromoethyl, n-butyl, 2-chloroethyl, 1-chloroethyl, chloromethyl, ethyl, 1-(9-fluorenyl)-ethyl, 9-fluorenylmethyl, isobutyl, menthyl, 4-methoxycarbonylphenyl, 4-methoxyphenyl, methyl, 4-nitrobenzyl, 2-nitrophenyl, 4-nitrophenyl, 4,5-dimethoxy-2-nitrobenzyl, phenyl, 2,2,2-trichloro-tert-butyl, 2,2,2-trichloroethyl, vinyl, 4-methylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, &agr;-chloro-(trifluoromethyl)benzyl, 3-tert-butylphenyl, 2,4,6-trichlorophenyl, pentafluorophenyl, 2-(p-toluenesulfonyl)ethyl, diphenylmethyl, 2-(trimethylsilyl)ethyl, methoxymethyl, methylthiomethyl, (2-trimethylsilyl)ethoxymethyl, benzyloxymethyl or (2-methoxy)ethyloxymethyl radical.
If desired, the compounds of the formula I may be bonded to a solid phase (resin) via one or more of the radicals R
1
to R
4
and, when present, R
6
and R
7
, also R
5
or Z. Suitable resins are, for example, any conventional resins that are used in organic solid phase synthesis, such as, for example, polystyrene/divinyl benzene, polyethylene glycol or polyethylene glycol/polystyrene resins.
The radicals R
1
to R
4
and, when present, R
6
and R
7
and also R
5
, as well as ring systems formed from those radicals, may be substituted by one, two, three or more, preferably a maximum of one, of the following groups: halogen, tert-amino, nitro, cyano, ether, silyloxyalkyl, thioether, carboxylic acid ester, tert-carboxylic acid amide, carboxylic acid imide, silyl, sulfonic acid ester, sulfenic acid ester, sulfinic acid ester and tert-sulfonamido functions.
The substituents of the radicals R
1
to R
4
and, when present, R
6
and R
7
may, for example, increase the acidity of the H atom in the &agr;-position to the isocyanide function and thus make it possible to use weak bases in the synthesis of the compound I. The choice of the radicals R
1
to R
7
is not essential for the suitability of the compound I for use in the isocyanide MCRs and the subsequent cleavage (see below), but they may be used, for example, to steer the solubility behaviour of the isocyanoalkylcarbonic acid derivatives or the cyclic urethanes formed in the cleavage.
A may especially be a group of the formula —C(CH
3
)
2
—CH
2
—.
Preferred compounds of the formula I are:
(2-isocyano-2-methyl)-propyl-1-carbonic acid allyl ester,
(2-isocyano-2-methyl)-propyl-1-carbonic acid benzyl ester,
(2-isocyano-2-methyl)-propyl-1-carbonic acid (4-nitrobenzyl) ester,
(2-isocyano-2-methyl)-propyl-1-carbonic acid ethyl ester,
(2-isocyano-2-methyl)-propyl-1-carbonic acid phenyl ester,
(2-isocyano-2-methyl)-propyl-1-carbonic acid (4-nitrophenyl) ester,
(2-isocyano-2-methyl)-propyl-1-carbonic acid vinyl ester,
(2-isocyano-2-methyl)-propyl-1-carbonic acid (2,2,2-tri-chloroethyl) ester,
(2-isocyano-2-methyl)-propyl-1-carbonic acid (2-trimethyl-silyl-ethyl) es
Bock Holger
Lindhorst Thomas
Ugi Ivar
Frommer & Lawrence & Haug LLP
McKane Joseph K.
Saeed Kamal
Santucci Ronald R.
Ugichem GmbH
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