ether.cleavage.msoh.mw, biotransformation
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JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2002; 45: 529–538.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.577
Research Article
Rapid microwave-assisted cleavage of methyl
phenyl ethers: new method for synthesizing
desmethyl precursors and for removing
protecting groups
Anna Fredriksson* and Sharon Stone-Elander
Karolinska Pharmacy, Karolinska Hospital, SE-171 76 Stockholm, Sweden
Summary
A new microwave-enhanced method for rapid demethylation of methyl phenyl
ethers using neat methanesulfonic acid (CH
3
SO
3
H) is presented. Using a
monomodal microwave cavity, cleavage of anisole (
1
), used as model
compound, to phenol (
2
) was achieved with high conversions (ca 80%) in
very short reaction times (10–20 s). The feasibility of cleaving one or both of
two methoxy groups was illustrated with 4-(3-bromoanilino)-6,7-dimethoxy-
quinazoline (PD153035,
3
). High conversions (582%) of
3
were attained
with four different conditions (i.e. combination of input effect (35–125W) and
time (15 s–2min)). 4-(3-Bromoanilino)-7-hydroxy-6-methoxyquinazoline (
4
),
4-(3-bromoanilino)-6-hydroxy-7-methoxyquinazoline (
5
) and 4-(3-bromoanili-
no)-6,7-dihydroxyquinazoline (
6
), the possible mono- or di-demethylated
compounds, were obtained. Methods for rapid demethylations are of interest
in radiochemistry for post-labeling deprotections of hydroxyl containing
aromatic rings and also provide a more direct route for synthesizing precursor
compounds for labeling by alkylation. Copyright # 2002 John Wiley & Sons,
Ltd.
Key Words: demethylation; deprotection; precursor synthesis; PD153035
*Correspondence to: A. Fredriksson, Karolinska Pharmacy, Karolinska Hospital, SE-171 76
Stockholm, Sweden. E-mail: anna.fredriksson@ks.se
Copyright # 2002 John Wiley & Sons, Ltd.
Received 31 December 2001
Revised 14 February 2002
Accepted 16 February 2002
530
A. FREDRIKSSON AND S. STONE-ELANDER
Introduction
The usefulness of microwaves for accelerating organic syntheses has
been recognized since the mid-1980s and the number of synthetic
publications involving microwave techniques is rapidly increasing.
Reviews
1
3
are available that summarize microwave applications in
different types of reactions, such as oxidations, condensations,
heterocyclizations and carbon–carbon couplings. Reactions that usually
require conventional heating, often proceed equally well or better, but
more rapidly with microwave heating. The reductions in reaction times
achievable are particularly important for syntheses with short-lived
radionuclides and microwave techniques have been successfully applied
in many radiolabelings.
4,5
In addition to the labeling step, many tracer
preparations require additional transformations such as functional
group protection and deprotection that might also profit from the
accelerations achieved with microwave heating. For example, phenols
are often protected as ethers during aromatic radiofluorinations and the
ethers must be removed post-labeling (review on ether clevage).
6,7
A
typical example is the synthesis of [6-
18
F]6-fluorodopa in which the
catechol hydroxyls must be deprotected after the labeling step.
8
Such
multi-step syntheses are more common in fluorine-18 chemistry, but
ecient and fast conditions for demethylation of N, O and S could also
be potentially beneficial for carbon-11 radiochemical strategies.
Microwave-assisted deprotections of aromatic methyl ethers have
previously been performed with pyridine hydrochloride,
9
KOBu-t and
crown ether
10
and with lithium iodide and solid supports.
11
These
methods were either not fast enough and/or the reagents used did not
lend themselves well to the handling constraints of fluorine-18 and
carbon-11 chemistry. We have examined here the use of monomodal
microwave heating to speed up the cleavage of methylphenylethers with
methanesulfonic acid
12
(CH
3
SO
3
H). Since CH
3
SO
3
H is very polar, it
would be expected to interact strongly with the oscillating electro-
magnetic field. Its high boiling point (1678C at 10mm Hg) suggested
that high temperatures could be employed without the pressure increase
typically observed in microwave heating of the more volatile mineral
acids.
We report the use of this deprotection method in a model reaction
(Scheme 1a) in which methyl phenyl ether (anisole,
1
) was converted to
phenol (
2
). Furthermore, the mono- and di-demethylation of PD153035
(4-(3-bromoanilino)-6,7-dimethoxyquinazoline,
3
, Scheme 1b), a tyrosine
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2002; 45: 529–538
531
RAPID DEMETHYLATIONS
Scheme 1. Methyl phenyl ether cleavage with methanesulfonic acid was studied
in: (a) the conversion of anisole (
1
) to phenol (
2
); and (b) the conversion of
PD153035 (
3
) to the two monomethoxy compounds (
4
and
5
) and the dihydroxy
product,
6
kinase inhibitor selective for the epidermal growth factor receptor,
13
was also studied. Finding feasible routes for rapidly synthesizing the
desmethyl counterparts of potentially interesting pharmaceuticals can
expedite the tracer developmental process. Directly demethylating the
parent compound avoids the alternative development and optimization
of sometimes complex and lengthy organic pathways. In compounds
with multiple methyl groups, access to all the different desmethyl
compounds may be desirable for labeling in different positions so that
the metabolism of the parent compound can be examined.
