POCl3 Chlorination of 4-Quinazolones

Article abstract of DOI:10.1021/jo102262k

The reaction of quinazolones with POCl₃ to form the corresponding chloroquinazolines occurs in two distinct stages, which can be separated through appropriate temperature control. An initial phosphorylation reaction occurs readily under basic conditions (R₃N, aq pK _a > 9) at t < 25 °C to give a variety of phosphorylated intermediates. Pseudodimer formation, arising from reaction between phosphorylated intermediates and unreacted quinazolone, is completely suppressed at these temperatures, provided the system remains basic throughout the POCl₃ addition. Clean turnover of phosphorylated quinazolones to the corresponding chloroquinazoline is then achieved by heating to 70-90 C. (N)- and (O)-phosphorylated intermediates, involving multiple substitution at phosphorus, have been identified and their reactions monitored using a combination of ¹H, ³¹P, and ¹⁹F NMR. Kinetic analysis of the reaction profiles suggest that the various intermediates react with both Cl^- and Cl₂P(O)O^-, but product formation arises exclusively from reaction of (O)-phosphorylated intermediates with Cl^-. (O)- and (N)-phosphorylated intermediates equilibrate rapidly on the time scale of the reaction. A minimum of 1 molar equiv of POCl₃ is required for efficient conversion of the intermediates to product.

Full text of DOI:10.1021/jo102262k

ARTICLE
pubs.acs.org/joc
POCl Chlorination of 4-Quinazolones
3
Euan A. Arnott, Lai C. Chan,* Brian G. Cox, Brian Meyrick, and Andy Phillips
AstraZeneca, Pharmaceutical Development, Silk Road Business Park, Charter Way, Macclesfield, Cheshire SK10 2NA, U.K.
S Supporting Information
b
ABSTRACT: The reaction of quinazolones with POCl to
3
form the corresponding chloroquinazolines occurs in two
distinct stages, which can be separated through appropriate
temperature control. An initial phosphorylation reaction
occurs readily under basic conditions (R N, aq pK > 9) at
3
a
t < 25 °C to give a variety of phosphorylated intermediates.
Pseudodimer formation, arising from reaction between
phosphorylated intermediates and unreacted quinazolone,
is completely suppressed at these temperatures, provided the
system remains basic throughout the POCl addition. Clean
3
turnover of phosphorylated quinazolones to the corre-
sponding chloroquinazoline is then achieved by heating to 70-90 °C. (N)- and (O)-phosphorylated intermediates, involving
1
31
19
multiple substitution at phosphorus, have been identified and their reactions monitored using a combination of H, P, and
F
-
-
NMR. Kinetic analysis of the reaction profiles suggest that the various intermediates react with both Cl and Cl P(O)O , but
product formation arises exclusively from reaction of (O)-phosphorylated intermediates with Cl . (O)- and (N)-phosphorylated
2
-
intermediates equilibrate rapidly on the time scale of the reaction. A minimum of 1 molar equiv of POCl is required for efficient
3
conversion of the intermediates to product.
’
INTRODUCTION
Scheme 1. Chlorination of 4-Quinazolones
Quinazolines are a common structural feature in a range
of drugs for the treatment of cancer, such as Gefitinib, N-(3-
chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpro-
poxy)quinazolin-4-amine, 1, and Erlotinib, N-(3-ethynylphenyl)-
1
6,7-bis(2-methoxyethoxy)quinazolin-4-amine, 2.
the intermediacy of a dichloridophosphate, analogous to 5,
3
Scheme 1, in the chlorination of guanosine triacetate, and such
intermediates have also been postulated for the chlorination of
4
4
-quinazolones and the related 4-pyrimidones.
4
-Chloroquinazolines, 3 (QCl), derived from the chlorination
The main problematic impurity arising during chlorination is
“(N)-dimer” 6, which results from the reaction between unpho-
sphorylated quinazolone, QOH, and the phosphate intermediate, 5.
of the corresponding 4-quinazolone, 4 (QOH), are therefore
synthetically valuable intermediates. Typically, (3) is not isolated
as a solid but telescoped through to desired derivatives by
reaction with a nucleophile (e.g., ArNH , ArOH/base).
