Note: Descriptions are shown in the official language in which they were submitted.
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METHOD OF PREPARING NAPHTHALOCYANINES
Field of the Invention
The present application relates generally to an improved method of
synthesizing
naphthalocyanines. It has been developed primarily to reduce the cost of
existing naphthalocyanine
syntheses and to facilitate large-scale preparations of these compounds.
Background of the Invention
We have described previously the use of naphthalocyanines as IR-absorbing
dyes.
Naphthalocyanines, and particularly gallium naphthalocyanines, have low
absorption in the visible
range and intense absorption in the near-IR region (750-810 nm). Accordingly,
naphthalocyanines
are attractive compounds for use in invisible inks. The Applicant's US Patent
Nos. 7,148,345 and
7,122,076 (the contents of which are herein incorporated by reference)
describe in detail the use of
naphthalocyanine dyes in the formulation of inks suitable for printing
invisible (or barely visible)
coded data onto a substrate. Detection of the coded data by an optical sensing
device can be used to
invoke a response in a remote computer system. Hence, the substrate is
interactive by virtue of the
coded data printed thereon.
The Applicant's netpage and Hyperlabel systems, which makes use of
interactive
substrates printed with coded data, are described extensively in the cross-
referenced patents and
patent applications above (the contents of which are herein incorporated by
reference).
In the anticipation of widespread adoption of netpage and Hyperlabel
technologies, there
exists a considerable need to develop efficient syntheses of dyes suitable for
use in inks for printing
coded data. As foreshadowed above, naphthalocyanines and especially gallium
naphthalocyanines
are excellent candidates for such dyes and, as a consequence, there is a
growing need to synthesize
naphthalocyanines efficiently and in high yield on a large scale.
Naphthalocyanines are challenging compounds to synthesize on a large scale. In
US Patent
Nos. 7,148,345 and 7,122,076, we described an efficient route to
naphthalocyanines via
macrocyclization of naphthalene-2,3-dicarbonitrile. Scheme 1 shows a route to
the sulfonated
gallium naphthalocyanine 1 from naphthalene-2,3-dicarbonitrile 2, as described
in US 7,148,345.
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0 CHZCHZ O
GaC13 N N N- N
NaDMe
I \ \ CN toluene N ` i
N-G; / / a-N N-Ga-N
/ / \ \
HO''-'OH
N N iN N ~ N
2 190-195 C
ZH2304
60-70 C/1 h
HOSOZ / \
/ \
N ~ ~N SOzOH
'OH i \ \
N-Ga-N
\ \ \ ; / /
S020H N N _N
SO2OH
Scheme 1
However, a problem with this route to naphthalocyanines is that the starting
material 2 is
expensive. Furthermore, naphthalene-2,3-dicarbonitrile 2 is prepared from two
expensive building
blocks: tetrabromo-o-xylene 3 and fumaronitrile 4, neither of which can be
readily prepared in
multi-kilogram quantities.
\ CHBr2 CN
I / CHBr2 NC"
3 4
Accordingly, if naphthalocyanines are to be used in large-scale applications,
there is a need
to improve on existing syntheses.
Summary of the Invention
In a first aspect, there is provided a method of preparing a naphthalocyanine
comprising
the steps of:
(i) providing a tetrahydronaphthalic anhydride;
(ii) converting said tetrahydronaphthalic anhydride to a benzisoindolenine;
and
(iii) macrocyclizing said benzisoindolenine to form a naphthalocyanine.
Optionally, the tetrahydronaphthalic anhydride is of formula (I):
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R1 0
R2
R3I
R4 0
wherein:
Ri, R2, R3 and R4 are each independently selected from hydrogen, hydroxyl, Ci-
zo alkyl, Ci-ao
alkoxy, amino, Ci-zo alkylamino, di(Ci-20 alkyl)amino, halogen, cyano, thiol,
Ci-zo alkylthio, nitro,
C1-20 alkylcarboxy, Ci-20 alkylcarbonyl, Ci-20 alkoxycarbonyl, Ci-20
alkylcarbonyloxy, Ci-20
alkylcarbonylamino, C5-20 aryl, Cs-20 arylalkyl, Cs-20 aryloxy, Cs-20
arylalkoxy, Cs-20 heteroaryl, Cs-ao
heteroaryloxy, Cs_2o heteroarylalkoxy or C5_20 heteroarylalkyl.
