Note: Descriptions are shown in the official language in which they were submitted.
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,.
~.-°"
WO 99/19332 - 1 - PCT/EP98/06162
Description
COMBINATORIAL PREPARATION OF PHOSPHINIC ACID
DERIVATIVES
The invention relates to the technical field of the synthesis of chemical
compounds having certain common structural features, in particular in the
field of the intermediates and active compounds from the group of the
phosphonous acids and phosphinic acids and esters thereof.
Phosphorus-containing compounds are frequently encountered in the
metabolism of animal and plant organisms. Using generally known
examples, it has already been shown that structural variations of such
compounds can be active compounds in the held of the medicaments or
crop protection agents. However, it is a growing problem to discover, from
the large number of structural variations of potential active compounds,
those having the desired properties. The increasing demands on the
properties of novel biologically active substances for crop protection or
medicine mean that the development of an active compound which is
ready for marketing is associated with the preparation and testing of an
increasingly large numbers of test substances. In the estimation of many
specialists, this tendency will probably persist despite improved knowledge
about the biochemistry of known active compounds and computer-assisted
calculations of molecular structures and properties ("molecular modeling").
In order not to allow the expense and consumption of time to increase
equally, the object for research into novel active compounds is to develop
more effective methods for the preparation of large numbers of novel or
systematically varied test compounds.
The methods for the systematic preparation of large numbers of test
compounds and especially methods suitable for their analysis and
biological examination are summarized under the term "combinatorial
chemistry"; cf. for example J. S. Friichtel, G. Jung in Angew. Chem. 108
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(1996) 1946 or Angew. Chem. Int. Ed. Engl. 35 (1996), pp. 17-42.
Some combinatorial synthesis methods are aimed at preparing jointly ("in a
pool"), in a manner which is as effective and standardized as possible, a
large number of structurally variant compounds in as few reaction steps as
possible and jointly testing them for biological activity; cf. for example the
divide, couple and recombine method according to a) K.S. Lam, S. E.
Salmon, E. M. Hersh, V. J. Hruby, W. M. Kazmeiersky, R. J. Knapp in
Nature 82 (1991 ) 354, b) A. Furka, F. Sebestyen, M. Asgedom, G. Dibo in
Int. J. Pept: Protein Res. 37 (1991 ) 487. If an entire group of compounds
("pool") contains no active compound, a single joint test suffices in
principle
to exclude these structural variants. If the joint test, however, indicates
activity, the variation in the preparation of the test compounds can be
decreased in a controlled manner in order to limit the group containing the
active compound or the active compounds and finally to determine the
structure of the active compounds.
Generally, however, the "pooling" method described can no longer be used
efficiently when it concerns the optimization of active compound structures
and many similarly active compounds are present or expected in the group
of test compounds or else when large amounts of the compounds are
needed for the first test.
To achieve the last-mentioned object, the starting compound used is often
a compound with known biological activity, the so-called lead structure or
lead compound, and the structure of the lead compound is varied
systematically with the aid of a preparation process which is standardized
to a great extent ("combinatorial preparation process"), by use of a large
number of different starting materials. The individual compounds prepared
in each case are then tested individually for their biological activity in
order
to find the optimally active compound with the same type of action.
The known synthesis methods from combinatorial chemistry (see
J. S. Fruchtel, G. Jung in Angew. Chem. 108 (1996) 19-46 and the
literature cited there) include a group of methods in which the respective
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active compound is prepared stepwise bound to a solid, in particular bound
to an organic polymer (hereinbelow referred to as "synthetic or natural
resin", "resin" or "resin polymer").
With the aid of the binding to the solid, for example to the resin in the form
of particles of large particle size or spheres, the intermediates are in
principle handleable macroscopically. The synthesis of an active
compound via several reaction steps then needs less expenditure on
isolation and purification than in conventional methods, because these
steps generally can be effected in the form of simple filtration and washing
of the resinous substances. The resin-bound finished active compound
molecule must finally be cleaved again from the resin.
In the choice of suitable resin-molecule systems, problems fundamentally
result due to the conflict of aims both in ensuring a desired high stability
of
the band between moieties synthesized and the resin when using different
reaction types and conditions and in making possible a gentle method for
the predominant or complete cleavage of the finished synthesis product
from the resin.
The invention is based on the object of making available a combinatorial
synthesis method based on resin-bound synthesis building blocks and
products, which allows the synthesis of a wide variation of potentially
biologically active compounds containing a phosphorus atom and having
similar partial structure.
The invention relates to a process using intermediates which are linked to
a resin polymer for preparing chemical compounds of the formula (I)
Y R' P RZ (I)
~O
~R3
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in which
R' is an unsubstituted or substituted aromatic or heteroaromatic
radical,
R2 is hydrogen or an organic radical which may be linked to the rest of
the compound of formula (I) via hetero atoms,
R3 is hydrogen or an organic radical which may be linked to the rest of
the compound of the formula (I) via hetero atoms and
Y is the functional group which is formed at the molecule of the
formula (I) after the compound (I) has been cleaved off from the
resin polymer,
which comprises
a) reacting a resin-linker adduct of the formula (II)
[resin polymer] - [linker - Z - E' - S']~ (I I)
in which
[resin polymer] is the radical of a resin which, in the resin-linker
compound (II), is connected via n binding sites
with the n groups of the formula [linker-Z-E'-S'],
linker is in each case an organic linker,
Z is a linker-specific functional group or bond
which, after cleavage of the compound (I) from
the resin polymer-linker radical, gives rise to the
group Y in formula (I),
E' is defined as R' in formula (I) or is a radical
which is suitable for preparing R' in compound
(I),
S' is a functional group suitable for palladium-
catalyzed substitutions analogous to the Heck
reaction,
n is the number of the functional groups [linker-
Z-E'-S'] at the resin, which depends on the
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molecular weight of the resin polymer and is
greater than or equal to 1,
in the presence of a suitable palladium catalyst with a compound
selected from the group of the phosphinates (derivatives of
hypophosphoric acid) of the formula (III)
A'-O-(PHO)A* (III)
in which
A' is hydrogen or an organic radical, preferably the radical of the
formula R3 in formula (I) or an alkyl radical which differs
therefrom, in particular (C,-C4)alkyl, or a trialkylsilyl radical
such as trimethylsilyl (TMS) and
A* is a group which can be removed hydrolytically or after an
intermediate reaction, for example an alkyl group, a
trialkylsilyl radical such as TMS, or dialkoxymethyl,
preferably with a compound of the formula (II I-1 ), (III-2) or (III-3)
H2P(=O) - O - A' (I I I-1 )
A'-O-PH-O-A* (III-2)
A' - O - P(H)(=O)(A*) (III-3)
in which A' and A* are as defined above,
in particular with a phosphinate derivative of the formula
O
H / A2
O
A1-O O or
1_ ~ ~ ~'
A (~ H ~ H
O-A3
H
TM~ / P\ /TMS
O O
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in which A' is an organic radical, preferably the radical of the
formula R3 in formula (I) or an alkyl radical which differs therefrom,
in particular (C,-C4)alkyl, AZ and A3 are each an alkyl radical such as
(C,-C4)alkyl and TMS = trimethylsilyl,
with substitution of the group S' to give a resin-bound compound of
the formula (IV)
[resin polymer]-[linker-Z-E'-P(H)(=O)-O-A' ]~ (IV)
in which A' is as defined in formula (III), and
b) derivatizing - preferably in the case where E' in the compound (II)
employed in a) is not R' - if appropriate, the compound (IV) in one or
more further reaction steps at the organic radical E' to give the
radical (E')', thus yielding one or more resin-bound intermediates of
the formula (IV)'
[resin polymer]-[linker-Z-(E')'-P(H)(=O)-O-A']~ (IV)'
in which A' is as defined in formula (III), and
c) hydrolyzing, if appropriate, the compound of the formula (IV) or (IV)'
from step a) or b) to give a compound (V) or (V)' suitable, i.e. in
particular suitable with regard to the reactivity of the linker bond and
the swelling capacity of the resin employed in each case, for the
resin-bound synthesis
[resin polymer]-[linker-Z-E'-P(H)(=O)-OH]~ (V)
[resin polymer]-[linker-Z-(E')'-P(H)(=O)-OH]~ (V)'
and
d) esterifying, if appropriate, the compound (V) or (V)' obtained
according to c) to give the compound of the formula (VI) or (VI)'
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[resin polymer]-[linker-Z-E'-P(H)(=O)-O-R3]~ (VI)
[resin polymer]-[linker-Z-(E')'-P(H)(=O)-O-R3J~ (VI)'
in which
R3 is defined as R3 in formula (I), but is not hydrogen, and
e) reacting, if appropriate, a compound (IV), (V) or (VI) or (IV)', (V)' or
(VI)' obtained according to a), b), c) or d), whose common structural
feature is the phosphonous acid or phosphonous ester group,
forming a phosphorus-carbon bond, to give compounds of the
formulae (VII) or (VIII) or (VII)' or (VIII)'
[resin polymer]-[linker-Z-E'-P(R2)(=O)-O-A°]~ (VII)
[resin polymer]-[linker-Z-(E')'-P(R2)(=O)-O-A4]~ (VII)'
[resin polymer]-[linker-Z-E'-P(E2)(=O)-O-A4]~ (VIII)
[resin polymer]-[linker-Z-(E')'-P(E2)(=O)-O-A4]~ (VIII)'
in which
RZ is as defined in formula (I),
EZ is an organic radical which can be derivatized to the radical
R2
A4 = A', H or R3, and
f) modifying the compounds obtained according to the
abovementioned steps if required at the radicals E', (E')', EZ and A4
in such a manner that the resin-bound compound of the formula (IX)
is obtained
[resin polymer]-[linker-Z-R'-P(R2)(=O)-O-R3]~ (IX)
in which R', R2, R3 are as defined in formula (I), and
g) cleaving the compound of the formula (I) from the resin-linker
adduct of the formula (IX),
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where in the formulae (IV) to (IX) and (IV)' to (VIII)' the radicals [resin
polymer], linker, Z are as defined in formula (II) and E' or (E')' in the
formulae (V) to (VIII) or (V)' to (VIII)' are as defined in formula (IV) or
(IV)'.