2
2
The chlorination of 4-quinazolones is well precedented and is
often effected by refluxing the 4-quinazolone in excess POCl in
Received: November 19, 2010
Published: February 04, 2011
3
the presence of a tertiary amine (Scheme 1). Evidence exists for
r 2011 American Chemical Society
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|J. Org. Chem. 2011, 76, 1653–1661

The Journal of Organic Chemistry
ARTICLE
31
a
Table 1. Typical P NMR Shifts for Phosphorus-Containing Species
b
P(O)O-
c
species
POCl
3
(O)
(N,O)
Cl
2
(O,O)
(N,O,O)
(O,O,O)
δ
P
/ppm
þ4.5 very broad s
-0.2 s
-0.9 d, 2 Hz
-7.5 broad s
-10.4 s
-14.1 d, 3 Hz
-25 s
D/10- m s
10
2 -1
17.9
10.9
7.9
7.6
7.9
7.0
7.0
a
b
2
0 °C, PhF þ d
5
-PhF lock. Abbreviations: (O) = monosubstituted, (O)-linked phosphate, (N,O) = disubstituted, (N)- and (O)-linked phosphate,
c
etc.; see text. Low abundance (<1%), tentative assignment only.
The minimization of the reaction of 5 with QOH relative to
that with Cl is, therefore, important for the success of the
phosphonochloridate, 10, and the trisubstituted phosphate bis-
5-fluoroquinazolin-4-yl) (5-fluoro-4-oxoquinazolin-3(4H)-yl)-
-
(
synthetic procedure. A process of “hot inverse addition”,
whereby a slurry of (highly insoluble) QOH is added slowly
to an excess of POCl /R N at 75-95 °C, can achieve sig-
phosphonate, 11. In 10 and 11, nonequivalent fluorines are
identified by subscripts a and b.
3
3
nificant reductions in dimer formation. The process is, how-
ever, operationally difficult, especially at larger scale, as it
depends upon rapid mixing and good dispersion of the
QOH slurry as it is added, making addition time critical and
sensitive to scale/reactor geometry. Overall yields by this
procedure are also typically relatively modest (∼70%). A
much preferred option would be the direct addition of POCl3
under conditions such that the reaction outcome is not
sensitive to the addition time. In order to achieve this, a greater
understanding of the nature and reactivity of the reaction inter-
mediates is required.
Identification of the species was achieved by a combination
of methods. Initially, the degree of substitution was deter-
mined by the relative apparent diffusion coefficients of the
We report here a detailed kinetic and mechanistic study of
the chlorination of quinazolones. 5-Fluoroquinazolin-4(3H)-
one, 7, in chlorobenzene was chosen for kinetic studies for
two reasons: first, the intermediates and product are soluble,
and, second, the presence of the spin-active “reporter” nuclei
1
19
31
various species determined using H, F, and P pulsed field
gradient stimulated echo NMR experiments as listed in
5
1
9
31
1
Table 1. Figure 1 shows a pseudo-2D (DOSY) representa-
F, along with P and the clearly resolved H signal from the
31
tion of a typical P diffusion experiment. The apparent
H-2 proton of the pyrimidine ring (δ ∼9 ppm), allows
convenient and comprehensive monitoring by NMR of the
reactant, product, and intermediates. The simple monopho-
sphorylated 5-fluoroquinazolin-4-yl dichloridophosphate, 8,
for example, contains all three nuclei. General conclusions
from this study have been confirmed for several additional
quinazolones.
diffusion coefficient (D) is a measure of the approximate
molecular weight and so for example, as seen in Table 1, the
disubstituted species, (N,O) and (O,O) have the same coeffi-
cient, which is significantly larger than that seen for the
trisubstituted (N,O,O) and (O,O,O) species. The spectral
assignments were subsequently confirmed by correlation of
31
1
19
intensity changes with time between P, H, and F NMR
3
1
signals as the reaction occurred. A typical set of P NMR
spectra obtained during a reaction are shown in Figure 2.
Substitution isomerism, involving various (O)-linked and (N)-
linked phosphates, as in (N,O) and (N,O,O), 10 and 11,
respectively, was confirmed by the presence of nonequivalent
fluorines in mixed phosphates and different coupling patterns:
3
JPH coupling of ∼3 Hz was characteristic of (N)-linked
phosphates, whereas there was no coupling for O-linked
phosphates, J = 0. P NMR for the various phosphorus-
5
31
PH
Since the quinazolones are ambident nucleophiles (O and N)
containing species are listed in Table 1.