Optionally, Ri, R2, R3 and R4 are all hydrogen.
Optionally, step (ii) comprises a one-pot conversion from the
tetrahydronaphthalic
anhydride to a benzisoindolenine salt. This one-pot conversion facilitates
synthesis of
naphthalocyanines via the route described above and greatly improves yields
and scalability.
Optionally, the benzisoindolenine salt is a nitrate salt although other salts
(e.g. benzene
sulfonate salt) are of course within the scope of the present invention.
Optionally, the one-pot conversion is effected by heating with a reagent
mixture
comprising ammonium nitrate.
Optionally, the reagent mixture comprises at least 2 equivalents of ammonium
nitrate with
respect to the tetrahydronaphthalic anhydride.
Optionally, the reagent mixture comprises urea.
Optionally, the reagent mixture comprises at least one further ammonium salt.
Optionally, the further ammonium salt is selected from: ammonium sulfate and
ammonium
benzenesulfonate
Optionally, the reagent mixture comprises a catalytic amount of ammonium
molybdate.
Optionally, the heating is within a temperature range of 150 to 200 C.
The reaction may be performed in the presence of or in the absence of a
solvent.
Optionally, heating is in the presence of an aromatic solvent. Examples of
suitable solvents are
nitrobenzene, biphenyl, diphenyl ether, mesitylene, anisole, phenetole,
dichlorobenzene,
trichlorobenzene and mixtures thereof.
Optionally, the benzisoindolenine is liberated from the benzisoindolenine salt
using a base.
Sodium methoxide is an example of a suitable base although the skilled person
will be readily
aware of other suitable bases.
Optionally, the benzisoindolenine is of formula (II):
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R1 NH
R2
/ N
R3 R4 NH2
(~~)
wherein:
Ri, R2, R3 and R4 are each independently selected from hydrogen, hydroxyl, Ci-
zo alkyl, Ci-ao
alkoxy, amino, Ci-zo alkylamino, di(Ci-20 alkyl)amino, halogen, cyano, thiol,
Ci-zo alkylthio, nitro,
Ci-zo alkylcarboxy, Ci-zo alkylcarbonyl, Ci-zo alkoxycarbonyl, Ci-zo
alkylcarbonyloxy, Ci-zo
alkylcarbonylamino, Cs-zo aryl, Cs-zo arylalkyl, Cs-20 aryloxy, Cs-zo
arylalkoxy, Cs-zo heteroaryl, Cs-zo
heteroaryloxy, Cs-2o heteroarylalkoxy or Cs-zo heteroarylalkyl.
Optionally, the naphthalocyanine is of formula (III):
R15 R14
R16 R13
R1 N ~N ~ N R12
~
R2 R11
I N-M-N
R3 R1o
R4 N N ~ N Rs
R5 ~ ~ R8
R6 R7
(III)
wherein:
Ri, R2, R3, R4, R5, R6, R7, R8, R9, Rio, Ril, R12, R13, R14, R15 and R16 are
each independently selected
from hydrogen, hydroxyl, Ci-zo alkyl, Ci-zo alkoxy, amino, Ci-zo alkylamino,
di(Ci-zo alkyl)amino,
halogen, cyano, thiol, Cl-zo alkylthio, nitro, Ci-zo alkylcarboxy, Ci-zo
alkylcarbonyl, Ci-zo
alkoxycarbonyl, C1-zo alkylcarbonyloxy, Ci-zo alkylcarbonylamino, Cs-zo aryl,
Cs-zo arylalkyl, Cs-ao
aryloxy, Cs-zo arylalkoxy, Cs-20heteroaryl, Cs-2o heteroarytoxy, Cs-zo
heteroarylalkoxy or Cs-ao
heteroarylalkyl;
M is absent or selected from Si(A)(A2), Ge(Ai)(A2), Ga(Ai), Mg, Al(Ai), TiO,
Ti(Ai)(A2), ZrO,
Zr(Ai)(A2), VO, V(Ai)(A2), Mn, Mn(Ai), Fe, Fe(A), Co, Ni, Cu, Zn, Sn, Sn(A')(A
2), Pb,
Pb(A')(A 2), Pd and Pt;
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A' and A2 are axial ligands, which may be the same or different, and are
selected from -OH,
halogen or -ORq;
Rq is selected from Ci-i6 alkyl, Cs-zo aryl, Cs-zo arylatkyl, Ci-zo
alkylcarbonyl, Ci-zo alkoxycarbonyl
or Si(R")(R'')(R'); and
5 R", R'' and R' may be the same or different and are selected from Ci-zo
alkyl, Cs-zo aryl, Cs-2o
arylalkyl, Ci-zo alkoxy, Cs-zo aryloxy or CS-zo arylalkoxy;
Optionally, Ri, R2, R3, R4, R5, R6, R7, R8, R9, Rio, Rii, R12, Ri3, R14, Ris
and R16 are all
hydrogen.