The invention also relates to the individual steps of the process according
to the invention and to the novel compounds of the formula (I), (II) and (IV)
to (IX) and (IV)' to (VIII)'.
A particular aspect of the invention is the wide range of structural
variations
of the compounds of the formula (I) which can be prepared. This is
possible primarily because a large number of derivatization reactions,
which can be carried out with high yields in the individual steps, are
suitable for the phosphorous acid or phosphorous ester groups introduced
in step a). It is particularly surprising that the introduction of the
phosphorus-containing groups on the resin skeleton succeeds with good
yield. From experience, many of the reactions known from free-solution
chemistry do not succeed under analogous conditions, do not succeed with
good yields or do not succeed at all when one of the reaction components
has been fixed on carriers. In solid phase syntheses, the introduction of
phosphorous acid or phosphorous ester groups under the conditions of
the palladium-catalyzed Heck reaction was hitherto unknown.
Likewise surprising is the good yield and purity of the end products (I)
which, owing to their functional groups, are very polar molecules. In
contrast, some corresponding syntheses in free solution result in extreme
loss of yield.
In the formula (I) and the other formulae (II) to (VII), an organic radical is
a
carbon-containing radical, for example a (hetero)aromatic radical with or
without substitution or an aliphatic, i.e. nonaromatic, organic radical which,
apart from carbon atoms and hydrogen atoms, can also contain hetero
atoms, or a corresponding araliphatic radical.
The size of the suitable organic radicals may vary considerably; an organic
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radical including possibly contained substituents preferably contains less
than 30 carbon atoms, in particular 1 to 20 carbon atoms, and preference
is generally given to smaller radicals having 1 to 12 carbon atoms. Possible
substituents of an organic radical are likewise (hetero)aromatic and
aliphatic radicals, including functional groups, the functional,groups
preferably being highly compatible with the functional groups otherwise
present in the fixed moiety. For example, as functional groups, no oxidative
groups should be present if the linker is sensitive to oxidation and thus
would react even under the conditions of the combinatorial synthesis.
Organic radicals are, for example, optionally substituted hydrocarbon
radicals or hydrocarbonyloxy radicals. A hydrocarbon radical is a straight-
chain, branched or cyclic and saturated or unsaturated or aromatic
hydrocarbon radical; for example alkyl, alkynyl, cycloalkyl, cycloalkenyl or
aryl; a hydrocarbon radical is preferably alkyl, alkenyl or alkynyl having up
to 12 carbon atoms or cycloalkyl having 3, 4, 5, 6, 7 or 8 ring atoms or aryl;
the same applies correspondingly to a hydrocarbon radical in a
hydrocarbonyloxy radical. Organic radicals which may be attached via a
hetero atom include groups such as trialkylsilyl, for example trimethylsilyl
(TMS).
Aryl is a mono-, bi- or polycyclic, carbocyclic aromatic ring system; in the
case of substitution, or more precisely in the case of cyclic substitution,
bicyclic or polycyclic ring systems having at least one aromatic ring which
is fused to one or more cycloaliphatic, optionally partially unsaturated
rings,
are in particular also included. Optionally cyclically substituted aryl is,
for
example, phenyl, naphthyl, tetrahydronaphthyl, indenyl, indanyl, pentalenyl,
fluorenyl and the like, it being possible for the ring systems mentioned to
be additionally further substituted in the case of general substitution;
preferably aryl is an unsubstituted phenyl or naphthyl ring; substituted aryl
is preferably a phenyl radical which is unsubstituted or substituted, the
substituents not being fused rings.
Heteroaryl or a heteroaromatic radical is a mono-, bi- or polycyclic aromatic
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ring system in which at least 1 ring contains one or more hetero atoms, for
example pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, thienyl,
thiazolyl, oxazolyl, isoxazolyl, furyl, pyrrolyl, pyrazolyl and imidazolyl. In
the
case of substitution, bicyclic or polycyclic aromatic or benzo-fused
compounds or compounds fused with cycloaliphatic rings, for example
quinolinyl, benzoxazolyl and the like, are also particularly included.
Heteroaryl also includes a heteroaromatic ring which is preferably 5- or 6-
membered and contains 1, 2 or 3 hetero ring atoms, in particular selected
from the group consisting of N, O and S.
A heterocyclic radical (heterocyclyl) or ring (heterocycle) can be saturated,
unsaturated or heteroaromatic (heteroaryl); it contains one or more hetero
ring atoms, preferably selected from the group consisting of N, O and S; it
is preferably a non-aromatic ring having 3 to 8 ring atoms and 1 to 3 hetero
ring atoms selected from the group consisting of N, O and S or it is a
heteroaromatic ring having 5 or 6 ring atoms and contains 1, 2 or 3 hetera
ring atoms selected from the group consisting of N, O and S. The radical
can be, for example, a heteroaromatic radical or ring as defined above, or
it is a partially hydrogenated radical such as oxiranyl, pyrrolidyl,
piperidyl,
piperazinyl, dioxolanyl, morpholinyl, tetrahydrofuryl. Substituents which are
suitable for a substituted heterocyclic radical are the substituents
mentioned further below, and additionally also oxo. The oxo group can also
be present on the hetero ring atoms, which can exist at various oxidation
levels, for example in the case of N and S.
Substituted radicals, such as substituted hydrocarbon radicals, for example
substituted alkyl, alkenyl, alkynyl, aryl, phenyl and benzyl, or substituted
heteroaryl, a substituted bicyclic radical with or without aromatic moieties,
are, for example, a substituted radical derived from the unsubstituted
skeleton, the substituents being, for example, one or more, preferably 1, 2
or 3, radicals selected from the group consisting of halogen, alkoxy,
haloalkoxy, alkylthio, hydroxyl, amino, nitro, cyano, azido, alkoxycarbonyl,
alkylcarbonyl, formyl, carbamoyl, mono- and dialkylaminocarbonyl,
substituted amino, such as acylamino, mono- or dialkylamino, and
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alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl and, in the
case of cyclic radicals, also alkyl and haloalkyl, and unsaturated aliphatic
radicals which correspond to the abovementioned saturated hydrocarbon-
containing radicals, such as alkenyl, alkynyl, alkenyloxy, alkynyloxy and the
like. Preferred among the radicals having carbon atoms are those having 1
to 4 carbon atoms, in particular 1 or 2 carbon atoms. Preferred
substituents are generally selected from the group consisting of halogen,
for example fluorine and chlorine, C,-C4 alkyl, preferably methyl or ethyl,
C,-C4 haloalkyl, preferably trifluoromethyl, C,-C4 alkoxy, preferably
methoxy or ethoxy, C,-C4 haloalkoxy, nitro and cyano. Especially preferred
are the substituents methyl, methoxy and chlorine.
Unsubstituted or substituted phenyl is preferably phenyl which is
unsubstituted or mono- or polysubstituted, preferably up to trisubstituted,
by identical or different radicals selected from the group consisting of
. halogen, C,-C4 alkyl, C,-C4 alkoxy, C,-C4 haloalkyl, C,-C4 haloalkoxy and
nitro, for example o-, m- and p-tolyl, dimethylphenyl radicals, 2-, 3- and
4-chlorophenyl, 2-, 3- and 4-trifluoro- and -trichlorophenyl, 2,4-, 3,5-, 2,5-
and 2,3-dichlorophenyl, o-, m- and p-methoxyphenyl.
The radicals alkyl, alkoxy, haloalkyl, haloalkoxy, alkylamino and alkylthio
and the corresponding unsaturated and/or substituted radicals are in each
case straight-chain or branched in the carbon skeleton. Unless specifically
mentioned, the lower carbon skeletons, for example those having 1 to 4
carbon atoms or, in the case of unsaturated groups, 2 to 4 carbon atoms,
are preferred for these radicals. Alkyl radicals, also in the composite
meanings such as alkoxy, haloalkyl and the like, are, for example, methyl,
ethyl, n- or i-propyl, n-, i-, t- or 2-butyl, pentyl radicals, hexyl radicals
such
as n-hexyl, i-hexyl and 1,3-dimethylbutyl, heptyl radicals, such as n-heptyl,
1-methylhexyl and 1,4-dimethylpentyl. Cycloalkyl is a cycloaliphatic
hydrocarbon radical such as cyclopropyl, cyclobutyl, cyclopentyl or
cyclohexyl and the like; alkenyl, cycloalkenyl and alkynyl have the meaning
of the unsaturated radicals which are possible and which correspond to the
alkyl radicals; alkenyl is, for example, allyl, 1-methylprop-2-en-1-yl,
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2-methylprop-2-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, methylbut-3-en-1-yl
and 1-methylbut-2-en-1-yl; cycloalkenyl is, for example, cyclopentenyl and
cyclohexenyl; alkynyl is, for example, propargyl, but-2-yn-1-yl, but-3-yn-1-yl
or 1-methylbut-3-yn-1-yl.
Alkenyl in the form "(C3 C4)alkenyl" or "(C3 C6)alkenyl" is preferably an
alkenyl radical having 3 to 4 and 3 to 6 carbon atoms, respectively, where
the double bond is not located on the carbon atom attached to the
remaining moiety of the compound ("yl" position). The same applies
analogously to (C3 C4)alkynyl and the like.
Halogen is~, for example, fluorine, chlorine, bromine or iodine, haloalkyl,
haloalkenyl and haloalkynyl are alkyl, alkenyl and alkynyl, respectively,
which are fully or partially substituted by halogen, preferably by fluorine,
chlorine and/or bromine, in particular by fluorine or chlorine, such as CF3,
CHF2, CH2F, CF3CF2, CHZFCHCI2, CCI3, CHCI2, CH2CHzCl; haloalkyl is, for
example, OCF3, OCHF2, OCHZF, CF3CF20, OCHZCF3 and OCH2CHZCI; the
same applies analogously to haloalkenyl and other halogen-substituted
radicals.
Mono- or disubstituted amino is a chemically stable radical selected from
the group consisting of the substituted amino radicals which are N-
substituted, for example, by one or two identical or different radicals
selected from the group consisting of alkyl, alkoxy, acyl and aryl; preferably
monoalkylamino, dialkylamino, acylamino, arylamino, N-alkyl-N-arylamino
and N-heterocycles; preferred are alkyl radicals having 1 to 4 carbon
atoms; aryl is preferably phenyl or substituted phenyl; acyl is defined as
indicated further below and is preferably (C,-C4)alkanoyl. The same applies
analogously to substituted hydroxylamino or hydrazino.