Inorganic Phosphate. At the completion of the reaction in
typical aromatic solvents, such as chlorobenzene or anisole,
and POCl possesses three reactive P-Cl bonds, multiple
3
intermediates might be expected. A subset of these possible
intermediates is indeed observed. We show, furthermore, that the
phosphorylation reactions occur much more rapidly than the
subsequent conversion of the various intermediates to product.
This can be used to advantage in designing a robust and efficient
synthetic process.
the exclusive stoichiometric phosphorus-containing bypro-
-
duct is Cl P(O)O , which coexists in solution with the excess
2
POCl . There was no measurable tendency for formation of
3
diphosphoryl chloride via the substitution reaction, eq 1, to
occur, although it is a known product of partially hydrolyzed
6
POCl . Rather, at longer reaction times, there is a gradual
3
-
tendency for Cl P(O)O to disproportionate, eq 2, giving the
2
’
RESULTS AND DISCUSSION
corresponding (nonsymmetrical) trichloropyrophosphate:
3
1
Identification of Intermediates. The significant intermedi-
P NMR δ (ppm) -8 (d, JPP = 40 Hz) and -16 (d, JPP
=
ate species observed were the (O)-phosphate 8, the disubstituted
phosphates bis(5-fluoroquinazolin-4-yl) chloridophosphate, 9,
and 5-fluoroquinazolin-4-yl (5-fluoro-4-oxoquinazolin-3(4H)-yl)-
40 Hz). We assume that the lack of reaction between
Cl
unfavorable equilibrium, as the rate of reaction in the forward
-
P(O)O and POCl in these solvents is a result of an
2
3
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31
Figure 1. P DOSY spectrum of species in Table 1 under the same experimental conditions. A pulse field gradient stimulated echo experiment with
bipolar gradient was used. To generate diffusion-weighted data, eight increments were acquired with increasing gradient strength. Data was fitted to a
single exponential; Bruker TopSpin software was used to generate the pseudo-2D plot. The dotted line represents the diffusion coefficient for (a)
monosubstituted, (b) disubstituted, and (c) trisubstituted species.
direction for eq 1 might be expected be greater than that
of eq 2.
with the substrate 7-fluoro-5-isopropoxyquinazolin-4(3H)-one,
12, in chlorobenzene with various added bases.
The work was carried out in an Omnical Ultralow Super CRC
calorimeter, using an external circulating bath (Presto bath with
Baysilone KT3 oil) to maintain the reaction temperature at
Phosphorylation Reaction. Preliminary studies showed that
20 °C. POCl was added to a mixture of the substrate and base
3
in the presence of a strong base, such as diisopropylethylamine
rapidly in a single portion (“dump-charge”), and the power
output was recorded every 15 s. Samples were taken for NMR
analysis when the power output had returned to baseline level.
The progressive and total heat output was calculated by integra-
tion of the heat-output curve, using baseline-to-baseline extra-
polation in MS Excel. Typical heat-output profiles and the
corresponding -ΔH values are included in Figure 3. They
show that the heat output, and hence the reaction, is largely
7
(
aq pK = 11), phosphorylation to give the intermediate Phos-
a
phates (e.g., 8-11) is essentially complete after 30 min at 20 °C.
Furthermore, at this temperature all other reactions are slow.
This means that direct addition of POCl can be performed at
3
<
25 °C to give only assorted phosphate intermediates, without
forming the dimer 6 impurity (<0.5%).
The phosphorylation reactions are strongly exothermic and
are particularly convenient for a calorimetric investigation. Quan-
titative details of the reaction were explored calorimetrically
31
19
(>98%) complete after 30-40 min. P and F NMR analysis of
the resulting reaction mixtures confirmed complete conversion
1
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31
Figure 2. P spectra showing the progress of the reaction under the experimental conditions (70 °C, hence the chemical shifts shown are slightly
different from those described in Table 1 which are obtained at 20 °C): (a) full spectrum (excluding POCl
and (N,O).
3
); (b) expansion of the region containing (O)
Figure 3. Heat flow for reaction of quinazolone, 12, with POCl (1.5 equiv) and R N (1.2 equiv) in PhCl at 20 °C: diisopropylethylamine (DIPEA)
3
3
(blue); triethylamine (red).
of QOH to phosphorylated intermediates with negligible forma-
tion of dimer 6 (<0.5%) (the relevant NMR spectra are available
in the Supporting Information).