Optionally, M is Ga(A), such as Ga(OCHzCHzOCHzCHzOCHzCHzOMe); that is where R9
is CHzCHzOCHzCHzOCHzCHzOMe. For the avoidance of doubt, ethers such as
CHzCHzOCHzCHzOCHzCHzOMe fall within the definition of alkyl groups as
specified
hereinbelow. Gallium compounds are preferred since they have excellent
lightfastness, strong
absorption in the near-IR region, and are virtually invisible to the human eye
when printed on a
page.
Optionally, step (iii) comprises heating the benzisoindolenine in the presence
of a metal
compound, such as A1C13 or GaC13 or a corresponding metal alkoxide. The
reaction may be
performed in the absence of or in the presence of a suitable solvent, such as
toluene, nitrobenzene
etc. When a metal alkoxide is used, the reaction may be catalyzed with a
suitable base, such as
sodium methoxide. Alcohols, such as triethylene glycol monomethyl ether or
glycol may also be
present to assist with naphthalocyanine formation. These alcohols may end up
as the axial ligand of
the naphthalocyanine or they may be cleaved from the metal under the reaction
conditions. The
skilled person will readily be able to optimize the conditions for
naphthalocyanine formation from
the benzisoindolenine.
Optionally, the method further comprises the step of sulfonating said
naphthalocyanine.
Sulfonate groups are useful for solubilizing the naphthalocyanines in ink
formulations, as described
in our earlier US Patents Nos. 7,148,345 and 7,122,076.
In a second aspect, there is provided a method of effecting a one-pot
conversion of a
tetrahydronaphthalic anhydride to a benzisoindolenine salt, said method
comprising heating said
tetrahydronaphthalic anhydride with a reagent mixture comprising ammonium
nitrate.
This transformation advantageously obviates a separate dehydrogenation step to
form the
naphthalene ring system. The ammonium nitrate performs the dual functions of
oxidation
(dehydrogenation) and isoindolenine formation.
The isoindolenine salts generated according to the second aspect may be used
in the
synthesis of naphthalocyanines. Hence, this key reaction provides a
significant improvement in
routes to naphthalocyanines.
In general, optional features of this second aspect mirror the optional
features described
above in respect of the first aspect.
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In a third aspect, there is provided a method of preparing a sultine of
formula (V) from a
dihalogeno compound of formula (IV)
R1 R
R2 X R2 S~0
R X R3 I O
3
R4 R4
(IV) (V)
the method comprising reacting the dihalogeno compound (IV) with a
hydroxymethanesulfinate
salt in a DMSO solvent so as to prepare the sultine (V);
wherein:
Ri, R2, R3 and R4 are each independently selected from hydrogen, hydroxyl, Ci-
zo alkyl, Ci-ao
alkoxy, amino, Ci-zo alkylamino, di(Ci-20 alkyl)amino, halogen, cyano, thiol,
Ci-zo alkylthio, nitro,
Ci-zo alkylcarboxy, Ci-zo alkylcarbonyl, Ci-zo alkoxycarbonyl, Ci-zo
alkylcarbonyloxy, Ci-zo
alkylcarbonylamino, Cs-zo aryl, Cs-zo arylalkyl, Cs-2o aryloxy, Cs-zo
arylalkoxy, Cs-zo heteroaryl, Cs-ao
heteroaryloxy, Cs-2o heteroarylalkoxy or Cs-zo heteroarylatkyl; and
X is Cl, Br or 1.