An acyl radical is the radical of an organic acid, for example the radical of
a
carboxylic acid and radicals of acids derived therefrom, such as
thiocarboxylic acid, iminocarboxylic acids with or without N-substitution, or
the radical of carbonic monoesters, carbamic acid with or without N-
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substitution, sulfonic acids, sulfinic acids, phosphonic acids, phosphinic
acids. Acyl is, for example, formyl, alkylcarbonyl such as [(C,-C4)-
alkyl]carbonyl, phenylcarbonyl where the phenyl ring may be substituted,
for example as shown above for phenyl, or alkyloxycarbonyl,
phenyloxycarbonyl, benzyloxycarbonyl, alkylsulfonyl, alkylsulfinyl,
N-alkyl-1-iminoalkyl and other radicals of organic acids.
The formulae also embrace stereoisomers containing, for example one or
more asymmetric carbon atoms or else double bonds which are not
specifically indicated in the respective formulae. The stereoisomers of the
same chemical linkage which are possible and which are defined by their
specific spatial form, such as enantiomers, diastereomers, Z isomers and
E isomers, are therefore all embraced by the formula and can be obtained
from stereoisomer mixtures by customary methods, or else be prepared by
stereoselective reactions in combination with the use of stereochemically
pure starting materials.
The formulae also embrace tautomers of the indicated compounds, as far
as they are formed by proton migration and as far as they are chemically
stable tautomers.
Many of the compounds of the formula (I) can form salts, for example
those where in the case of R3 = H the hydrogen of the group
-P(=O)(Rz)(OH) or else other acidic hydrogen atoms which are present (for
example from carboxyl groups, inter alia) are replaced by an agriculturally
suitable cation. These salts are, for example, metal salts; preferably alkali
metal or alkaline earth metal salts, in particular sodium salts and potassium
salts, or else ammonium salts or salts with organic amines. Salt formation
can also take place by addition of an acid to basic groups, such as, for
example, amino and alkylamino. Suitable acids for this purpose are strong
inorganic and organic acids, for example HCI, HBr, HZS04 or HN03.
The organic linker in the compounds of the formulae (II) and (IV) to (IX)
has the function of a bridge between the resin polymer and the part of the
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molecule which is to be structurally modified. The linker must make
possible the binding of the part of the molecule mentioned and its later
removal. The linker must additionally be able to be applied to the resin
polymer, generally by means of a chemical reaction if the resin polymer
cannot be synthesized from suitable monomers which contain the linker. It
may be possible to do entirely without a structurally specific linker; in this
case, the linker is a direct bond.
Suitable linkers are structurally very different radicals which, depending on
the binding sites on the resin polymer, have to have suitable binding sites
and functional groups, and usually a resin-linker compound of the formula
(X)
[resin polymer]-[linker-X ]~ (X)
where [resin polymer], linker and n are as defined in the abovementioned
formula (II) and X is a functional group which is specific for the linker used
in each case, is first prepared or made available. The resin-linker
compound (X) is then reacted with an aromatic or heteroaromatic
compound ("scaffold system") of the formula (XI)
Y, _ E, _ S, (XI)
where E' and S' are defined as in the abovementioned formula (II) and Y'
is a functional group which reacts with the functional group X of the resin-
linker compound to give the bridge Z, similar to known methods to give the
resin-linker adduct of the formula (II).
Suitable for the process are structurally very different linkers including,
for
example, those which can also be employed from resin-bound synthesis
for the binding of carboxylic acids, for example of amino acids, in peptide
synthesis.
Compounds (linker components) which can be employed for the synthesis
of the linker in combination with a resin containing amino groups, for
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example an aminomethylenepolystyrene resin, or a resin containing
hydroxyl groups, are, for example, linker components having a carboxylic
acid group. The preparation of the resin-linker compound of the formula (X)
is then carried out in each case by reaction of the carboxyl group of a linker
component (XII) with an amino group or hydroxyl group of the resin (amide
formation or ester formation).
In some cases, the linkers can also be prepared stepwise; in a first step a
carboxylic acid is condensed with the resin containing amino acids and the
resulting modified resin is further modified on the introduced groups as far
as the desired resin-linker compound.
In addition, resin-linker compounds are known which are synthesized on
the basis of further resins and in another manner.
Examples of linker components (XII) and resin-linker compounds of the
formula (X) are listed below in Tables 1 and 2; a linker component is in
each case the compound of the formula (XII)
W-linker-X (XII)
where W is the leaving group or functional group to be activated to give the
leaving group, which is replaced in the reaction with the functional group of
the resin, for example the amino group or hydroxyl group of the resin; in
the case where the resin-linker compound (X) is prepared differently or the
preparation is not given in detail, the radical W = polymer or MME is
given, indicating the binding site of the functional group linker-X on the
resin polymer; X is as defined further above; literature references: see J.S.
Fruchtel, G. Jung, Angew. Chem. 108 (1996) 19-46 and literature cited
therein:
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Table 1: Base-stable linker groups between substrate and solid phase
W-linker-X Notes
a) Wang linker (R=H); suitable for
the fixation of carboxylic acids;
W / \ X cleavage with 95% strength
~ ~ ~ trifluoroacetic acid (TFA)
R
W = polymer, X = OH b) SASRIN linker; (R = OMe);
fixation of carboxylic acids; cleavage
with 1 % strength TFA
a) Tritylchloride linker (R=H);
fixation of nucleophiles, cleavage
with weak acids (HOAc)
X=CI
b) 2-Chlorotritylchloride linker
R (R=CI), fixation of nucleophiles,
cleavage with very weak acids
such as HOAc/CH2C12 (114)
o PAM linker;
~ ~ X fixation of carboxylic acids,
cleavage with HF, TFMSA;
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Table 1 (continued):
W-linker -X Notes
O a) Rink acid (X = OH);
fixation of carboxylic acids
cleavage with HOAGCHzCIz
b) Rink amide (X = NH-Fmoc);
fixation of carboxylic acids as
amide, cleavage with TFAICH2CIz
NH2 BHA anchor; fixation of carboxylic acids;
/ \ cleavage with TFMSA
\ /
Sieber amide; fixation of carboxylic
acids; cleavage with TFA/CHZCIz (1/99)
_ Fmoc = 9-fluorenylmethoxy-
~ carbonyl
O
X = NH-Fmoc
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Table 2: Acid-stable linker groups between substrate and solid phase
W-linker-X Notes
Fixation of carboxylic acids
NO~ cleavage with DBUlpiperidine (f~-
X elimination);
W W = OH
X=OH
O O Fixation of alcohols, amines; cleavage
with NaOH (hydrolysis);
W X
O
X~gOz~ Fixation of carboxylic acids; cleavage
W with NaOH (f3-elimination)
W = OH, X = OH
NH-CO-(CH2)3 CO-W
X
O - Si ~ ~ W = OH, X = OH
( \
Fixation of carboxylic acids; cleavage
with Bu4NF;
CA 02306076 2000-04-07
-19-
Table 2 (continued):
W-linker-X Notes
/ \ CO-W
CH3 Fixation of carboxylic acids; cleavage
X Si \ with Bu4NF
CH3 W = OH, X = OH
3
, X
N Fixation of carboxylic acids; cleavage
with hydrazine hydrate (hydrazinolysis);
stable in 25 percent strength TFA;
/ W = polymer, X = OH
W
OzN
X Fixation of carboxylic acids; cleavage
O with Pd°/Hz (catalytic hydrogenation);
W = OH, X = OH HYCRAM carrier
SCAL linker, fixation of carboxylic acids,
cleavage with (Et0)zP(S)SH/TFA
~S g ~ O (reductive acidolysis);
W = OH, X = NH2
CH3 W CH3
X
3Q ~ ~ CO-W Fixation of carboxylic acids; cleavage by
O photolysis (h = 350 nm, room
temperature, 72 h); stable in 50 percent
strength TFA, unstable in hydrazine
hydrate;
W = OH, X = CI
CA 02306076 2000-04-07
-20-
Table 2 (continued):
W-linker-X Notes
Me / W
Fixation of carboxylic acids; cleavage by
\ photolysis (~ = 350 nm); unstable in
piperidineIDMF; more stable in
piperidine/CHzCIz
W =polymer, X = Br
N O Fixation of carboxylic acids; cleavage by
X photolysis (~ = 350 nm, oxygen-free
CO-W under inert gas)
X = Hal, OH, NH2, W = OH
W-CO-p-C6H4-S-CHZCHZ-X Rydon linker; P. M. Hardy, H. N. Rydon,
R. C. Thompson, Tetrahedron Lett.
1968, 2525-2526
X = OH, W = OH
The resin polymers which can be used should be insoluble in the liquid
phases which are used for the reactions and the isolation of the
compounds, substantially inert to the reaction conditions in steps a) to g)
and filterable; each resin polymer particle preferably has many binding
sites for the respective linkers. Depending on the structure of the selected
linkers, structurally completely different resin polymers are possible, for
example polystyrene resins, polyamide resins, polydimethylacrylamide
resins, modified resins based on the resins mentioned and copolymers.
Preferred resins are aminomethylenepolystyrene resins, i.e.
aminomethylated polystyrene resins, or alternatively differently modified
resins based on polystyrene, for example graft polymers of polystyrene
and polyethylene glycol such as those from the series ~TentaGel (Rapp
Polymere, Tiibingen, Germany), in the form of swellable particles in a
particle size range from, for example, 0.01 to 1 mm, preferably 0.05 to
CA 02306076 2000-04-07
-21 -
0.5 mm, and a loading of aminomethyl groups from 0.01 to 10 mmol per
gram of resin, preferably 0.1 to 2 mmol per gram of resin.
The individual linkers are applied to the resin in a manner known per se;
see references mentioned in Tables 1 and 2. All different sorts of
techniques can be employed here. Suitable linker components for the
combination with the hydroxyl- or aminomethylated polystyrene resins are
linkers having carboxylic acid groups which are reacted under the
customary conditions for condensations and especially for ester and amide
formation reactions. Gentle methods at moderate temperatures are
suitable. The reaction can be carried out, for example, in a substantially
anhydrous inert organic solvent in the presence of catalysts or customary
condensing agents at temperatures from, for example, -30°C to
200°C,
preferably from 0°C to 150°C, in particular 0°C to
100°C. Depending on the
respective resin, it is also possible to employ aqueous-organic solvents.
