Metal free texaphyrin synthesis

Details Metal free texaphyrin synthesis Metal free texaphyrin synthesis

2002-10-18

2003-12-02

Shah, Mukund J. (Department: 1624)

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

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

Reexamination Certificate

active

06657058

ABSTRACT:

FIELD OF INVENTION
The present invention related to the synthesis of a metal-free form of Texaphyrin (compounds of Formula I), an aromatic porphyrin-like macrocycle.
BACKGROUND OF THE INVENTION
The synthesis of the first metal complex of Texaphyrin, an aromatic Schiff-base macrocycle comprised of a tripyrrolyldimethene unit joined to a phenylenediamine through two imine-type linkages, was reported in 1988. This species, an aromatic cadmium(II) complex, was prepared via a simultaneous oxidation-metalation process, that involved treating a reduced non-aromatic porphyrinogen-like precursor, a so-called “sp
3
-texaphyrin” (named to reflect the hybridization at the bridging carbon atoms) with a Cd(II) salt and air as reported by Jonathan Sessler et al. (see Sessler, J. L., Johnson, M. R. & Lynch, V.,
J. Org. Chem
. 1987, v. 52, pp. 4394-4397). Analysis of the metal complex of Texaphyrin showing that it contains a central core that is 20% larger than that of porphyrin, led to the conclusion that this “expanded porphyrin” should coordinate other large cations, including ones that do not fit within the confines of the porphyrin core. This prediction was subsequently realized with nearly the full series of lanthanide(III), as well as Y(III) and In(III), Texaphyrin complexes now being known.
In early work it was reported that the free-base form, Compound of Formula I, of an organic-soluble Texaphyrin was obtained by heating a solution of sp
3
-texaphyrin and N,N-N′,N′-tetramethyl-1,8-naphthalenediamine to reflux while open to air. However, all efforts to reproduce and generalize this result met with failure. As a result, the chemistry and characterization of metal-free texaphyrins has been limited. In this paper, we report an efficient synthesis of this long-sought species.
Keeping the above progress in mind, there is a need for a process that can produce the free base form of an organic-soluble Texaphyrin.
SUMMARY OF THE INVENTION
The present invention provides a process of synthesizing a compound of Formula I
wherein
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
and R
8
are independently selected from acyl, acyloxy, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, carboxyl, (optionally substituted alkoxy)carbonyl, (optionally substituted amino)carbonyl, (optionally substituted alkoxy)carbonyloxy, (optionally substituted amino)carbonyloxy, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, halogen, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heterocyclyl, optionally substituted heterocyclooxy, hydrogen, hydroxyl, nitro, optionally substituted azo, S—R
31
, SO—R
31
, SO
2
-R
31
, and the moiety X—Y;
R
9
and R
10
are independently selected from H, acyl, acyloxy, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, carboxyl, (optionally substituted alkoxy)carbonyl, (optionally substituted amino)carbonyl, (optionally substituted alkoxy)carbonyloxy, (optionally substituted amino)carbonyloxy, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, fluoro, chloro, bromo, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heterocyclyl, optionally substituted heterocyclooxy, hydrogen, hydroxyl, nitro, optionally substituted azo, sulfanyl, sulfinyl, sulfonyl, and the moiety Y—Z;
R
23
and R
24
independently at each occurrence are selected from H, OH, optionally substituted C
1-4
alkyl, optionally substituted C
3-10
cycloalkyl, halogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl;
R
31
represents acyl, optionally substituted alkenyl, optionally substituted alky, optionally substituted alkoxy, optionally substituted alkoxycarbonyl, optionally substituted alkynyl, optionally substituted aminocarbonyl, optionally substituted aryl, carboxy, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
X represents a charge balancing species (counter ion) selected from halide, NO
2
, OCOCH
3
, PF
6
, BF
4
, COO, and SO
4
;
Y is a covalent bond or a linker; and
Z is a catalytic group, a chemotherapeutic agent or a site-directing group;
said process comprising
treating, in an inert medium and in the presence of an organic base, a compound of formula A
with an organ metallic agent capable of acting as an outer sphere oxidant to form a compound of Formula I.
DETAILED DESCRIPTION
Preferred embodiments of the present invention provide a process wherein the compound of formula A is treated with about 2 to about 8 equivalents of an organo metallic agent, in the presence of a base selected from 2,6-lutidine, collidine, potassium trimethylsilanoate, pyridine triethylamine Hünig's base, 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU), isoquinolinie, piperidine, quinoline, sodium tosylamide, and dimethylaniline.
Another preferred embodiment of the present invention provides a process wherein R
1
and R
6
are independently selected from H, methyl, CH
2
CH
2
OH, CH
2
CH
2
CH
2
OH, and ethyl;
R
2
and R
5
are independently selected from H, methyl and ethyl;
R
3
and R
4
are independently selected from H, OCH
3
, OC
2
H
5
, and O(CH
2
CH
2
O)
3
CH
3
;
R
7
and R
8
are independently selected from H, methyl and ethyl;
R
9
, R
10
, R
23
and R
24
independently at each occurrence are selected from H, methyl, ethyl, propyl, alkynyl, alkenyl, halogen, and aryl; and
X represents [PF
6
].
Provided in yet another preferred embodiment is a process wherein the inert medium is selected from THF, acetonitrile, methylene chloride, DMF, benzene, toluene, chloroform, dichloroethane, and diethyl ether, with THF and acetonitrile being particularly preferred. Yet another preferred embodiment provides a process wherein a compound of formula A is treated with about 3 to about 6 equivalents of an organo metallic agent capable of acting as an outer sphere oxidant, in the presence of from about 1 to about 20 equivalents of 2,6-lutidine.
A further preferred embodiment of the present invention provides a process of synthesizing a compound of Formula I
wherein
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
and R
10
are independently selected from H, ethyl, methyl, methoxy, methyl, CH
2
CH
2
OH, CH
2
CH
2
CH
2
OH, O(CH
2
CH
2
O)
3
CH
3
, and butyl;
R
9
, R
10
, R
23
and R
24
independently at each occurrence are selected from H, methyl, ethyl, propyl, alkynyl, alkenyl, halogen, and aryl; and
X represents [PF
6
];
said process comprising
treating one equivalent of a compound of formula A, dissolved in acetonitrile,
with about 4 to 5 equivalents of an organ metallic agent capable of acting as an outer sphere oxidant selected from the complex ions and salts selected from
[Cp
2
Fe]
+
, [Co(III)(bipyridine)
3
]
3+
, [Co(III)(phenanthroline)
3
]
3+
,
[Co(III)(edta)]
−
, [Fe(III)(phenanthroline)
3
]
3+
, and [Ru(III)(bipyridine)
3
]
3+
,
in the presence of from about 5 to about 10 equivalents of 2,6-lutidine to form a compound of Formula I.
A further preferred process on one where R
1
represents ethyl; R
2
represents methyl; R
3
and R
4
represent methoxy; R
5
represents methyl; R
6
represents ethyl; R
7
represents ethyl; R
8
represents ethyl; R
9
, R
10
, R
23
and R
24
independently at each occurrence are selected from H, methyl, ethyl, propyl, alkynyl, alkenyl, halogen, and aryl; X represents [PF
6
]; the organo metallic agent capable of acting as an outer sphere oxidant is ferrocenium hexafluorophasphate.
Another preferred embodiment provides a process wherein R
1
represents CH
2
CH
2
OH or CH
2
CH
2
CH
2
OH;

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