The method according to the third aspect surprisingly minimizes polymeric by-
products
and improves yields, when compared to literature methods for this reaction
employing DMF as the
solvent. These advantages are amplified when the reaction is performed on a
large scale (e.g. at
least 0.3 molar, at least 0.4 molar or at least 0.5 molar scale).
Optionally, Nal is used to catalyze the coupling reactions when X is Cl or Br.
Optionally, a metal carbonate base (e.g. Na2CO3, K2C03, CszCO3 etc) is
present.
Optionally, the hydroxymethanesulfinate salt is sodium hydroxymethanesulfinate
(RongaliteTM)
Optionally, Ri, R2, R3 and R4 are all hydrogen.
Optionally, the method comprises the further step of reacting the sultine (V)
with an olefin
at elevated temperature (e.g. about 80 C) to generate a Diels-Alder adduct.
Optionally, the olefin is maleic anhydride and said Diels-Alder adduct is a
tetrahydronaphthalic anhydride.
Optionally, the tetrahydronaphthalic anhydride is used as a precursor for
naphthalocyanine
synthesis, as described herein.
Optionally, the naphthalocyanine synthesis proceeds via conversion of the
tetrahydronaphthalic anhydride to a benzisoindolenine, as described herein.
Brief Description of the Drawings
The invention will now be described in detail with reference to the following
drawings, in
which:
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Figure 1 is a 'H NMR spectrum of the crude sultine 10 in d6-DMSO;
Figure 2 is a 'H NMR spectrum of the anhydride 8 in d6-DMSO;
Figure 3 is a 'H NMR spectrum of the crude benzisoindolenine salt 12 in d6-
DMSO;
Figure 4 is an expansion of the aromatic region of the 'H NMR spectrum shown
in Figure
3;
Figure 5 is a 'H NMR spectrum of the benzisoindolenine 7 in d6-DMSO.
Figure 6 is an expansion of the aromatic region of the 'H NMR spectrum shown
in Figure
5; and
Figure 7 is a UV-VIS spectrum of naphthalocyanatogallium
methoxytriethyleneoxide in
NMP.
Detailed Description
As an alternative to dicarbonitriles, the general class of phthalocyanines is
known to be
prepared from isoindolenines. In US 7,148,345, we proposed the
benzisoindolenine 5 as a possible
precursor to naphthalocyanines.
NH
I \ \
N
5 NH2
However, efficient syntheses of the benzisoindolenine 5 were unknown in the
literature,
and it was hitherto understood that dicarbonitriles, such as naphthalene-2,3-
dicarbonitrile 2, were
the only viable route to naphthalocyanines.
Nevertheless, with the potentially prohibitive cost of naphthalene-2,3-
dicarbonitrile 2, the
present inventors sought to explore a new route to the benzisoindolenine 5, as
outlined in Scheme
2.
O O NH
I\ / i I \ / \
/ - I\ / \
/ 41 N
6 7 5 NHz
Scheme 2
Tetrahydronaphthalic anhydride 6 was an attractive starting point, because
this is a known
Diels-Alder adduct which may be synthesized via the route shown in Scheme 3.
0 0
0 o ~ \ + ~o
6 9
Scheme 3
Referring to Scheme 2, it was hoped that the conversion of naphthalic
anhydride 7 to the
benzisoindolenine 5 would proceed analogously to the known conversion of
phthalic anhydride to
the isoindolenine 8, as described in W098/31667.
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8
NH
8 NH2
However, a number of problems remained with the route outlined in Scheme 2.
Firstly, the
dehydrogenation of tetrahydronaphthalic anhydride 6 typically requires high
temperature catalysis.
Under these conditions, tetrahydronaphthalic anhydride 6 readily sublimes
resulting in very poor
yields. Secondly, the preparation of tetrahydronaphthalic anhydride 6 on a
large scale was not
known. Whilst a number of small-scale routes to this compound were known in
the literature, these
generally suffered either from poor yields or scalability problems.
The use of sultines as diene precursors is well known and 1,4-dihydro-2,3-
benzoxathiin-3-
oxide 10 has been used in a synthesis of 6 on a small scale (Hoey, M. D.;
Dittmer, D. A. J. Org.
