Solid phase supports

Details Solid phase supports Solid phase supports

2000-04-17

2002-11-26

Venkat, Jyothsna (Department: 1627)

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

Organic compounds

Sulfur containing

C435S007100, C435S007200, C435S091500, C435S091500, C436S501000, C436S518000, C530S333000, C530S334000, C530S335000, C540S139000, C568S028000, C568S032000, C568S621000, C568S622000, C568S623000

Reexamination Certificate

active

06486354

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to carrying out organic chemistry on solid supports comprising derivatised functionalities, methods for synthesising said supports, methods for synthesising compounds comprising amine groups or N-containing heterocycles using said solid supports, intermediate compounds linked to said supports and uses therefor. In particular, the invention relates to solid supports comprising derivatised amide or sulphone groups, methods for synthesising said supports, methods for synthesising compounds comprising tertiary amine groups or N-containing heterocyclic compounds using said supports and intermediate compounds comprising quaternary ammonium groups linked to said supports and uses therefor.
BACKGROUND OF THE INVENTION
Solid phase chemistry is well known in the art, particularly in the fields of peptide and oligonucleotide synthesis. Advantages associated with solid phase synthesis include the ability to drive reactions to completion by use of excess reagents, ease of work up and potential automation of synthetic procedures. Organic compounds have traditionally been attached to the solid support by certain cleavable linker groups which yield, on cleavage, compounds in which polar functionality remains at the point of attachment, for example a CO
2
H, OH, NH
2
, CONH
2
or a CONHR group. The synthesis of non-oligomeric organic compounds using resin-bound synthetic routes is a key component of the emerging technology of combinatorial chemistry (Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A.
J. Med. Chem.
1994, 37, 1385-1401; Lowe, G.
Acc. Chem. Res.
1995, 24, 309-317; Fruchtel, J. S.; Jung, G.
Angew. Chem. Int. Ed. Engl.
1996, 35, 17-42).
One of the current limitations of this approach is the requirement for a “handle” to link small organic molecules onto a polymeric resin. In Merrifield peptide synthesis, for example, a carboxylic acid is linked via an ester group. Recently the range of linkers has increased (Fruchtel, J. S., and Jung G. supra).
Morphy J. R. et al.
Tetrahedron Letters,
1996, 37, 3209-3212 report a novel linker strategy and describe a new type of linker and release system for resin-bound synthesis which is based upon Michael addition and Hofmann elimination (&bgr;-elimination) reactions. The synthetic route is outlined in the following Scheme below:
where R
1
, R
2
R
3
each represent an alkyl group and X is Br or I. Where
3
a
is a secondary amine (R
2
=H), conversion to a tertiary amine is achieved by reductive alkylation on the resin using a suitable aldehyde and NaBH(OAc)
3
in 1% acetic acid/dimethylformamide for 18 hours at 20° C.
The outlined synthetic route above utilises hydroxymethyl polystyrene resin derivatised with acryloylchloride to the acrylate ester 1. Michael addition of a secondary amine 2 gives the resin-bound tertiary amine 3. Alternatively, a primary amine 2 (R
2
=H) gives a resin-bound secondary amine which is converted into the tertiary amine 3 (R
2
=alkyl) by reductive alkylation. Quaternisation of the tertiary amine 3 with an alkyl halide 4 to give 5 introduces another site of diversity and activates the linker for cleavage by a facile Hofmann elimination reaction. Thus iPr
2
NEt (diisopropylethylamine; DIEA) at room temperature liberates the tertiary amine 6 into solution and regenerates the resin 1.
Since the resin linker 1 is regenerated after cleavage of the product and is functionalised via a Michael reaction, the resin is referred to as a REM resin (Morphy, supra).
A disadvantage of the above outlined reaction is that the ester derivatised resin, in this case originating from an acrylate ester, can be unstable under certain reaction conditions such as strong acid, strong base, or others reaction conditions including reagents such as Grignard reagents, and reducing agents such as LiAlH