The observed rates of phosphorylation depend upon the pKa
7
of the base (water values, 25 °C, bracketed), DIPEA (11.0) ≈
Et N (10.5) > n-Bu N (9.0), and completion of reaction on a
3
3
-
1
The total heat output (ΔH ∼ -80 kJ mol ) includes the heat
practical time scale requires a base with aq pK g 9. The use of
a
of reaction and the heat of crystallization of the accompanying
weaker bases, such as N-methylmorpholine (7.6), produces only
þ
-
amine hydrochlorides, RNH Cl . The reaction in the presence of
a very sluggish reaction at 20 °C. These observations suggest that
3
-
n-Bu N, for which the hydrochloride is soluble, gave ΔH ∼ -70
the quinazolone phosphorylates via its anion, QO . It was also
3
-
1
kJ mol , indicating that the major portion of the heat comes from
the phosphorylation reaction. The hydrochloride of DIPEA is
moderately soluble and crystallization occurs as a delayed event,
found that it is essential to have g1.0 equiv of R N to keep
3
conditions basic throughout POCl addition: acidic conditions
3
leads to not only slower phosphorylation but also much more
but for Et N the much lower solubility of the hydrochloride results
side product dimer 6.
In summary, in the presence of a strong base (aq pK g 9),
rapid reaction occurs between QOH and POCl to give phos-
phate intermediates at room temperature. The use of tempera-
3
in precipitation occurring throughout the reaction rather as a
separate event. It should be noted that the amine hydrochloride
formed during the phosphorylation provides the chloride ion
required for subsequent product formation.
a
3
tures in the range 0-25 °C effectively “freezes out” all reactions
1
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ARTICLE
Scheme 2. Phosphorylation of Quinazolone 7
There is clear evidence for an equilibration of (O,O) and
N,O) species which is rapid on the time scale of the reaction; the
(
equilibrium constant K , eq 3, has a value of 2.8 at 70 °C.
e
1
½
ðO; OÞꢀ
ꢀ ¼ 2:81
K ¼
e
ð3Þ
½
ðN; O
Thus, the ratio [(O,O)]/[(N,O)] was independent of the
initial distribution of intermediates and remained constant
throughout the conversion of the intermediates to the product,
QCl. We assume that the interconversion must be intramolecular.
Alternative potential mechanisms involving, for example, rever-
-
-
sion of (O,O) to (O) and QO by reaction at P with Cl , follow-
-
ed by a recombination of (O) and QO to give (N,O), are not
feasible, as they would be disrupted by a competitive reaction of
-
the liberated QO with POCl to give (O). We also assume that
3
8
this interconversion is general for N-/O-substituted species.
Kinetic modeling was consistent with the following reactions
occurring for the various intermediate phosphates.
(
a). (O)-Phosphate. Direct conversion to product by S Ar
N
-
reaction with Cl , eq 4:
An analogous reaction of (O) with the dichlorophosphate anion
-
Cl P(O)O is also possible but merely leads to phosphate exchange.
2
(
b). (O,O)/(N,O)-Phosphates. Two possible reactions occur:
-
-
-
(
i) S Ar reaction with Cl to give product and (O )/(N ),
illustrated for (O ), 14 (5-fluoroquinazolin-4-yl) chloridopho-
N
-
sphate, eq 5:
except phosphorylation: a slow, direct addition of POCl is
3
therefore possible (addition times of up to 120 min are tole-
rated). This is especially important on a manufacturing scale
because of the highly exothermic nature of the phosphorylation
-
1
reaction (ΔH ∼ -80 kJ mol ).
Conversion of Phosphates to Product Chloroquinazoline:
Kinetic and Mechanistic Studies. Once complete phosphor-
ylation has occurred at 20 °C, the mixture of phosphates can
-
-
In the presence of excess POCl , however, (O )/(N ) react
3
rapidly in a non-rate-determining step to give (O) and (Cl) -
2
-
P(O)O , eq 6.
be heated to 70-90 °C to bring about clean turnover to
-
4
-chloro-5-fluoroquinazoline, (13) QCl, by attack of Cl .