Chem. 1991, 56, 1947-1948). As shown in Scheme 4, this route commences with
the relatively
inexpensive dichloro-o-xylene 11, but the feasibility of scaling up this
reaction sequence is limited
by the formation of undesirable polymeric by-products in the sultine-forming
step. The formation
of these by-products makes reproducible production of 6 in high purity and
high yield difficult.
0
~o 0
HOVS.ONa
S~ / - ~ \ p
i ->
CI DMF O gp C \ I/
11 Nal 10 9 6 0
Scheme 4
Nevertheless, the route outlined in Scheme 4 is potentially attractive from a
cost
standpoint, since dichloro-o-xylene 11 and maleic anhydride are both
inexpensive materials.
Whilst the reaction sequence shown in Schemes 4 and 2 present significant
synthetic
challenges, the present inventors have surprisingly found that, using modified
reaction conditions,
the benzisoindolenine 5 can be generated on a large scale and in high yield.
Hence, the present
invention enables the production of naphthalocyanines from inexpensive
starting materials, and
represents a significant cost improvement over known syntheses, which start
from naphthalene-2,3-
dicarbonitrile 2.
Referring to Scheme 5, there is shown a route to the benzisoindolenine 5,
which
incorporates two synthetic improvements in accordance with the present
invention.
0
~o 0
HOVS.ONa
S~ ~
I \ CI _~ 1 i ------- ).- I C
/ CI DMSO O 80 C /
11 K2CO3 10 9 6 0
cat. Nal toluene or
trifluorotoluene NH4NO3/(NH4)2SO4
170 C urea/ritroben
zene
NH NH
I \ \ NaOMe I \ \ N
/ / ~N
acetone / / ~/
5 NH2 0 C 12 NH3NO3
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Scheme 5
Unexpectedly, it was found that by using DMSO as the reaction solvent in the
conversion
of 11 into 10, the reaction rate and selectivity for the formation of sultine
10 increases significantly.
This is in contrast to known conditions (Hoey, M. D.; Dittmer, D. A. T. Org.
Chem. 1991, 56,
1947-1948) employing DMF as the solvent, where the formation of undesirable
polymeric side-
products is a major problem, especially on a large scale. Accordingly, the
present invention
provides a significant improvement in the synthesis of tetrahydronaphthalic
anhydride 6.
The present invention also provides a significant improvement in the
conversion of
tetrahydronaphthalic anhydride 6 to the benzisoindolenine 5. Surprisingly, it
was found that the
ammonium nitrate used for this step readily effects oxidation of the saturated
ring system as well as
converting the anhydride to the isoindolenine. Conversion to a
tetrahydroisoindolenine was
expected to proceed smoothly, in accordance with the isoindolenine similar
systems described in
W098/31667. However, concomitant dehydrogenation under these reaction
conditions
advantageously provided a direct one-pot route from the tetrahydronaphthalic
anhydride 6 to the
benzisoindolenine salt 12. This avoids problematic and low-yielding
dehydrogenation of the
tetrahydronaphthalic anhydride 6 in a separate step. Subsequent treatment of
the salt 12 with a
suitable base, such as sodium methoxide, liberates the benzisoindolenine 5. As
a result of these
improvements, the entire reaction sequence from 11 to 5 is very conveniently
carried out, and
employs inexpensive starting materials and reagents (Scheme 5).
The benzisoindolenine 5 may be converted into any required naphthalocyanine
using
known conditions. For example, the preparation of a gallium naphthalocyanine
from
benzisoindolenine 5 is exemplified herein. Subsequent manipulation of the
naphthalocyanine
macrocycle may also be performed in accordance with known protocols. For
example, sulfonation
may be performed using oleum, as described in US Patent Nos. 7,148,345 and
7,122,076.
Hitherto, the use of tetrahydronaphthalic anhydride 6 as a building block for
naphthalocyanine synthesis had not previously been reported. However, it has
now been shown that
tetrahydronaphthalic anhydride 6 is a viable intermediate in the synthesis of
these important
compounds. Moreover, it is understood by the present inventors that the route
shown in Scheme 5
represents the most cost-effective synthesis of benzisoindolenines 5.
