Solid phase nitrile synthesis

Details Solid phase nitrile synthesis Solid phase nitrile synthesis

2002-08-13

2003-12-16

Lambkin, Deborah C. (Department: 1626)

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

Organic compounds

Nitriles

C558S311000

Reexamination Certificate

active

06664410

ABSTRACT:

This invention relates to solid phase nitrile synthesis and particularly, although not exclusively, provides a method of preparing a nitrile compound.
An object of the present invention is to provide an advantageous method of preparing a nitrile compound.
According to the invention, there is provided a method of preparing a nitrile compound, the method comprising treating a solid supported amide to cause formation of the nitrile compound and cleavage from the support.
Thus, there is suitably provided a solid phase reaction which allows formation of nitrites with concomitant release of the solid support. Preferably, in the method, the amide is dehydrated. Preferably the amide is treated such that cleavage and dehydration of the amide are accomplished in one operation.
Said nitrile compound is preferably of formula RCN where R represents an optionally-substituted alicyclic, aliphatic or aromatic (which includes heteroaromatic) group.
Except where otherwise stated in this specification, an alicyclic group may have five or six carbon atoms; it preferably has six. Such a group may be optionally-substituted by any atoms or groups hereinafter described. Additionally, a said alicyclic group may be optionally substituted by forming a polycyclic, for example bicyclic, ring system with other cyclic or aromatic groups. In one embodiment, an alicyclic group may form a bicyclic ring system with a five or six-member aromatic group, an example of this arrangement being a tetrahydronaphthyl group.
Except where otherwise stated in this specification, optional substituents of alicyclic, aliphatic and aromatic groups include halogen atoms for example fluorine, chlorine or bromine atoms and optionally-substituted phenyl, nitro, cyano, alkoxy, hydroxy, amino, alkylamino, sulphinyl, alkylsulphinyl, sulphonyl, amido, alkylamido, alkoxycarbonyl, haloalkyoxycarbonyl and haloalkyl groups. optional substituents, especially nucleophilic groups, also include protected forms of any of the aforesaid.
Except where otherwise stated in this specification, an aliphatic group suitably has up to 8, preferably up to 6, more preferably up to 4, especially up to 2, carbon atoms and may be of straight chain or, where possible, branched chain structure.
Except where other stated in this specification, an aromatic group may include a monocyclic or polycyclic (fused) aromatic ring system. Any aromatic ring of such a system may include one or more heteroatoms selected from nitrogen, oxygen and sulphur atoms. Preferred monocyclic or polycyclic groups include five or six ring atoms.
Where R represents an alicyclic group, it is preferably an optionally-substituted group which includes six ring atoms. Preferably said alicyclic group is substituted so as to define a polycyclic group, especially a bicyclic group, suitably wherein one ring thereof is aromatic. An especially preferred alicyclic group is an optionally-substituted, preferably unsubstituted, tetrahydronaphthyl group.
Where R represents an aliphatic group, such a group is preferably substituted. It may be substituted, preferably monosubstituted, suitably by an amino, or a derivative of an amino (especially a protected) group or an optionally-substituted aromatic group. Examples of protected amino groups include Fmoc- and Boc-protecting groups. A preferred aliphatic group R is of formula
wherein X is a substituent, especially a protected amino group and R
1
is an optionally substituted alkyl (preferably a C
1-8
, more preferably C
1-4
alkyl, especially a methyl) group.
Examples of aliphatic groups optionally-substituted by an aromatic group include a C
1-8
, preferably a C
1-6
, more preferably a C
1-4
, especially a C
1-2
, alkyl group substituted by an optionally-substituted, especially an unsubstituted, phenyl group. A preferred such group is a phenylethylyl group.
Where R represents an aromatic group, it preferably represents an optionally-substituted phenyl or optionally-substituted bicyclic (fused) group. A preferred optionally-substituted phenyl group is substituted by any of the substituents described above, the preferred ones of which include an optionally-substituted phenyl group or a nitro, alkoxy (suitably a C
1-8
, preferably C
1-6
, more preferably C
1-4
, especially a C
1
, alkoxy) group. A preferred bicyclic (fused) group comprises a benzo moiety fused to a five-membered heteroaromatic moiety and preferably represents a benzoheterophenyl (e.g. benzothiophenyl) group.
Preferably, group R incorporates an aromatic moiety and/or an amino group, especially a protected amino group. More preferably, group R incorporates an aromatic moiety.
Said amide may be of formula
RCONR
2
-SS  II
wherein R
2
is a hydrogen atom or an optionally-substituted alkyl group and SS represents a solid support.
R
2
is preferably a hydrogen atom.
SS preferably includes a moiety of formula
wherein the free bond is bonded to the nitrogen atom in the amide of formula II and wherein R
3
, R
4
and R
5
, independently represent a hydrogen atom or an optionally-substituted alkyl or aromatic group, provided that at least one of groups R
3
, R
4
, or R
5
represents an optionally-substituted aromatic group. Atoms or groups on one of R
3
R
4
or R
5
may be bonded to another one of R
3
R
4
or R
5
so that bridging atoms or groups are defined between a part of one of R
3
, R
4
or R
5
and a part of another of R
3
, R
4
or R
5
Preferably, R
5
represents a hydrogen atom or an optionally-substituted, especially an unsubstituted, alkyl group. More preferably, R
5
represents a hydrogen atom.
Preferably, R
3
does not represent a hydrogen atom. Preferably, R
3
represents an electron-donating group. R
3
preferably represents an optionally-substituted aromatic group. R
3
may be optionally-substituted by one or more electron donating groups, for example by alkoxy, preferably C
1-4
, more preferably C
1-2
, especially methoxy, groups. Preferably, R
3
represents an optionally-substituted phenyl group. R
3
may be optionally-substituted by a bridging atom or group which defines a bridge between groups R
3
and R
4
Wherein R
3
is substituted, it is preferably substituted in the ortho- and/or para-position(s).
Preferably, R
4
does not represent a hydrogen atom. Preferably, R
4
represents an electron-donating group. R
4
preferably represents an optionally-substituted aromatic group. R
4
may be substituted by one or more electron-donating groups, for example by a group incorporating an —O— moiety. Preferably R
4
, represents an optionally-substituted phenyl group. Where a bridge is defined between groups R
3
and R
4
said bridge may be defined by —O— or —S— moieties, especially by an —O— moiety which suitably forms with part of groups R
3
and R
4
a component of a six-membered ring. Where R
4
is substituted, it is preferably substituted in the ortho and/or para position(s).
Preferably, one of R
3
and R
4
, more preferably R
4
, is linked to a polymer support.
In one embodiment, SS may represent
wherein PS represents a polymer-support and the free bond between the phenyl groups represents the point of attachment to the nitrogen atom in formula II.
In another embodiment, SS may represent
where the free bond is as described above.
Preferably the method comprises treating said solid supported amide to cause formation of the nitrile compound and cleavage of it from the support.
Preferably, in the method, formation of the nitrile compound and cleavage of it from the support occur substantially concurrently.
Preferably, preparation of said nitrile compound involves dehydrating said solid supported amide. In the preparation of the nitrile compound, the amide may be acetylated, suitably by trifluoroacetylation, which suitably allows cleavage/dehydration in one operation. Dehydration may be undertaken in the presence of a base. Preferred dehydrating agents are highly electrophilic and may include: a nitrogen-containing base, for example an aromatic nitrogen containing base such as pyridine; an acid halide, especially an acid chloride and preferably one including an electron withd

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