Chemistry: analytical and immunological testing – Oxygen containing – Molecular oxygen
Reexamination Certificate
1999-01-21
2001-03-27
Wallenhorst, Maureen M. (Department: 2877)
Chemistry: analytical and immunological testing
Oxygen containing
Molecular oxygen
C436S127000, C436S172000, C540S145000
Reexamination Certificate
active
06207461
ABSTRACT:
The present invention relates to a process for the preparation of platinum and palladium benzoporphyrins and platinum or palladium cyclohexenoporphyrins by reacting unsubstituted or substituted cyclohexenoporphyrins in a polar solvent with complexed platinum or palladium salts at elevated temperatures; to novel palladium and platinum cyclohexenoporphyrins; to coating compositions comprising palladium and platinum cyclohexenoporphyrins; to oxygen sensors comprising palladium or platinum cyclohexenoporphyrins; and to the use of palladium and platinum cyclohexenoporphyrins as fluorescence indicators for the qualitative or quantitative determination of oxygen in gases or liquids.
Platinum(II) and palladium(II) porphyrins are suitable as phosphorescence dyes for the optical determination of physiological oxygen concentrations in cells or blood because they have absorption bands in the visible range and emission bands in the long-wave range, especially emission bands in the NIR range, and the phosphorescence radiation can therefore be excited and measured directly in the blood or in cells. Furthermore, they are distinguished by advantageous decay times in the excited state, which are in the microsecond range. Those properties are described by D. B. Papovsky et at in Biosensors & Bioelectronics 7 (1991), pages 199 to 206.
In J. Am. Chem. Soc., Vol. 104, No. 23, pages 6278 to 6283, T. J. Aartsma et al describe a process for the preparation of platinum(II) tetrabenzoporphyrin by adding tetrabenzoporphyrin to a boiling solution of PtCl
2
in benzonitrile using an extraction apparatus. No yields are given. The re-working of that process gives, after the specified reaction time of 48 hours, a contaminated crude product in a yield of only 6.5%, which can be purified to a usable phosphorescence dye only by repeated chromatography, in a correspondingly lower yield. That preparation process is therefore of no interest at all from the point of view of economics.
WO 95/10522 discloses metal porphyrins as phosphorescence indicators in oxygen sensors. In order to prepare the metal porphyrins, for example palladium tetraphenylbenzoporphyirn, it is proposed to react tetraphenylbenzoporphyrin with Pd(CH
3
CO
2
)
2
in an imidazole melt at up to 250° C. Although good yields are achieved, melt processes are difficult to carry out and are uneconomic on an industrial scale.
Surprisingly, it has now been found that, in contrast to benzoporphyrins, tetracyclohexenoporphyrins are reacted in the presence of nitrites with platinum or palladium salts in considerably shorter reaction times and with better yields and high purities. Furthermore, it has been found, surprisingly, that the reaction times can be shortened further if dinitrile complexes of platinum or palladium salts are used. It has also been found, surprisingly, that representatives of the novel class of the tetracyclohexenoporphyrins are also excellent phosphorescence indicators for the optical detection of oxygen because they exhibit high phosphorescence yields of around 42% and advantageous decay times in their excited state of around 80 &mgr;s. It has also been found that tetracyclohexenoporphyrins can be converted surprisingly readily into the corresponding tetrabenzoporphyrins by dehydrogenation, and simple preparation is thus possible even on an industrial scale. The tetracyclohexenoporphyrins forming the novel class are, therefore, valuable intermediates for the preparation of tetrabenzoporphyrins, especially tetraphenyltetrabenzoporphyrins. The invention relates firstly to compounds of formula I
wherein
Me is Pd(II) or Pt(II);
R is H or C
1
-C
18
alkyl, or is C
3
-C
8
cycloalkyl, phenyl, pyridyl or phenyl-C
1
-C
4
alkylene, each of which is unsubstituted or substituted by C
1
-C
18
alkyl, C
1
-C
18
alkoxy, R
3
—O—C(O)—, halogen, —CN or by —NO
2
;
R
1
and R
2
are each independently of the other H, C
1
-C
12
alkyl or C
1
-C
12
alkoxy, or R
1
and R
2
together are —OCH
2
O—, —OCH
2
CH
2
O— or —CH═CH—CH═CH—; and
R
3
is C
1
-C
18
alkyl, C
3
-C
8
cycloalkyl, phenyl, benzyl, C
1
-C
12
alkylphenyl or C
1
-C
12
alkylbenzyl.