The term "inert solvent" refers to solvents which are inert under the
reaction conditions in question, but need not be inert under all reaction
conditions. For the abovementioned condensation, for example, the
following are possible:
- ethers such as tert-butyl methyl ether, dimethoxyethane (DME),
tetrahydrofuran (THF), diethyl ether, diisopropyl ether,
- dipolar aprotic solvents such as dimethylformamide (DMF), N,N-
dimethylacetamide (DMA), N-methylpyrrolidone (NMP), acetonitrile,
- optionally halogenated aliphatic or aromatic hydrocarbons such as
dichloromethane, toluene, o-chlorotoluene, chlorobenzene, or
- mixtures of inert solvents.
Suitable condensing means for the preparation of the resin-linker
compound (X) from the linker component (XII) and a hydroxymethylene- or
aminomethylenepolystyrene resin are customary means such as
azeotropic distillation, reaction with activated derivatives of the carboxylic
acid such as halides or activated esters. Gentle methods are particularly
CA 02306076 2000-04-07
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suitable, such as reaction in the presence of carbodiimides such as
dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide.
Once the [resin polymer]-linker-X-structures (X) described above have
been prepared, they are reacted with compounds of the formula (XI) to
give compounds of the formula (II). These are, for example, compounds
(X) where X = OH or NH2 which are reacted with carboxylic acids of the
formula (XI) (Y' _ -COOH) to give resin-linked esters or amides (Z =
-O-CO- or -NH-CO-)
The optionally substituted (hetero)aromatic adducts of the formula (II)
which are accessible in this manner must carry a functional group (S')
which enables Pd-catalyzed reactions for the synthesis of (hetero)aryl-
phosphorus(III) compounds to be carried out (cf. the similar conditions of
the Heck reaction; see Lit.; R.F. Heck, Palladium, Reagents in Organic
Synthesis, Academic Press 1985).
A central step of the process according to the invention is the synthesis of
an arylphosphorus compound (phosphorus(III) compound) on the solid
phase (step a) where derivatives of the hypophosphoric acid of the formula
(III) are employed under conditions similar to the Heck reaction.
Processes of this type where phosphinates such as HZP02CH3 or
H2POZC2H5 are used are known from the literature; see Palladium
Reagents and Catalysts, Innovations in Organic Synthesis, Jiro Tsuji, John
Wiley & Sons, Chichester England 1995, p. 243 ff, furthermore in Haiyan
Lei, Mark S. Stoakes, Kamal P.B. Herath, Jinho Lee and Alan W.
Schwabacher, J. Org. Chem. 59 (1994), 4206-4210, furthermore in Haiyan
Lei, Mark. S. Stoakes, Alan W. Schwabacher, Synthesis 1992, p. 1255-
1260.
Typical examples of a group with which palladium-catalyzed reactions of
the abovementioned nature can be carried out are organic halogen
compounds, preferably iodides and bromides, but also pseudohalogens
such as triflates or tosylates and others; see, for example, similar reactions
and reaction conditions in R.F. Heck, Palladium Reagents in Organic
CA 02306076 2000-04-07
-23-
Synthesis, Academic Press, 1985. Preferred starting materials for the
process according to the invention are iodides, and alternatively bromides.
Pseudohalides, for example triflates or tosylates, can be prepared from
suitable precursors, for example phenols. This synthesis of pseudohalides
can be carried out on solid phase.
Similar to the Heck reaction which is known from the literature, the
palladium can be employed in the form of Pd(II) salts, for example
bistriphenylphosphane-Pd (II) dichloride, which form a reactive Pd(0)
complex in situ. Alternatively, it is possible to employ Pd(0) complexes
such as tetrakistriphenylphosphane-Pd inter alia.
The abovementioned process for the palladium-catalyzed introduction of a
phosphorus-carbon bond yields compounds of the formula (IV) or, after
derivatization of the group E' to (E')', compounds of the formula (IV)' as
optionally substituted (hetero)aromatic phosphonous esters, preferably
having lower alkyl groups A', for example C,-C$ alkyl, in particular C,-C5
alkyl, in the ester moiety.
A further optional step of the invention comprises the hydrolysis of the
phosphonous esters on solid phase to phosphonous acids (V) or (V)'. For
this purpose, a strong organic base such as, for example,
1,8-diazabicyclo[5.4.0]undec-7-ene, is reacted in a solvent in which the
resin polymer is swellable and which is inert under the reaction conditions,
for example in general the solvents mentioned further above, preferably
tetrahydrofuran (THF), dioxane or ethylene glycol diethers, with addition of
a suitable amount of water, preferably 1 to 100 equivalents, preferably 1 to
10 equivalents, at temperatures from 0 to 100°C, preferably 10 to
50°C.
The resulting phosphonous acids can then be reacted on solid phase to
give activated esters, for example by reaction with pivaloyl chloride in
acetonitrile/pyridine (for literature on similar reactions, see B.C.Froehler;
M.
D. Matteucci, Tetrahedron Lett. 27 (1986), 469), and these can be reacted
with virtually any alcohols R3-OH to give a wide variety of phosphonous
esters to give compounds of the formula (VI) or (VI)'.
CA 02306076 2000-04-07
-24-
Further suitable esterification methods for phosphonous acids are
described in the following literature references:
- Xiadong Cao, A.M.M. Mjalli, Tetrahedron Letters 37 (1996) 6073-
6076,
- Changzhi Zhang, A. M.M. Mjalli, Tetrahedron Letters 37 (1996)
5457-5460,
In principle, the step of the hydrolysis and the esterification provides
access to a wide variety of the radical R3 in formula (I).
The invention in particular also relates to the resin-bound processes for
reacting adducts of the formulae (IV) to (VI) or (IV)' to (VI)', whose common
structural feature is the phosphonous acid or phosphonous monoester
group with a series of compounds having functional groups which add to
the abovementioned phosphorus(III) compounds forming phosphorus-
carbon bonds (introduction of the radical R2)
It is possible, for example, to activate the compounds mentioned,
preferably after reaction of the phosphorus component with silylating
agents such as, for example, trimethylsilyl chloride/triethylamine,
bistrimethylsilylacetamide, or hexamethyldisilazane or else mixtures of the
silylation agents, and to convert them with electrophiles, for example
aldehydes, imines, isocyanates or Michael acceptors, into the
corresponding products of the formula (VII) and (VIII) or (VII)' to (VIII)';
see
similar methods for the silylation in:
- Kamyar Afarinkia, Charles W. Rees, Tetrahedron 46 (1990) 7175-
7196;
- E.A. Boyd A.C. Reagan, Tetrahedron Letters 35 (1994), 4223-4226;
- J.K. Thottathil, O.E. Ryono, C.A. Przybyla, J.L. Moniot, R. Neubeck
Tetrahedron Lett. 25 (1984) 4741-4744;
- O.A. Evans, K. Hurst, J.M. Jakaes, J.Am Chem. Soc. 100 (1978)
3467;
- K. Issleib et al., DD-Patent 24 28 10,
CA 02306076 2000-04-07
-25-
Alternatively, the compounds of the formula (IV) to (VI) or (IV)' to (VI)' can
be reacted with the abovementioned electrophiles under base catalysis.
Suitable bases are, in addition to inorganic salts such as, for example,
potassium tert-butoxide, in particular organic nitrogen bases such as, for
example, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, N-isopropyl-N-
ethylamine and similar compounds (Lit: R.B. Fox, W.J. Bailey, J.Org.
Chem. 25 (1960) 1447; see also Houben-Weyl, "Methoden der Org.
Chemie", Georg Thieme Verlag 1963, vol. 12/1, "Organische
Phosphorverbindungen")
The selection of the suitable reaction sequence for activating the
compounds of the formula (IV) to (VI) or (IV)' to (VI)' depends on the
specific chemical reactivities of further functional groups in E', (E')' or R'
and gives the person skilled in the art the opportunity to carry out diverse
chemical modifications of E' or (E')'. The resulting phosphinic acid
derivatives of the formula (VII) to (VIII) or (VII)' to (VIII)' are likewise
sufficiently stable to allow diverse chemical modifications of the radicals
E',
(E')' and E2. The radicals E', (E')' and EZ have to be selected in such a way
as to make possible a modification of the radicals to the radicals R' or R2 in
formula (I).
In the manner described, it is possible to prepare preferably compounds of
the formula (I) in which
R' is phenylene which is unsubstituted or substituted by 1 to 4 radicals
selected from the group consisting of halogen, alkyl, haloalkyl,
alkoxy, haloalkoxy, alkylthio, hydroxyl, amino, nitro, cyano, azido,
alkoxycarbonyl, alkylcarbonyl, formyl, carbamoyl, mono- and
dialkylaminocarbonyl, acylamino, preferably alkanoylamino having 1
to 6 carbon atoms, mono- and dialkylamino, alkylsulfinyl,
haloalkylsulfinyl, alkylsulfonyl and haloalkylsulfonyl, where each
substituent may have up to 6 carbon atoms in the alkyl moiety,
or is a heteroaromatic radical selected from the group consisting of
CA 02306076 2000-04-07
-26-
the 5- or 6-membered ring having in each case 1, 2 or 3 hetero
atoms selected from the group consisting of N, O and S, where the
radical is unsubstituted or substituted by 1 to 4 radicals selected
from the group consisting of halogen, alkyl, haloalkyl, alkoxy,
haloalkoxy, alkylthio, hydroxyl, amino, vitro, cyano, azido,
alkoxycarbonyl, alkylcarbonyl, formyl, carbamoyl, mono- and
dialkylaminocarbonyl, substituted amino such as acylamino,
preferably alkanoylamino having 1 to 6 carbon atoms, mono- and
dialkylamino, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl and
haloalkylsulfonyl, and where each substituent may preferably have
up to 6 carbon atoms, in particular 4 carbon atoms, in the alkyl
moiety, and
RZ is hydrogen, an aliphatic hydrocarbon radical which is unsubstituted
or substituted and contains, inclusive of substituents, 1 to 30 carbon
atoms, preferably 1 to 20 carbon atoms,
R3 is hydrogen or an aliphatic hydrocarbon radical which is
unsubstituted or substituted and contains, inclusive of substituents,
1 to 30 carbon atoms, preferably 1 to 20 carbon atoms, or
is an aryl or heteroaryl radical which is unsubstituted or substituted
and contains, inclusive of substituents, 1 to 30 carbon atoms,
preferably alkyl, alkenyl, alkynyl having in each case 1 to 12 carbon
atoms where each of the 3 abovementioned radicals is
unsubstituted or substituted by one or more radicals selected from
the group consisting of halogen, haloalkyl, alkoxy, haloalkoxy,
alkylthio, vitro, cyano, alkoxycarbonyl, alkylcarbonyl or unsubstituted
or substituted phenyl, where each substituent may have up to
4 carbon atoms in the alkyl moiety
Y is H, COOH, CONH2, OH, NHZ or alkylamino.
