Dye intermediate and method

Details Dye intermediate and method Dye intermediate and method

2000-04-24

2002-10-01

Ceperley, Mary E. (Department: 1641)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C435S006120, C436S527000, C436S546000, C530S391500, C530S409000, C546S165000, C546S192000, C546S208000, C546S277400, C562S041000, C562S045000, C562S087000, C564S287000

Reexamination Certificate

active

06458966

ABSTRACT:

Dyes have applications in many technologies, both new and well established, which count amongst them textile dyeing, optical data storage media and various detection methods, for both chemical and biological use. Within these applications various properties of the dyes are exploited in their actual detection which may ultimately be traced back to absorption, reflectance and luminescence (chemiluminescence, fluorescence and phosphorescence). However, a recurring theme of many applications is the need to form a relatively permanent link, in the form of a covalent bond, between the dye and the substrate of choice. The substrate may be inter alia: a relatively inert surface or probe possibly of insoluble polymeric origin; a macromolecule of biological origin e.g. a protein, antibody or oligonucleotide; or a small molecule of either biological or synthetic origin e.g. a hapten for use in directed or molecular recognition based applications; or a molecule which may modify the properties of the dye e.g. a water solubilising group such as a carbohydrate or other polar residues; or a species which protects the dyes from or decreases the rate of photofading of the dye, such as hindered amines and various transition metal complexes; or possibly another dye conjugate system thus enabling the possibility of energy transfer or fluorescence quenching based applications. The requirement for a covalent linkage means that many commercial products, spanning a large range of dye classes and possessing the desired spectral properties, cannot be used. This therefore necessitates either the modification of an existing product or the complete synthesis from appropriate materials such that a suitable grouping is available for linking the dye and substrate. There are many different sorts of linkage known, the main requirements being that the linkage is relatively stable and that it is easily introduced in high yield or efficiency. One of the most versatile groupings is that of the carboxylic acid which is readily converted to a range of reactive species or used to form a link to another substance containing the reactive linking species of choice.
This invention is concerned with a relatively simple and easily prepared dye intermediate and its use for preparing a range of dyes particularly fluorescent dyes having reactive groups by which they can be linked to various substrates. The intermediate is a m-aminophenol having the formula (I)
Where
R
1
is —R
a
R
b
, where R
a
is C
1
-C
10
alkylene or aralkylene which may optionally contain 1 to 4 oxygen, nitrogen or sulphur atoms in a straight or branched chain, and R
b
is carboxy including acid, is salt, ester including N-hydroxysuccinimide, activated ester or amide,
R
2
, R
3
, R
4
and R
5
are the same or different and each is: H; or C
1
-C
10
alkyl or aralkyl which may optionally contain 1 to 4 oxygen, nitrogen or sulphur atoms in a straight or branched chain; or R
c
where R
c
is a group to modify solubility, or a group to modify electronic and/or spectral properties, or a functional linking group; or —R
a
R
c
wherein R
a
and R
c
are herein defined,
or R
4
-R
5
and/or R
2
-R
4
and/or R
2
-R
3
are linked to form an extended ring system, carbocyclic or heterocyclic, aromatic or aliphatic which is unsubstituted or substituted as above,
R
6
is H or —CR
9
O or N—O.
R
9
is H, C
1
-C
6
alkyl phenyl or R
a
R
c
wherein R
a
and R
c
are herein defined.
R
1
may be different or the same as R
2
.
R
2
, R
3
, R
4
and R
5
may contain carbon chains which are linked to form extended ring systems, either aliphatic or aromatic, for example
where
each of R
7
and R
8
are defined as R
2
, R
3
, R
4
and R
5
.
Many of the dyes described below are made from compounds of formula (I) in which R
6
has been changed from H to either formyl or nitroso, for example