Experimental
General
All reagents, unless otherwise specified, were of analytical grade and
commercially available. Anisole (
1
) and CH
3
SO
3
H were obtained from
Aldrich and phenol (
2
) from Merck. 4-(3-Bromoanilino)-6,7-dimeth-
oxyquinazoline (PD153035,
3
) was synthesized as described previously
14
based on the method of Rewcastle et al.
15
HPLC analyses were
performed using a Shimadzu SPD-6A spectrophotometric detector, a
Shimadzu C-R4AX integrator and two Shimadzu LC-10AD pumps.
LC/MS-analysis were performed using a VG Platform II, Fisons
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2002; 45: 529–538
532
A. FREDRIKSSON AND S. STONE-ELANDER
Instrument. The monomodal microwave cavity used was a Microwell 10
(Personal Chemistry AB, Uppsala, Sweden).
Demethylation procedures
In pyrex vessels
16
1
(15 ml, 138 mmol) or
3
(1.5–20mg,. 4.2–55.5 mmol)
was dissolved in CH
3
SO
3
H (200 or 500 ml, respectively). The samples
were vortexed, the tube openings were covered with parafilm (to prevent
loss of sample in case of bumping) and they were subsequently treated
with microwaves of different input power (35–125 watts (W)) for
different times (10 s–2min). Immediately after irradiation (
eor,
end of
reaction) the temperature in the reaction mixture was measured using a
mercury thermometer (measuring interval 70–3608C). The demethyla-
tion of
3
was also performed with conventional heating at 200
58C
(silicon oil bath). Aliquots (5 ml) taken were diluted in distilled water
(dH
2
O, 200–400 ml depending on the initial concentration of
3
) for
HPLC analysis. In the model reaction aliquots (and reference
2
) were
diluted in ethanol.
Analysis
The conversion of
1
to
2
was followed at 270 nm using a PRP-1 column
(300
7.0mm, 10 mm) and a mobile phase of A (acetonitrile (MeCN)
containing 0.085 vol% trifluoroacetic acid (TFA)) and B (dH
2
O
containing 0.1 vol% TFA). At a flow rate of 2.0ml/min, the mobile
phase composition was changed by increasing A in a linear gradient
from 40 to 60% during 14min and then an isocratic elution at 75% A
from 14 to 25min. The demethylation of
3
was followed at 249 nm using
a C18 mBondapak
TM
column (Waters, 3.9
300mm, 10 mm), isocratic
elution with MeCN:dH
2
O:TFA-30:70:0.1 at 1.5ml/min.
The product of the demethylation of
1
was identified by coelution on
HPLC with reference
2
. The products
4
–
6
obtained in the demethylation
reaction of
3
were identified by LC/MS-analysis (positive (50–100 V)
electrospray ionization (ESI)) performed at the Swedish Pharmacy’s
Central Laboratory (Kungens Kurva, Sweden). The unfragmented
[M+H]
+
ions (m/z) were 359.8, 345.8, 345.8 and 331.8 for
3
–
6
,
respectively, based on the bromine-79 peak.
Conversions were estimated from the total area (area units, AU) of
the peaks deemed to be derived from the starting material. In the
demethylation of
1
, the AUs for
1
and
2
were related to the total AUs
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2002; 45: 529–538
533
RAPID DEMETHYLATIONS
Figure 1. HPLC chromatograms from the product distribution analyses (UV-
absorbance) for: (a)
1
(t
R
21.3 min) cleaved to
2
(t
R
9.4 min); and (b)
3
cleaved to the two mono demethylated products,
4
and
5
and the didemethylated
product,
6
. The approximate t
R
for
3
–
6
were 12.4, 9.7, 8.1 and 6.8 min,
respectively. The unidentified hydrophilic byproduct (t
R
1.8–1.9min) is marked
with an asterisk
Figure 2. (a) The temperature of CH
3
SO
3
H (500 ml) as a function of time
measured after microwave irradiation with different input power or during
conventional heating in an oil bath of 195–2008C; (b) A bar diagram showing the
conversions of
1
to
2
for different microwave input powers and times. Unidentified
byproducts are indicated with an asterisk
calculated (see a typical HPLC chromatogram in Figure 1(a)). The
molar absorptivities at 270 nm of
1
and
2
are nearly the same, with that
of
1
being slightly larger than that of
2
. Thus, conversions to
2
might be
slightly underestimated. All peaks other than
1
and
2
were considered as
unidentified byproducts (marked with an asterisk in Figure 2b). Since
independently synthesized references
4
–
6
were either not available at all
or in very small quantities, the amounts of
3
–
6
were calculated based on
their area as related to the initial concentration of
3
. An unidentified
polar byproduct (marked with an asterisk in Figure 1b) was also
produced in increasing amounts at longer times or higher input power.
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2002; 45: 529–538
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