Of particular interest are compounds (I) where R3 = (C,-C4)alkyl and Y =
COOH.
Preference is given to compounds of the formula (I), or to the preparation
thereof according to the invention, in which two or more of the radicals R'
CA 02306076 2000-04-07
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to R3 and Y have in each case one of the meanings already mentioned or
one of the preferred meanings mentioned further below.
The phosphonous acid (ester) group can be derivatized using very different
processes with electrophilic reaction partners; for example, in most
instances it is possible to react the following classes of substances with
compounds of the formula (IV):
1 ) Aldehydes react to a-hydroxyphosphinic acid derivatives
O
resin polymer linker - Z - R' / E' - P H
I
O-R3
O
Rz ,/ EZ ,
H
O
II off , ,
resin polymer linker - Z - R' I E' P -I- R2 I EZ
O-R3
2) Imines react to subst. a-aminophosphinic acid derivatives
O
resin polymer - linker - Z - R' / E' - P H
OR3
-R z.,/ E z"
E z" / R a.~
O
II NH R z~~/ E z~.
resin polymer - linker - Z - R' / E' P
O R' R 2~ / E ~.
CA 02306076 2000-04-07
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3) Isocyanates react to substituted aminoacylphosphinic acid
derivatives
O
resin polymer linker Z R' / E' P H
O
OCN-R z~/ E z~
R
p O
Rz,/Ez
II~
resin polymer linker Z R'/ E' P N ~
O H
~R s
4) Michael acceptors react to substituted ethylphosphinic acid
derivatives
(V = electronegative group)
O
resin polymer linker Z R' / E' P H
O
~ ~R3
v
O
II ~~
resin polymer linker Z R'/ E' P
o R 3
CA 02306076 2000-04-07
_29_
5) Halogen compounds react to phosphinic acids or esters thereof
(Arbuzov-type reaction)
0
resin polymer linker Z R' / E' P H
o
\Rs
Hal - R2 / Hal - E2
i
O
resin polymer linker Z R'/ E' P - R2/ E2
OR3
The radicals RZ' and EZ', R2" and E2" shown in the formulae of the reaction
schemes 1 ) to 5) are only parts of those radicals R2 and E2 in the
compounds of the formulae (VII) and (VIII) or (VII)' and (VIII)' which are
introduced at the phosphorus atom in the respective reaction. The
remaining parts of the radicals R2 and EZ lie in the functional groups of the
reactants and have been drawn explicitly in the reaction schemes for
clarification. Therefore, attention has to be paid to the fact that the
radicals
R2' and Ez', Rz" and Ez" are not identical to the radicals RZ and E2 in the
formulae (VII) and (VIII) or (VII)' and (VIII)'.
For all reaction types 1 ) to 5), the phosphorus(III) compounds of the
formulae (IV) can be deprotonated, for example by adding a suitable base
such as, for example, triethylamine, 1,8-diazabicyclo[5.4.0)undec-7-ene
and diisopropylethylamine, or they can be activated by silylations and
subsequently reacted with the abovementioned suitably functionalized
compounds. Corresponding reactions can also be carried out with the
compounds of the formulae (V) and (VI) or (IV)' to (VI)'.
Suitable reagents for silylating the abovementioned compounds are, for
example, trialkylsilyl chlorides/trialkylamines, hexamethyldisilazane,
bistrimethylsilylacetamide and other silylating agents known to the person
CA 02306076 2000-04-07
-30-
skilled in the art.
Possible interactions between functional groups in the organic radicals E',
R', (E')', E2 and RZ have to be taken into account in a manner known to the
person skilled in the art in the selection of the activation reactions by
deprotonation or silylation. There is no general limitation on the radicals in
the compounds of the type (IV), (V) or (VI), (VII) or (IV)', (V)' or (VI)'.
In general, the types of derivatization reactions or reactions where the
radicals E' or EZ described above are converted into radicals R' or RZ are
known, and most can be applied under similar reaction conditions, some
preferred process measures being required by special features of the resin
body. Possible interactions between functional groups in the organic
radicals E' and EZ or (E')' and (E2)' or R' and R2 have to be taken into
account in a manner known to the person skilled in the art in the selection
of the derivatization reactions. There is no general limitation on the organic
radicals in the compounds (VII), (VIII) or (IX) or (VII)' or (VIII)'.
In the manner described, it is possible to prepare, in an orderly fashion,
structure-based substance libraries which are particularly suitable for the
systematic examination of the individual compounds it comprises or
mixtures thereof for biological or physical-technical properties. Depending
on the number of the starting materials of different structure and the
number of different reactions and reaction steps, such a substance library
can contain from one compound to as many compounds as desired. In
particular by the structure of the starting materials, by the reactions and by
the reaction sequence, each of the compounds in a substance library is
structurally defined. The invention therefore also provides the novel
compounds which are contained in the substance libraries according to the
invention.
An example of the preparation of a systematic substance library for test
compounds is shown in scheme 1 (see next page).
CA 02306076 2000-04-07
-31 -
Scheme 1
PS-Wang-OH + HO-CO ~ ~ I ~ PS-Wang-O-CO
1 ) Pd catalyst l
orthoester
0 2) opt. hydrolysis of
i i R=ester to R=H
PS-Wang-O-CO ~ / P-H 3)opt.esterificationto
OR R=ester'
R'-CHO _ O O
PS-Wang-O-CO ~ ~ P
OR R'
_ O O
R'-NCO
-~ PS-Wang-O-CO ~ ~ P
OR N-R'
R'-N=C-R" - ~ N - R'
PS-W ang-O- CO ~ ~ P
O R R"
_ O~X_R'
H2C=CH-XR'
PS-Wang-O-CO ~ ~ P
OR
Hal-R'
--~ PS-Wang-O-CO ~ ~ P-R'
OR
CA 02306076 2000-04-07
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According to Scheme 1, by linking an iodobenzoic acid (here, for example,
p-iodobenzoic acid as compound (XI)) to the resin-linker compound (X)
(here for example a polystyrene-Wang-linker compound) the p-
iodobenzenecarbonyloxy-resin-linker adduct (= compound (II)) is obtained
which, with an alkyl orthoformate under Pd catalysis, affords the
corresponding benzenephosphonous acid-resin-linker adduct (= compound
(IV)). The resin-bound intermediate of the formula (II) according to the
invention is subsequently used for preparing corresponding sub-groups of
phosphinic ester derivatives of the kind shown by addition and substitution
reactions with a series of aldehydes, imines, isocyanates, Michael
acceptors and haloorganic compounds (Scheme 1, R = alkyl).
If the phosphonous ester group is hydrolyzed to the compound of the
formula (V) prior to the reaction of the compound (IV), a corresponding
substance library having resin-bound free phosphonic acids results
(Scheme 1, R = H). Likewise, after renewed esterification of the compound
(V), for example with benzyl alcohol to the compound of the type (VI), a
corresponding substance library having resin-bound free benzyl
phosphinates is obtained (Scheme 1, R = CHZC6H5).
In similar reactions using other resin-linker systems according to Table 1,
for example using a polystyrene-Rink-amide linker, it is likewise possible to
prepare the resin-bound products.
Subsequent to the reactions according to Scheme 1 and similar
derivatizations, the resin-bound products ("scaffold") are advantageously
removed by cleavage of the linker-scaffold bond. The cleavage conditions
depend on the individual linker; generally, they are known from the
literature or can be optimized in preliminary experiments. The cleavage
yields the desired synthesis products of the formula (I). In the case of the
Wang linker and the Arbuzov reaction according to Scheme 1, bottom row,
an alkyl (p-carboxyphenyl)(R')phosphinate of the formula (la)
CA 02306076 2000-04-07
-33-
HO O
P-- R~ (la)
O OR
in which R' is as defined for RZ except hydrogen, is obtained as product
after cleavage using trifluoroacetic acid.
The process variants described offer a wide choice of structures of the
radical Rz in compounds of the formula (I). Of particular interest are
compounds (I) and the resin-bound intermediates mentioned in which
R2 is hydrogen or an aliphatic acyclic or cyclic hydrocarbon radical
having 1 to 20 carbon atoms or heterocyclyl having 3 to 7 ring atoms and
1, 2 or 3 hetero atoms selected from the group consisting of N, O and S,
where the hydrocarbon radical or the heterocyclyl radical is in each case
unsubstituted or substituted by one or more radicals selected from the
group consisting of halogen, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy,
haloalkenyloxy, haloalkynyloxy, alkylthio, amino, nitro, cyano, azido,
alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyl,
alkenylcarbonyl, alkynylcarbonyl, formyl, carbamoyl, mono- and
dialkylaminocarbonyl, acylamino, mono- and dialkylamino, alkylsulfinyl,
haloalkylsulfinyl, alkylsulfonyl and haloalkylsulfonyl, unsubstituted and
substituted cycloalkyl, unsubstituted and substituted cycloalkenyl,
unsubstituted and substituted aryl, unsubstituted and substituted
heterocyclyl, unsubstituted and substituted cycloalkoxy, unsubstituted and
substituted cycloalkenyloxy, unsubstituted and substituted aryloxy,
unsubstituted and substituted heterocyclyloxy, unsubstituted and
substituted cycloalkylamino, unsubstituted and substituted
cycloalkenylamino, unsubstituted and substituted arylamino, unsubstituted
and substituted heterocyclylamino, and in the case of cyclic radicals also
alkyl and haloalkyl.