The term "aryl" is used herein to refer to an aromatic group, such as phenyl,
naphthyl or
triptycenyl. C6_i2 aryl, for example, refers to an aromatic group having from
6 to 12 carbon atoms,
excluding any substituents. The term "arylene", of course, refers to divalent
groups corresponding
to the monovalent aryl groups described above. Any reference to aryl
implicitly includes arylene,
where appropriate.
The term "heteroaryl" refers to an aryl group, where 1, 2, 3 or 4 carbon atoms
are replaced
by a heteroatom selected from N, 0 or S. Examples of heteroaryl (or
heteroaromatic) groups
include pyridyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl,
indolinyl, isoindolinyl,
indolyl, isoindolyl, furanyl, thiophenyl, pyrrolyl, thiazolyl, imidazolyl,
oxazolyl, isoxazolyl,
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pyrazolyl, isoxazolonyl, piperazinyl, pyrimidinyl, piperidinyl, morpholinyl,
pyrrolidinyl,
isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl,
benzopyrimidinyl,
benzotriazole, quinoxalinyl, pyridazyl, coumarinyl etc. The term
"heteroarylene", of course, refers
to divalent groups corresponding to the monovalent heteroaryl groups described
above. Any
5 reference to heteroaryl implicitly includes heteroarylene, where
appropriate.
Unless specifically stated otherwise, aryl and heteroaryl groups may be
optionally
substituted with l, 2, 3, 4 or 5 of the substituents described below.
Where reference is made to optionally substituted groups (e.g. in connection
with aryl
groups or heteroaryl groups), the optional substituent(s) are independently
selected from Ci_8 alkyl,
10 Ci_8 alkoxy, -(OCH2CH2)aORd (wherein d is an integer from 2 to 5000 and Rd
is H, Ci_s alkyl or
C(O)Ci_8 alkyl), cyano, halogen, amino, hydroxyl, thiol, -SR , -NR"R , nitro,
phenyl, phenoxy,
-C02R , -C(O)R , -OCOR , -S02R , -OS02R , -S020R , -NHC(O)R , -CONR`"R , -
CONR'"R ,
-S02NRuR , wherein R" and R' are independently selected from hydrogen, Ci_20
alkyl, phenyl or
phenyl-Ci_$ alkyl (e.g. benzyl). Where, for example, a group contains more
than one substituent,
different substituents can have different R" or R groups.
The term "alkyl" is used herein to refer to alkyl groups in both straight and
branched
forms. Unless stated otherwise, the alkyl group may be interrupted with 1, 2,
3 or 4 heteroatoms
selected from 0, NH or S. Unless stated otherwise, the alkyl group may also be
interrupted with 1,
2 or 3 double and/or triple bonds. However, the term "alkyl" usually refers to
alkyl groups having
double or triple bond interruptions. Where "alkenyl" groups are specifically
mentioned, this is not
intended to be construed as a limitation on the definition of "alkyl" above.
Where reference is made to, for example, Cl_ZO alkyl, it is meant the alkyl
group may
contain any number of carbon atoms between 1 and 20. Unless specifically
stated otherwise, any
reference to "alkyl" means Ci_20 alkyl, preferably C1_12 alkyl or Ci_6 alkyl.
The term "alkyl" also includes cycloalkyl groups. As used herein, the term
"cycloalkyl"
includes cycloalkyl, polycycloalkyl, and cycloalkenyl groups, as well as
combinations of these with
linear alkyl groups, such as cycloalkylalkyl groups. The cycloalkyl group may
be interrupted with
1, 2 or 3 heteroatoms selected from 0, N or S. However, the term "cycloalkyl"
usually refers to
cycloalkyl groups having no heteroatom interruptions. Examples of cycloalkyl
groups include
cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexylmethyl and adamantyl groups.
The term "arylalkyl" refers to groups such as benzyl, phenylethyl and
naphthylmethyl.
The term "halogen" or "halo" is used herein to refer to any of fluorine,
chlorine, bromine
and iodine. Usually, however, halogen refers to chlorine or fluorine
substituents.
Where reference is made herein to "a naphthalocyanine", "a benzisoindolenine",
"a
tetrahydronaphthalic anhydride" etc, this is understood to be a reference to
the general class of
compounds embodied by these generic names, and is not intended to refer to any
one specific
compound. References to specific compounds are accompanied with a reference
numeral.