4
and the like. In such reaction conditions, cleavage at the ester bond may occur. Thus, the general applicability of the ester derivatised resin can be limited. and as a consequence, the solid phase synthesis of desired amine-containing compounds or N-containing heterocyclic compounds may not be realised.
SUMMARY OF THE INVENTION
The present invention seeks to mitigate against the disadvantages associated with the prior art and to provide derivatised solid supports which are stable to a wide range of chemistries and whereon a broad scope of amines or N-heterocyclic containing compounds can be prepared utilising the Hoffmann elimination reaction, as described above, to release the amines from the solid supports.
DETAILED DESCRIPTION OF THE INVENTION
According to a first variant of the invention there is provided a solid support comprising a functionalised amide according to Formula (I).
wherein
represents the solid support;
B is a conventional spacer arm or a bond;
R is selected from H, (C
1
-C
6
)alkyl, optionally substituted with halogen. aryl(C
1
-C
6
)alkyl and aryl, optionally substituted with (C
1
-C
6
)alkoxy, OH or halogen;
W is selected from O and S;
Y is CHR
4
where R
4
is selected from H, (C
1
-C
4
)alkyl, optionally substituted with halogen, and phenyl, optionally substituted with CF
3
, (C
1
-C
6
)alkoxy;
Z is CR
5
R
6
—L where R
5
and R
6
are independently selected from H, (C
1
-C
4
)-alkyl, and phenyl; L is a leaving group; or
Y and Z together form CR
4
═CR
5
R
6
wherein R
4
and R
5
are as defined above, or wherein R
4
and R
5
together with the carbon atoms to which they are bonded form a (C
4
-C
8
)cycloalkene ring.
The term (C
1
-C
6
)-alkyl as used in the definition of formula I means a straight or branched-chain alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, pentyl and hexyl.
The term (C
1
-C
4
)alkyl means, likewise, a straight or branched-chain alkyl group having 1-4 carbon atoms.
The term (C
1
-C6)alkoxy means a (C
1
-C
6
)alkyloxy group, wherein (C
1
-C
6
)alkyl has the previously given meaning. A preferred (C
1
-C
6
)alkoxy group is methoxy. Preferred (C
1
-C
6
)alkoxy substituted aryl groups are 2-methoxyphenyl and 4-methoxyphenyl.
The term halogen means F, Cl, Br or I.
The term aryl means an aromatic ring system having from 6-12 carbon atoms, such as for example phenyl and naphthyl; a preferred aryl group is phenyl.
The term aryl(C
1
-C
6
)alkyl as used in the definition of formula I means an aryl group, having the meaning as previously defined, linked to a (C
1
-C
6
)alkyl group as previously defined, such as benzyl (phenylmethyl).
The term (C
4
-C
8
)cycloalkene ring, as used in the definition of formula I means a cycloalkene ring having 4-8 carbon atoms, like cyclobutene, cycloheptene, cyclohexene, cycloheptene and cyclooctene.
The term leaving group is known in the art of substitution reactions (Advanced Org. Chem (1992) (4th Ed.) March J, p 352, Wiley and Sons). Examples of well known leaving groups are Cl, Br, I, tosyloxy, mesyloxy, trifluoromethanesulphonyloxy, trifluoroethanesulphonyloxy (tresyloxy) and the like.
The conventional spacer arm B, as used in the definition of Formula I, means a chemical structure linking (or interspaced between) a functional group to the backbone structure of the solid support. B may be any conventional spacer arm commonly employed in solid phase organic chemistry. For instance, the spacer arm B of a chloromethylated or an aminomethylated polystyrene divinylbenzene (Merrifield) resin, is the methylene, —CH
2
— group. Further examples of spacer arms B are (CH
2
)
n
, CH
2
(OCH
2
CH
2
)
n
wherein n=0, 1, 2, 3 or 4, CH
2
C(CH
3
)(PEG)
2
, PEG (polyethyleneglycol)-CH
2
and the like. Examples of these and other suitable spacer arms can be found in The Combinatorial Chemistry Catalog, February 1997 (NovaBiochem) pp1-37.
In a preferred embodiment of the first main aspect of the invention, B is selected from (CH
2
)
n
and CH
2
(OCH
2
CH
2
)
n
and n is 0, 1 or 2; R is selected from H, (C
1
-C
4
)alkyl and phenyl; W is O; and Y and Z together form CR
4
═CR
5
R
6
wherein R
4
, R
5
and R
6
are independently selecte

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