Preference is given to radicals having lower-chain hydrocarbon (alkyl)
moieties, for example having 1 to 8 carbon atoms, preferably 1 to 6 carbon
atoms, in particular having 1 to 4 carbon atoms.
CA 02306076 2000-04-07
-34-
Preference is also given to compounds (I) and resin-bound intermediates
thereof in which
R2 is a radical of the formula (R2a), (R2b), (RZc), (RZd) or (RZe),
-CHOH-R* (R2a)
-CO-NH-R* (R2b)
-CHR**-N H-R* (Rzc)
_CRaRb_CRcRd_X_Re (RZd)
-R* (R2e)
in which
R* is an an aliphatic acyclic or cyclic hydrocarbon radical having 1 to 12
carbon atoms or heterocyclyl having 3 to 6 ring atoms and 1, 2 or 3
hetero atoms selected from the group consisting of N, O and S,
where the hydrocarbon radical or the heterocyclyl radical is in each
case unsubstituted or substituted by one or more radicals selected
from the group consisting of halogen, alkoxy, alkenyloxy, alkynyloxy,
haloalkoxy, haloalkenyloxy, haloalkynyloxy, alkylthio, amino, nitro,
cyano, azido, alkoxycarbonyl, alkenyloxycarbonyl,
alkynyloxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,
formyl, carbamoyl, mono- and dialkylaminocarbonyl, acylamino,
preferably alkanoylamino, mono- and dialkylamino, alkylsulfinyl,
haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, unsubstituted and
substituted cycloalkyl, unsubstituted and substituted cycloalkenyl,
unsubstituted and substituted aryl, unsubstituted and substituted
heterocyclyl, unsubstituted and substituted cycloalkoxy,
unsubstituted and substituted cycloalkenyloxy, unsubstituted or
substituted aryloxy, unsubstituted and substituted heterocyclyloxy,
unsubstituted and substituted cycloalkylamino, unsubstituted and
substituted cycloalkenylamino, unsubstituted and substituted
arylamino, unsubstituted or substituted heterocyclylamino, and in
the case of cyclic radicals also alkyl and haloalkyl,
R** is a radical selected from the group of the radicals defined for R* or
R* and R** together are an alkylene bridge which is unsubstituted or
CA 02306076 2000-04-07
-35-
substituted by one or more radicals which are, independently of one
another, selected from the group of the substituents at the
hydrocarbon radical for R*, and
Ra, Rb, R~, Rd, RQ independently of one another are in each case a radical
selected from the group of the radicals defined for R* or
Ra, R° or R°, Re or R', Re in pairs are an alkylene bridge
which is
unsubstituted or substituted by one or more radicals which are,
independently of one another, selected from the group of the
substituents at the hydrocarbon radical for R*.
Preference is given to radicals having lower-chain hydrocarbon (alkyl)
moieties, for example having 1 to 8 carbon atoms, preferably 1 to 6 carbon
atoms, in particular having 1 to 4 carbon atoms.
Preferred substituents of particular interest in the general terms such as
"substituted cycloalkyl, aryl, heterocyclyl" are the preferred substituents
mentioned further above in the general definition of substituted radicals.
Further possibilities for variations in the preparation of compounds of the
formula (I) result from the possibility to modify the resin-bound
intermediates of the formula (II). A derivatization of the compound (II) and
its subsequent processing are outlined in an example in Scheme 2 (see
next page).
According to Scheme 2, for example 5-iodoanthranilic acid is linked to a
resin polymer carrying the Wang linker. 5-lodoanthranilic acid contains a
functional group (amino group) which can be derivatized. Instead of
introducing the amino group via anthranilic acid, its preparation is also
possible by reduction of a vitro group. Suitable for the reduction are many
chemical reducing agents suitable for vitro groups, for example metal salts
under acidic conditions, and preference is given to mild reducing agents
which can be employed in organic solvents, for example tin dichloride
dihydrate -HCI or catalytic reductions.
CA 02306076 2000-04-07
-36-
Scheme 2
HZN HzN
PS-Wang-OH + HOOC O ~ PS-Wang - O /
O
I I
R~O
H N~ HN
PS-Wang-O / ~ --~ PS-Wang-O /
I - /H
O O
I O iP\
O-R.
R\ /O
~I/N
PS-Wang- O ~ ~ OH
O
ii P \
O O_R'
The resulting amino compound can be modified further, for example by
(reductive) alkylation or, as shown here, by acylation. The acylation in tum
can be carried out successfully with a large number of acylating agents, for
example with acyl halides or carboxylic acids, if appropriate with addition of
suitable activating reagents such as, for example, triethylamine or
carbodiimides. The process according to the invention is subsequently
employed in the synthesis of the palladium-catalyzed preparation of the
phosphorus-carbon bond. Further derivatization can then be carried out
analogously to Scheme 1, for example the reaction with 4
fluorobenzaldehyde to give the last compound in Scheme 2.
CA 02306076 2000-04-07
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Examples
Abbreviations:
The commercially available polystyrene-Wang-linker compound 4-
hydroxymethylphenyloxymethylpolystyrene resin (Rapp Polymere,
Tiibingen, Germany) is hereinbelow abbreviated to hydroxy-
Wangpolystyrene resin.
DMF - Dimethylformamide
THF - Tetrahydrofuran
TFA - Trifluoroacetic acid
TMS - Trimethylsilane or trimethylsilyl
CHzCl2 - Dichloromethane, Methylene chloride
DBU - 1,8-Diazabicyclo[5.4.0]undec-7-ene
DMSO - Dimethyl sulfoxide
min - minute(s)
h - hour(s)
and other quantitative ratios relate to the weight, unless they are
specifically otherwise defined in the text.
1 ) Preparation of the resin-linker compound
4-lodobenzoyloxy-Wangpolystyrene resin
500 ml of anhydrous methylene chloride were initially charged together
with 12.5 g (15.4 mmol of hydroxyl function) of hydroxy-Wangpolystyrene
resin (200-400 mesh, 1.23 mmol of OH per gram of resin). This
suspension was admixed with 11.44 g (4.6 mmol) of 4-iodobenzoic acid,
0.83 g (6.55 mmol) of dimethylaminopyridine and 10.5 g (83.1 mmol) of
diisopropylcarbodiimide. The suspension was shaken for 3 h and then left
to stand for 16 h. The suspension was filtered and the resin polymer was
washed repeatedly with DMF (5 times), THF (5 times) and methylene
chloride (5 times), in each case a total of 1 I of solvent. The resin polymer
CA 02306076 2000-04-07
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was subsequently washed with 400 ml of diethyl ether. The crude product
was dried under reduced pressure. Yield of crude product: 15.41 g
(82.2%).
2) Preparation of the resin-linker adduct
4-(Ethoxyphosphinoyl)benzoyloxy-Wangpolystyrene resin
(= ethyl phosphonite (IVa))
Under an argon atmosphere, 15.00 g (14.4 mmol of iodoaryl function) of 4-
iodobenzoyloxy-wangpolystyrene resin were suspended in 250 ml of
tetrahydrofuran and admixed with 4.75 g (6.80 mmol) of
bis(triphenylphosphane)palladium(II) dichloride and 17.46 g (172 mmol) of
anhydrous N-methylmorpholine. To this suspension, a solution which had
been prepared as follows was added under an atmosphere of protective
gas:
10.44 g (158.2 mmol) of anhydrous hypophosphoric acid, prepared by
evaporation of 21 g of a 50% strength aqueous solution of this acid and
subsequent drying (1 hour) over 4 A molecular sieves, was stirred in
184.4 g of triethyl orthoformate (1.244 mol) for 2 hours. After the addition,
the suspension was immediately heated to 65°C and kept under reflux for
45 min. The suspension was subsequently cooled under protective gas
and the resin polymer was filtered off and washed with 400 ml of a 5%
strength acetic acid in tetrahydrofuran and subsequently with 600 ml of
tetrahydrofuran, repeatedly with methylene chloride and repeatedly with
diethyl ester. The resin was dried under reduced pressure. Yield of crude
product: 14.53 g (100.14%).
3) Ethyl P-(4-carboxyphenyl)-P-[(4-nitrophenyl)hydroxymethyl)-
phosphinate
300 mg (0.3 mmol) of 4-(ethoxyphosphinoyl)benzoyloxy-Wangpolystyrene
resin were suspended in 2 ml of anhydrous methylene chloride. The
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solution was then cooled to 5°C and 7.50 ml of a 1 M solution of
triethylamine in methylene chloride and then 6.75 ml of a 1 M solution of
trimethylsilyl chloride in methyiene chloride were added. Within 1 h, the
reaction mixture was warmed to room temperature, then filtered under
protective gas and subsequently admixed with 6.0 ml of a 1 M solution of
4-nitrobenzaldehyde in methylene chloride. The mixture was shaken at
room temperature for 2 h and the resin was filtered off and washed
repeatedly with tetrahydrofuran and methylene chloride. The resin was
dried under reduced pressure.
The product is subsequently cleaved off by shaking the resin in a 20%
strength solution of trifluoroacetic acid in methylene chloride for 1 h. After
filtration and concentration of the organic phase, the product is obtained
without any further purification in more then 90% purity. Yield: 100 mg
(92% of theory).
'H-NMR (TMS/DMSO d6):
b (ppm) =1.08 (t, J = 6.9 Hz, 1.8 H, CHZ CH , diastereomer 1 ), 1.10 (t, J =
6.9 Hz, 1.2 H, CH2 CH , diastereomer 2), 3.88 (q, J = 6.9 Hz, 2.6 H, CHZ
CH3, diastereomer 1 ), 3.94 (q, J = 6.9 Hz, 1.4 H, CHZ CH3, diastereomer
2), 5.35 (d, J = 12 Hz, 0.6 H, CH-OH, diastereomer 1 ), 5.43 (d, J = 16 Hz,
0.4 H, CH-OH, diastereomer 2), 6.4 (s br., 1 H, COOH), 7.48 - 7.60 (m, 3H,
aromatic H, 7.72 - 7.83 (m, 3 H, aromatic H) 8.0 - 8.2 (m, 2 H, aromatic H),
8.13 - 8.2 (m, 1 H, aromatic H).