In formula I, Me is preferably Pt(II).
The substituents in the cyclic radicals of R, for example cyclohexyl or phenyl, may be bonded in the 2-, 3- or 4-position. The radicals are preferably monosubstituted, with the substituent being bonded especially in the 4-position.
When R in formula I is alkyl, it is preferably linear or branched C
1
-C
12
-, especially C
1
-C
8
- and more especially C
1
-C
4
-alkyl. Some examples are methyl, ethyl and the isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl and octadecyl. Linear alkyl is also preferred.
When R in formula I is cycloalkyl, it is preferably C
4
-C
7
cycloalkyl, especially C
5
- or C
6
-cycloalkyl. Some examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
When R in formula I is phenylalkyl, it is preferably benzyl or 1-phenyleth-2-yl.
In a preferred sub-group, R in formula I is H or is phenyl that is unsubstituted or substituted by C
1
-C
18
alkyl, C
1
-C
18
alkoxy, R
3
—O—C(O)—, halogen, —CN or by —NO
2
, R
3
being C
1
-C
18
alkyl, C
3
-C
8
cycloalkyl, phenyl, benzyl, C
1
-C
12
alkylphenyl or C
1
-C
12
alkylbenzyl.
R
3
is preferably C
1
-C
12
alkyl, especially C
1
-C
6
alkyl.
R
1
and R
2
as alkyl and alkoxy may be linear or branched and are preferably C
1
-C
8
alkyl or C
1
-C
8
alkoxy, more preferably C
1
-C
6
alkyl or C
1
-C
6
alkoxy and especially C
1
-C
4
alkyl or C
1
-C
4
alkoxy. Some examples are methyl, ethyl, n- and iso-propyl, n-, iso- or tert-butyl, pentyl, hexyl, methoxy, ethoxy, n- or iso-propoxy, n-, iso- or tert-butoxy, pentoxy and hexoxy.
An especially preferred sub-group of the compounds of formula I comprises those wherein Me is Pt(II), R is H or is phenyl that is unsubstituted or substituted by C
1
-C
12
alkyl, C
1
-C
12
alkoxy, C
1
-C
18
alkyl-O—C(O)—, F, Cl, Br, —CN or by —NO
2
, and each of R
1
and R
2
is H.
A very especially preferred sub-group of the compounds of formula I comprises those wherein Me is Pt(II), R is H, phenyl or C
1
-C
4
alkylphenyl, and each of R
1
and R
2
is H.
The invention relates also to a process for the preparation of the compounds of formula I, which comprises reacting a compound of formula II
wherein
R, R
1
and R
2
are as defined for formula I.
with a palladium(II) or platinum(II) salt in the presence of an organic nitrile and, where appropriate, a solvent, at elevated temperatures.
Elevated temperatures may be, for example, from 50 to 300° C., preferably from 100 to 250° C., especially from 150 to 250° C. and more especially from 160 to 220° C.
The process can be carried out under normal pressure or elevated pressure. High pressure is advantageously used when low-boiling organic nitriles and/or solvents are employed.
The salts of Pd and Pt may be salts of inorganic or organic acids.
Examples of inorganic acids are hydrohalic acids (for example HCl, HBr and HI), oxy acids of carbon, sulfur, nitrogen and phosphorus (for example carbonic acid, sulfuric acid, sulfurous acid, nitric acid, phosphorous acid and phosphoric acid), and per acids, for example HClO
4
or HBrO
4
. Preferred acids are hydrohalic acids, especially HCl.
Examples of organic acids are carboxylic acids and halocarboxylic acids (for example acetic acid, propionic acid, butyric acid, benzoic acid, phenylacetic acid, chlorobenzoic acid, trichloroacetic acid and trifluoroacetic acid), sulfonic acids and halosulfonic acids (for example methylsulfonic acid, ethylsulfonic acid, phenylsulfonic acid, p-toluenesulfonic acid, trichloromethylsulfonic acid, trifluoromethylsulfonic acid and chlorophenylsulfonic acid), and phosphonic acids and halophosphonic acids (for example methanephosphonic acid, phenylphosphonic acid, phenylphosphinic acid and trifluoromethylphosphonic acid).
In a preferred form, palladium and platinum halides are used as the palladium and platinum salts, especially PdCl
2
and PtCl
2
.
Suitable organic
Baumann Marcus
Waldner Adrian
Cross LaToya I.
Novartis AG
Wallenhorst Maureen M.
Wenderoth , Lind & Ponack, L.L.P.
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