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Chiral compounds described herein have not been given stereo-descriptors.
However, when
compounds may exist in stereoisomeric forms, then all possible stereoisomers
and mixtures thereof
are included (e.g. enantiomers, diastereomers and all combinations including
racemic mixtures
etc.).
Likewise, when compounds may exist in a number of regioisomeric or tautomeric
forms,
then all possible regioisomers, tautomers and mixtures thereof are included.
For the avoidance of doubt, the term "a" (or "an"), in phrases such as
"comprising a",
means "at least one" and not "one and only one". Where the term "at least one"
is specifically used,
this should not be construed as having a limitation on the definition of "a".
Throughout the specification, the term "comprising", or variations such as
"comprise" or
"comprises", should be construed as including a stated element, integer or
step, but not excluding
any other element, integer or step.
The invention will now be described with reference to the following drawings
and
examples. However, it will of course be appreciated that this invention may be
embodied in many
other forms without departing from the scope of the invention, as defined in
the accompanying
claims.
Example 1
1,4-dihydro-2,3-benzoxathiin-3-oxide 10
Sodium hydroxymethanesulfinate (RongaliteTM) (180 g; 1.17 mol) was suspended
in DMSO (400
mL) and left to stir for 10 min. before dichloro-o-xylene (102.5 g; 0.59 mol),
potassium carbonate
(121.4 g; 0.88 mol) and sodium iodide (1.1 g; 7 mmol) were added
consecutively. More DMSO
(112 mL) was used to rinse residual materials into the reaction mixture before
the whole was
allowed to stir at room temperature. The initial endothermic reaction became
mildly exothermic
after around 1 h causing the internal temperature to rise to ca. 32-33 C. The
reaction was followed
by TLC (ethyl acetate/hexane, 50:50) and found to be complete after 3 h. The
reaction mixture was
diluted with methanol/ethyl acetate (20:80; 400 mL) and the solids were
filtered off, and washed
with more methanol/ethyl acetate (20:80; 100 mL, 2 x 50 mL). The filtrate was
transferred to a
separating funnel and brine (1 L) was added. This caused more sodium chloride
from the product
mixture to precipitate out. The addition of water (200 mL) redissolved the
sodium chloride. The
mixture was shaken and the organic layer was separated and then the aqueous
layer was extracted
further with methanol/ethyl acetate (20:80; 200 mL, 150 mL, 250 mL). The
combined extracts
were dried (NazSO4) and rotary evaporated (bath 37-38 C). More solvent was
removed under high
vacuum to give the sultine 10 as a pale orange liquid (126 g) that was found
by 'H NMR
spectroscopy to be relatively free of by-product but containing residual DMSO
and ethyl acetate
(Figure 1).
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Example 2
Tetrahydronaphthalic anhydride 6
The crude sultine from above (126 g) was diluted in trifluorotoluene (100 mL)
and then added to a
preheated (bath 80 C) suspension of maleic anhydride (86 g; 0.88 mol) in
trifluorotoluene (450
mL). The residual sultine was washed with more trifluorotoluene into the
reaction mixture and
then the final volume was made up to 970 mL. The reaction mixture was heated
at 80 C for 15 h,
more maleic anhydride (28.7 g; 0.29 mol) was added and then heating was
continued for a further 8
h until TLC showed that the sultine had been consumed. While still at 80 C,
the solvent was
removed by evaporation with a water aspirator and then the residual solvent
was removed under
high vacuum. The moist solid was triturated with methanol (200 mL) and
filtered off, washing
with more methanol (3 x 100 mL). The tetrahydronaphthalic anhydride 6 was
obtained as a fine
white crystalline solid (75.4 g; 64% from 10) after drying under high vacuum
at 60-70 C for 4 h.
Example 3
The sultine was prepared from dichloro-o-xylene (31.9 g; 0.182 mol), as
described in Example 2,
and then reacted with maleic anhydride (26.8 g; 0.273 mol) in toluene (300 mL
total volume) as
described above. This afforded the tetrahydronaphthalc anhydride 6 as a white
crystalline solid
(23.5 g; 64%).