4) Ethyl P-(4-carboxyphenyl)-P-[N-isopropyl-1-aminoethyl]phosphinate
1.00 g (1.0 mmol of P-H-functionality) of 4-(ethoxyphosphinoyl)benzoyloxy-
Wangpolystyrene resin were preswollen with 2 ml of methylene chloride,
then admixed with 2.30 g (22.7 mmol) of triethylamine in 2.0 ml of
methylene chloride and subsequently reacted with a solution of 2.24 g
(20.7 mmol) of trimethylsilyl chloride. The mixture was shaken at room
temperature for 1.5 h, the liquid was filtered off and a solution of 2.55 g
(29.9 mmol) of N-isopropylethaneimine in 4 ml of methylene chloride was
added. The suspension was shaken at room temperature for 3 h. The
suspension was then filtered off and washed repeatedly with methylene
CA 02306076 2000-04-07
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chloride, tetrahydrofuran and finally again with methylene chloride and
diethyl ether.
Yield of crude product: 1.07 g (99%)
The cleavage of 27.3 mg of the crude product with a 50% strength solution
of TFA in dichloromethane gave 9.2 mg of the title product (94.6% yield).
'H-NMR (DMSO-dslTMS):
b (ppm) = 1.05 - 1.45 (m, br., 12H, all CH ), 3.42 (sept., J = 7.0 Hz, 0.6 H),
(CH3)2 CH diastereomer 1 ), 3.60 (sept, J = 7.0 Hz, 0.4 H, (CH3)2 CH
diastereomer 2), 3.90 to 4.20 (m br., 3 H, CH20, P-CH-N), 7.96 (m, 2H,
aromatic H), 8.70 (m, 2H, aromatic H), 9.0 (s. br, 2H COOH, NH)
5) 4-(Hydroxyphosphinoyl)benzoyloxy-Wangpolystyrene resin
(= Phosphonous acid (Va))
7.00 g (6.90 mmol of P-H functionality) of 4-
(ethoxyphosphinoyl)benzoyloxy-Wangpolystyrene resin were initially
charged in 70 ml of tetrahydrofuran and admixed with 312 mg (17.3 mmol)
of water and 5.28 g (34.7 mmol) of DBU. The suspension was shaken at
room temperature for 1 h and filtered and the solid phase was washed with
5% strength acetic acid in THF (5 times 100 ml), with THF (5 times
100 ml), with methylene chloride (5 times 100 ml) and finally with diethyl
ether (2 times). The resin polymer was dried under reduced pressure for
12 h.
Yield of crude product: 7.57 g (112%) of the title compound.
6) P-(4-Carboxyphenyl)-P-(1-isopropyl-1-hydroxymethyl)phosphinic
acid
50 mg (0.05 mmol of P-H-functionality) of 4-
(hydroxyphosphinoyl)benzoyloxy-Wangpolystyrene resin were admixed
with 1 ml of methylene chloride. After 30 min, 1.1 ml of a 1 M solution of
triethylamine in methylene chloride were added and the mixture was
CA 02306076 2000-04-07
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subsequently admixed with 1 ml of a 1 M solution of trimethylsilyl chloride
in methylene chloride. The mixture was shaken at room temperature for
30 min and the liquid was filtered off and admixed with 1 ml of a 1 M
solution of isobutyraldehyde in methylene chloride and shaken at room
temperature for 1 h. The liquid was then filtered off and the resin was
washed with THF (10 times) and methylene chloride (10 times). The resin
was subsequently treated with 5 ml of 50% strength trifluoroacetic acid in
methylene chloride for 30 min and filtered. The filtrate was concentrated.
Yield of crude product: 14 mg of the title compound (108%).
'H-NMR (DMSO-ds/TMS):
a (ppm) = 0.95 (d, J = 11 Hz, 3 H, CH -CH, rotational isomer 1 ), 0.98 (d, J
= 11 Hz, 3H, CH -CH, rotational isomer 2), 1.95 (sept, J = 11 Hz, 1 H
(CH3)2 CH-), 3.50 (t, J = 6 Hz, CH-OH), 4.0 - 5.0 (s br., 3 H, COOH, POH
and CH-OH), 7.8 (m, 2H, aromatic H), 8.0 (m, 2H, aromatic H)
7) P-(4-Carboxyphenyl)-P-{1-(4-chlorophenyl)-1-hydroxymethyl)-
phosphinic acid
The process was carried out similarly to the process described in Example
6, except that the aldehyde used was 4-chlorobenzaldehyde. Yield of
crude product: 17.3 mg of title compound (105.8%).
'H-NMR (DMSO, TMS):
i5 (ppm) = 4.0 {s, br, 3 H, COOH, P-OH, C-OH), 4.93 (d, J = 11.2 Hz, 1 H,
CH-O), 7.24 (m, 4H, aromatic H), 7.72 (m, 2H, aromatic H), 7.98 (m, 2H,
aromatic H).
8) P-{4-Carboxyphenyl)-P-(2-ethoxycarbonylethyl)phosphinic acid
50 mg (0.05 mmol of OH functionality) of 4-
(hydroxyphosphinoyl)benzoyloxy-Wangpolystyrene resin were admixed
with 1 ml of methylene chloride and then reacted at room temperature for 1
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hour with 392 mg (19 mmol) of bistrimethylsilylacetamide dissolved in 2 ml
of methylene chloride. The liquid was filtered off and the reaction described
above was repeated. The filter resin was then treated with 1 ml of 1 M
solution of ethyl acrylate in methylene chloride and stood at room
temperature for 16 h. The liquid was filtered off and, the resin was washed
with THF (10 times) and methylene chloride (10 times). The resin was then
reacted with a 50% strength solution of trifluoroacetic acid in methylene
chloride for 30 min. Concentration of the filtrate gave the crude product in a
purity of more than 90%; yield: 17.5 mg (122%).
'H-NMR (DMSO-d6 / TMS):
b (ppm) = 1.12 (t, 7.2 Hz, 3H, CHZ CH3), 2.04 (m, 2H, CH -COOEt), 2.38
(m, 2H, CH2 CHzCOOEt), 3.98 (q, J = 7.2 Hz, OCH2 CH3), 7.82 (m, 2H,
aromatic H), 8.06 (m, 2H, aromatic H).
9) P-(4-Carboxyphenyl)-P-[N-benzy?-1-isopropylaminomethyl]-
phosphinic acid
The process was carried out exactly like the process described in Example
8. Instead of the aldehyde solution, 15 ml of a C.5 molar solution of N-
benzylisopropylmethaneimine in methylene chloride were added and the
mixture was stirred at room temperature for 3 h. The liquid was filtered off
and the resin was washed with methylene chloride (10 times), THF (10
times) and again with methylene chloride (10 times). The cleavage was
carried out by reacting the resin with 3 ml of a 50% strength solution of
trifluoroacetic acid in methylene chloride for 30 minutes.
Concentration of the solution gave the crude product in a purity of more
than 90%.
Yield of the crude product: 22 mg (126%).
'H-NMR (DMSO-d6 / TMS):
a = 0.82 (d, J = 8.0 Hz, 3H, CH -CH-CH3), 0.98 (d, J = 7.0 Hz, 3H, CH3 CH-
CH3), 2.10 (m, 1 H, (CH3)ZCH), 3.06 (dd, JPH = 12.4 Hz, J~_H = 4 Hz, 1 H, P-
CH-C), 4.34 (AB-spectrum, JHAHB = 12.0 Hz, 2H, CH2 N), 7.4 (m, 5H,
CA 02306076 2000-04-07
- 43 -
aromatic H), 7.82 (m, 2H, aromatic H), 8.06 (m, 2H, aromatic H).
10) 2-Amino-5-iodobenzoyloxy-Wangpolystyrene resin
Under an atmosphere of protective gas, 15.0 g (18.5 mmol) of hydroxyl-
Wangpolystyrene resin (200 - 400 Nm, Rapp Polymere) were suspended in
200 ml of anhydrous methylene chloride. 14.56 g (55 mmol) of
iodoanthranilic acid, 12.58 g (99.6 mmol) of diisopropylcarbodiimide and
0.990 g (8.10 mmol) of 4-N,N-dimethylaminopyridine were then added and
the suspension was shaken for 24 h. The resin was filtered off and washed
5 times with a total of 2 I of DMF, 5 times with a total of 1 I of THF and
repeatedly with a total of 1 I of methylene chloride. The solid was then
washed twice with ether and thoroughly dried under reduced pressure.
Yield: 18.58 g (94.9%).
11 ) 2-Isopropylcarbonylamino-5-iodobenzoyloxy-Wangpolystyrene resin
550 mg (0.52 mmol) of 2-amino-5-iodobenzoyloxy-Wangpolystyrene resin
were suspended in 15 ml of anhydrous methylene chloride, cooled to 0°C
and subsequently admixed with 526 mg (5.2 mmol) of triethylamine and
554 mg of isobutyryl chloride. The reaction solution had warmed to room
temperature. After 16 h of stirring the solid phase was then filtered off and
washed fifteen times with methylene chloride and three times with ether.
Yield: 530 mg = 90.4%.
12) 5-Ethoxyphosphinoyl-2-isopropylcarbonylaminobenzoyloxy-
Wangpolystyrene resin
0.500 g (0.443 mmol of aryliodide functionality) of 2-
isopropylcarbonylamino-5-iodobenzoyloxy-Wangpolystyrene resin were
suspended in 5 ml of anhydrous THF under an atmosphere of argon and
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admixed with 0.538 g (5.30 mmol) of N-methylmorpholine and 0.146 g
(0.208 mmol) of bis(triphenylphosphane)palladium(II) dichloride. A solution
that had been prepared as follows was subsequently added to this
suspension:
0.320 g (4.90 mmol) of crystalline hypophosphoric acid were, dried for one
hour under an atmosphere of protective gas using 4 A molecular sieves
and stirred with 5.68 g (38.3 mmol) of triethyl orthoformate for 2.5 h. This
solution was added to the suspension described above which was then
rapidly heated to reflux temperature for 1 h. The reaction mixture was then
quickly cooled, washed ten times with a 5% strength solution of acetic acid
in tetrahydrofuran, ten times with methylene chloride and finally three times
with diethyl~ether. The resulting resin was dried under reduced pressure;
yield of crude product: 458 mg (94.5%).