These may be made from the corresponding compounds where R
6
is H by standard methods.
Groups to modify solubility include phosphate, sulphonate, carbohydrate, poly(oxyethylene) and perfluoroalkyl. Groups to modify electronic and/or spectral properties include nitro, cyano, halogen and alkoxy. Functional groups for linking to another component include carboxylic acid or derivative or activated ester, azide, amine, hydroxyl, sulphonyl chloride, isothiocyanate, phosphoramidite, vinyl sulphone, maleimide, halotriazine, iodoacetamide and N-hydroxysuccinimide; see also Andrew Garman: “Non-Radioactive Labelling: A Practical Introduction” published by Academic Press, London, 1997, and references cited therein.
These compounds may be linked, preferably through R
b
or alternatively through R
2
, R
3
, R
4
, R
5
, R
7
or R
8
to a support such as polyethylene glycol, polyethyleneimine, polysaccharides such as dextran, or a derivatised substrate such as that used in solid phase synthesis e.g. polystyrene, polyacrylate or glass.
Preferably R
a
is C
1
-C
4
alkylene. Certain of these compounds can be made by an advantageous process which forms another aspect of this invention, and which comprises reacting
with GG
1
where
G is CHR=CR— where R is H or C
1
-C
4
alkyl
and G
1
is an electron withdrawing group for example CN or carboxy where the carboxy group is acid, salt, ester or amide.
Other compounds may be made by the use of G
2
R
a
G
1
where G
2
is a leaving group and R
a
and G
1
are herein defined.
An intermediate compound of formula (I) may be immobilised on a support and there reacted to form the desired dye. This method may give access to a combinatorial library of dyes or an easy way of purifying dyes, or may permit the labelling of a first nucleotide or amino acid of a solid phase oligonucleotide or oligopeptide synthesiser.
In one aspect, this invention provides use of the said intermediate to make a dye selected from a defined group, or a leuco-dye or reduced analogue of said dye. In another aspect, the invention provides the resulting dyes, and their leucodye analogues, as new compounds. The dyes are as follows (in each case, R
1
, R
2
, R
3
, R
4
and R
5
are as defined above for the intermediate compound (I); and may be the same or different at different parts of the molecule):
where
X is O, NH or =NCOAr
X
1
is H, CN, CHO, CH=N
+
(R
d
R
e
), NO, COOH, COOR
f
, CONR
g
R
h
, C
1
-C
10
alkyl, aralkyl or aryl or
where
X
3
is NH, N-R
k
, O or S, wherein X
1
is either unsubstituted or substituted by: a group to modify solubility; or a group to modify electronic and/or spectral properties; or a functional group for linking to another component,
R
d
and R
e
are alkyl, aryl, aralkyl,
R
f
, R
g
, R
h
and R
k
are R
a
R
c
wherein R
a
and R
c
are herein defined,
X
2
is H, CN, OR
i
, Cl, Br, alkyl or aryl which maybe unsubstituted or substituted by: a group to modify solubility; or a group to modify electronic and/or spectral properties; or a functional group for linking to another component;
where R
i
is MeC
6
H
4
SO
2
—, CH
3
SO
2
—, P=O(OR
j
)
2
R
j
is alkyl, aryl, aralkyl
X
1
and X
2
may contain atoms which are linked to form a carbocyclic, heterocyclic, aliphatic or aromatic ring system which may be substituted or unsubstituted with a group to modify electronic and/or spectral properties and/or a group to modify solubility properties and/or a functional linking group;
provided that, when X is O, then X
1
is not H, CN, or C
1
-C
10
alkyl, aralkyl or aryl; and provided that when X is O, then X
3
is not S;
where
Y is CN or CONH
2
or CH
2
NH
2
,
Y
1
is NH or O or =NCOAr,
Y
2
and Y
4
are: H; or C
1
-C
10
alkyl or aralkyl which may optionally contain 1 to 4 oxygen, nitrogen or sulphur atom in a straight or branched chain; or R
c
where R
c
is a group to modify solubility, or a group to modify electronic and/or spectral properties, or a functional linking group; or —R
a
R
c
wherein R
a
and R
c
are herein defined,
Y
3
is H or CN;
where
R
10
, R
11
, R
12
, R
13
and R
14
are the same or different and each is: H; or C
1
-C
10
alkyl or aralkyl which may optionally contain 1 to 4 oxygen, nitrogen or sulphur atoms in a straight or

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