Example 4
1-amino-3-iminoben2[f]isoindolenine nitrate salt 12
Urea (467 g; 7.78 mol) was added to a mechanically stirred mixture of ammonium
sulfate (38.6 g;
0.29 mol), ammonium molybdate (1.8 g) and nitrobenzene (75 mL). The whole was
heated with a
heating mantle to ca. 130 C (internal temperature) for 1 h causing the urea
to melt. At this point
the anhydride 6 (98.4 g; 0.49 mol) was added all at once as a solid. After 15
min ammonium
nitrate (126.4 g; 1.58 mol) was added with stirring (internal temperature 140
C) accompanied by
substantial gas evolution. The reaction temperature was increased to 170-175
C over 45 min and
held there for 2 h 20 min. The viscous brown mixture was allowed to cool to
ca. 100 C and then
methanol (400 mL) was slowly introduced while stirring. The resulting
suspension was poured on
a sintered glass funnel, using more methanol (100 mL) to rinse out the
reaction flask. After
removing most of the methanol by gravity filtration, the brown solid was
sucked dry and then
washed with more methanol (3 x 200 mL, 50 mL), air-dried overnight and dried
under high
vacuum in a warm water bath for 1.5 h. The benzisoindolenine salt 12 was
obtained as a fine
brown powder (154.6 g) and was found by NMR analysis to contain urea (5.43
ppm) and other
salts (6.80 ppm). This material was used directly in the next step without
further purification.
Example 5
1-amino-3-iminoben2[f]isoindolenine 7
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The crude nitrate salt 12 (154.6 g) was suspended in acetone (400 mL) with
cooling in an ice/water
bath to 0 C. Sodium methoxide (25% in methanol; 284 ml; 1.3 mol) was added
slowly dropwise
via a dropping funnel at such a rate as to maintain an internal temperature of
0-5 C. Upon
completion of the addition, the reaction mixture was poured into cold water (2
x 2 L) in two 2 L
conical flasks. The mixtures were then filtered on sintered glass funnels and
the solids were
washed thoroughly with water (250 mL; 200 mL for each funnel). The fine brown
solids were air-
dried over 2 days and then further dried under high vacuum to give the
benzisoindolenine 5 as a
fine brown powder (69.1 g; 73%).
Example 6
Naphthalocyanatogallium methoxytriethyleneoxide
N N
I~OR9' \
\ \ I N-GN /
N N - N
\ /
R4 = CHZCHZOCHZCHZOCHZCHZOMe
Gallium chloride (15.7 g; 0.089 mol) was dissolved in anhydrous toluene (230
mL) in a 3-neck
flask (1 L) equipped with a mechanical stirrer, heating mantle, thermometer,
and distillation outlet.
The resulting solution was cooled in an ice/water bath to 10 C and then
sodium methoxide in
methanol (25%; 63 mL) was added slowly with stirring such that the internal
temperature was
maintained below 25 C thereby affording a white precipitate. The mixture was
then treated with
triethylene glycol monomethyl ether (TEGMME; 190 mL) and then the whole was
heated to distill
off all the methanol and toluene (3 h). The mixture was then cooled to 90-100
C (internal
temperature) by removing the heating mantle and then the benzisoindolenine 5
from the previous
step (69.0 g; 0.35 mol) was added all at once as a solid with the last traces
being washed into the
reaction vessel with diethyl ether (30 mL). The reaction mixture was then
placed in the preheated
heating mantle such that an internal temperature of 170 C was established
after 20 min. Stirring
was then continued at 175-180 C for a further 3 h during which time a dark
green/brown colour
appeared and the evolution of ammonia took place. The reaction mixture was
allowed to cool to
ca. 100 C before diluting with DMF (100 mL) and filtering through a sintered
glass funnel under
gravity overnight. The moist filter cake was sucked dry and washed
consecutively with DMF (80
mL), acetone (2 x 100 mL), water (2 x 100 mL), DMF (50 mL), acetone (2 x 50
mL; 100 mL) and
diethyl ether (100 mL) with suction. After brief air drying, the product was
dried under high
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vacuum at 60-70 C to constant weight. Naphthalocyanatogallium
methoxytriethyleneoxide was
obtained as a microcrystalline dark blue/green solid (60.7 g; 76%); k. (NMP)
771 nm (Figure 7).
15