A trial cleavage using 50 mg of resin (1 h, 20% strength trifluoroacetic
acid/methylene chloride) gave 17.3 mg (105%) of crude product.
'H-NMR (DMSO-ds/TMS)
b (ppm) = 1.08 (d, J = 8.0 Hz, 6H, (CH )2CH), 1.23 (t, J = 5.6 Hz, 3H, CHZ
CH ), 2.60 (sept, J = 8.0 Hz, 1 H, (CH3)CH), 4.07 (m, 2H, P-O-CHZ), 7.55 (d,
J = 576 Hz, 1 H, P-H), 7.83 (m, 1 H, aromatic H), 8.35 (m, 1 H, aromatic H),
8.73 (m, 1 H, aromatic H).
13) Ethyl P-(3-carboxy-4-isopropylcarbonylaminophenyl)-P-(pyrid-4-yl-
hydroxymethyl)phosphinate
50 mg (0.046 mmol of P-H functionality) of 5-ethoxyphosphinoyl-2-
isopropylcarbonylaminobenzoyloxy-Wangpolystyrene resin were
suspended in 1 ml of methylene chloride and admixed with 1.1 ml of a 1 M
solution of triethylamine in methylene chloride and 1.0 ml of a 1 M solution
of trimethylsilyl chloride in methylene chloride. The solution was shaken for
30 min and then filtered off and admixed with 1 ml of a 1 M solution of
nicotinaldehyde in methylene chloride. After 1 h of reaction at room
temperature, the reaction solution was filtered off, the resin [lacuna] ten
CA 02306076 2000-04-07
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times with tetrahydrofuran and methylene chloride and the product was
liberated from the resin by cleaving for 30 min using 50% strength
trifluoroacetic acid in methylene chloride. The crude product was
concentrated using a rotary evaporator and obtained in a purity of more
then 95% as a glass-like material. Yield: 21 mg (96%).
'H-NMR (DMSO-d6/TMS):
b (ppm) = 1.13 (t, 6.4 Hz, 2H, O-CHZ CH diastereomer 1 ), 1.18 (d, 7 Hz,
6H, (CH )2CH), 1.23 (t, 6.4 Hz, 1.8 H, OCHZCH3, diastereomer 2), 2.60
(sept, J = 7. Hz, 1 H, (CH3)2 CH), 3.89 (quart, J = 8.0 Hz, 0.8 H, CHZ CH3,
diastereomer 1 ), 4.06 (quart, J = 8.0 H2, 1.2 H, CH2 CH3, diastereomer 2),
5.43 (d, J =.12.8 Hz, 0.4 H, P-CH diastereomer 1 ), 5.60 (d, J = 16.0 Hz, 0.6
H, P-CH diastereomer 2), 7.97 (m, 2H, aromatic H, 7.80 (m, 1 H, aromatic
H), 8.28 (m, 1 H, aromatic H), 8.64 (m, 1 H, aromatic H), 8.76 (m, 2H,
aromatic H), 11.4 (s, 1 H, COOH).
14) N-(4-lodobenzoylamino)-Rink-amide-polystyrene resin
The Fmoc group was removed from 10.00 g (7.8 mmol of NH functionality)
of Fmoc-Rink-amide-polystyrene resin by shaking the resin with 100 ml of
a 20% strength piperidine/DMF solution for 30 minutes, followed by
filtration. The process was repeated once more and the resin was then
washed thoroughly with DMF. The resin was resuspended in 120 ml of
DMF and admixed with 6.15 g (25.0 mmol) of 4-iodobenzoic acid, 3.20 g
(25.0 mmol) of diisopropylcarbodiimide and 3.33 g (25.0 mmol) of
1-hydroxybenzotriazol. The mixture was shaken for 4 hours and the resin
was then filtered off and subsequently washed five times each with DMF,
THF and methylene chloride. The resin was dried under reduced pressure.
Yield of crude product: 9.80 g (99% of theory) of the title compound.
CA 02306076 2000-04-07
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15) N-[4-(ethoxyphosphinoyl)benzoyl]-Rink-amide-polystyrene resin
Under an atmosphere of argon, 1.00 g (0.77 mmol of iodoaryl function) of
N-(4-iodobenzoyl)-Rink-amide-polystyrene resin was suspended in 10 ml
of anhydrous tetrahydrofuran and admixed with 258 mg (0.370 mmol) of
bistriphenylphosphanepalladium(II) dichloride and 1.00 ml (9.09 mmol,
0.92 g) of anhydrous N-methylmorpholine. Under an atmosphere of
protective gas, this suspension was admixed with a solution which had
been prepared as follows:
0.55 g (8.3. mmol) of anhydrous hypophosphoric acid, prepared by
evaporation of 1.1 g of a 50% strength aqueous solution of this acid and
drying for one hour over a 4 A molecular sieve, and 10.0 g (67.5 mmol) of
triethyl orthoformate were stirred together for 2 h.
After the addition of the resulting solution, the suspension was immecJiately
heated to 65°C and kept at reflux for 45 min. The mixture was
subsequently cooled under protective gas and the resin polymer was
filtered off and washed with 50 ml of a 5% strength acetic acid in
tetrahydrofuran and subsequently with 150 ml of tetrahydrofuran,
repeatedly with methylene chloride and repeatedly with diethyl ether. The
resin was dried under reduced pressure. Yield: 0.950 g (97% of theory) of
the title compound.
16) Ethyl P-(4-aminocarbonylphenyl)-P-[(4-fluoro-
phenyl)hydroxymethyl]phosphinate
50 mg (0.063 mmol of P-H functionality) of N-[4-(ethoxy-
phosphinoyl)benzoyl)-Rink-amide-polystyrene resin were admixed with
1.5 ml (1.5 mmol) of a 1 M solution of 1,8-diazobicyclo[5.4.0]undec-7-ene
(DBU) in dichloromethane. After 15 min, the solution was filtered off and
[lacuna] was admixed with 1.5 ml of a 1 M solution of 4-fluoro-
benzaldehyde in dichloromethane. After 1 h of shaking at room
temperature, the resin was filtered off and washed repeatedly with
tetrahydrofuran and dichloromethane. The resin was dried under reduced
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pressure. The product was subsequently cleaved off by shaking the resin
in a 20% strength solution of trifluoroacetic acid in dichloromethane for 1 h.
Filtration and concentration of the organic phase gave the product without
any further purification in a purity of more than 90%. Yield: 11 mg (82% of
theory).
'H-NMR (DMSO-d6ITMS):
b (ppm) = 1.18 (t, J = 6.9 Hz, 3H, CHZ CH , diastereomer 1 ), 1.19 (t, J =
6.9 Hz, 3H, CH2-CH , diastereomer 2), 3.85 (q, J = 6.9 Hz, 2H, CHZ CH3,
diastereomer 1 ), 3.91 (q, J = 6.9 Hz, 2H, CH2 CH3, diastereomer 2), 5.10
(d, J = 12 Hz, 1 H, CH-OH, diastereomer 1 ), 5.22 (d, J = 15 Hz, 1 H, CH-
OH, diastereomer 2), 7.10 (t, J = 6 Hz, 2H, aromatic H), 7.31 (m, 2H,
aromatic H), 7.55 (s, brd, 1 H, NH), 7.7 (m, 2H, aromatic H), 7.91 (m, 2H,
aromatic H), 8.12 (s, brd, 1 H, NH).
17) Synthesis of a substance library according to Scheme 1 and
Scheme 2
The systematic synthesis of substance libraries is possible using the
experimental procedure described in the text above. Starting from 5-
iodoanthranilic acid which is bound to a polymer via the carboxylic acid
function and the Wang linker, a substance library was synthesized by the
following stepwise reactions:
The compound of the formula
HZN
PS-Wang - O /
I
O I
was reacted with the acylating agents acetyl chloride, propionyl chloride,
isopropylcarbonyl chloride and cyclohexylcarbonyl chloride to give the four
different N-acyl compounds. The palladium-catalyzed reaction with
CA 02306076 2000-04-07
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bis(triphenylphosphane)palladium(II) dichloride with hypophosphoric acid
and triethyl orthoformate similar to Example 2 gave the four ethyl
phosphonites according to the formula (IV), and subsequent hydrolysis
gave the four phosphonous acids according to the formula (V). The eight
resulting phosphorus-containing resin-linker adducts according to (IV) and
(V) were in each case reacted with 10 different aldehydes and 10 different
isocyanates according to Tables A and B:
Table A: Aldehydes of the formula (A1 )
H-CO-R* (A1)
No. R*
1 Phenyl
2 4-Chlorophenyl
3 4-Methoxyphenyl
4 3,4-Dichlorophenyl
5 2-Chlorophenyl
6 2,4-Dichlorophenyl
7 2-Fluorophenyl
8 3-Bromo-4-fluorophenyl
9 2-Methoxyphenyl
10 2,6-Dichlorophenyl
CA 02306076 2000-04-07
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Table B: Isocyanates of the formula (A2)
O=C=N-R* (A2)
No. R*
1 4-Chlorophenyl
2 3,4-Dichlorophenyl
3 3,5-Dichlorophenyl
4 2,4-Dichlorophenyl
5 4-Bromophenyl
6 4-Isopropylphenyl
7 1-Naphthyl
8 3-(2,2-Dichloro-1,1-difluoroethoxy)phenyl
9 3-Methoxycarbonylphenyl
. 10 2-Butoxyphenyl
The substance library which was obtained, comprising 160 resin-linker
adducts of the formula (IX)
[resin polymer]-[linker-Z-R'-P(RZ)(=O)-O-R3]~ (IX)
in which R2 is a radical of the formulae (R2a) or (R2b),
-CHOH-R* (R2a)
-CO-NH-R* (R2b)
in which R* is as defined by Tables A or B, and the remaining radicals and
groups are as defined above,
was cleaved using 20% strength trifluoroacetic acid in methylene chloride,
and a further substance library comprising 160 compounds of the formula
(Ib)
CA 02306076 2000-04-07
-50-
i cyl
HN
HO ( ~ O
P- R2 (Ib)
i
O O~ s
R
in which
Acyl = Acetyl, propionyl, isopropylcarbonyl or cyclohexylcarbonyl,
R2 - (R2a) or (R2b), which are the 20 different radicals mentioned,
R3 = H or ethyl and
Y = COOH
was obtained.