Reaction profiles were obtained by NMR and kinetic model-
ing has been carried out for the chlorination of 5-fluoroqui-
nazolin-4(3H)-one, 7, with POCl /diisopropylethylamine in
3
chlorobenzene, PhCl, at 70 °C. This combination of base/
solvent gave homogeneous solutions with reasonable concen-
trations ([QOH] ∼ 0.3 M), allowing direct monitoring of the
reaction by NMR. The reaction scheme for the phosphoryla-
tion and the abbreviations used for the intermediate species
are shown in Scheme 2. Small amounts of (N) (e1%) and di-
or trisubstituted phosphates, other than those included in
Scheme 2, were observed.
The net reaction is therefore given by eq 7.
k2
-
-
ðO; OÞ=ðN; OÞ þ Cl
f
QCl þ ðOÞ þ Cl2PðOÞO
ð7Þ
POCl3
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ii) Reaction analogous to eq 5 of (O,O)/(N,O) occurred, but
ARTICLE
(
Table 2. Rate Constants Derived from the Reaction of
a
-
-
with Cl P(O)O attacking (O,O)/(N,O) rather than Cl , to
Quinazolone 7 with POCl in Chlorobenzene at 70°C
2
3
-
-
give (O) and (O )/(N ). The latter again reacts with excess
1
reaction
rate constant/M- s-1
POCl (eq 6) to form another 1 mol of (O). The net reaction is,
3
-
-3
therefore, given by eq 8:
(
O) þ Cl (eq 4)
k
k
k
1
2
3
= 1.1
= 3.4
= 2.1
7
7
1
ꢁ 10
ꢁ 10
ꢁ 10
-
-4
-4
(
O,O)/(N,O) þ Cl (eq 7)
k3
-
-
P(O)O- (eq 8)
2
ðO; OÞ=ðN; OÞ þ Cl2PðOÞO
f
2ðOÞ þ Cl2PðOÞO
(O,O)/(N,O) þ Cl
POCl3
-
P(O)O- (eq 9)b
-4
(
N,O,O) þ Cl /Cl
2
k
4
= 2.1 ꢁ 10
= 2.8
ð8Þ
-
(
N,O) h (O,O)
K
e
1
a
b
Diisopropylethylamine as base. Average rate constant for attack by
-
(
c). (N,O,O)-Phosphate. Reactions with Cl or Cl P(O)O ,
-
-
2
2
Cl and (Cl) P(O)O .
analogous to those in eq 7 and 8, occur giving product QCl and
O,O)/(N,O). The relatively low levels of (N,O,O) present in the
(
31
19
initial phosphate distribution (<2% on P, 6% on F (QOH))
meant that we were unable sensibly to distinguish between the
-
-
reactivity of Cl and (Cl) P(O)O . The disappearance of (N,O,
2
O) was therefore represented by a single, average rate constant,
k4, eq 9.
k4
-
-
ðN; O; OÞ þ Cl =Cl2PðOÞO
f
QCl þ ðO; OÞ=ðN; OÞ
POCl3
-
þ ðOÞ þ Cl PðOÞO
ð9Þ
2
It is important to note that reactions of di- and trisubstituted
phosphorylated intermediates give initially anionic phosphates
-
-
(
e.g., (O ) and (N ) from (O,O)/(N,O), eq 5), which under our
reaction conditions of excess POCl (g1 molar equiv relative to
3
QOH, typically 1.5 equiv) are observed transiently in trace
quantities only. In the absence of an excess of POCl , however,
3
although phosphorylation proceeds readily (1/3 equiv POCl3
only is required), conversion to product stalls. Instead, there is a
progressive build-up of two predominant, unreactive intermedi-
-
ates, whose NMR is consistent with the anionic species (N ), 15
3
1
(
5-fluoro-4-oxoquinazolin-3(4H)-yl)phosphonochloridate) ( P
-
NMR δ = -10.1 ppm, d, J = 4 Hz), and (N,N ), 16 (bis-
5-fluoro-4-oxoquinazolin-3(4H)-yl)phosphinate) ( P NMR
31
(
δ = -15.1 ppm, t, J = 4 Hz).
Figure 4. Reaction profiles for intermediates and product for quinazo-
at
lone 7 at 70 °C in chlorobenzene following 30 min addition of POCl
3
This observation is consistent with the involvement of POCl3
20 °C (see text); [7] = 0.301 M, POCl (1.5 equiv), diisopropylethy-
3
in the conversion of the initial products resulting from the reac-
lamine (1.5 equiv). Full lines are calculated using the rate constants from
-
-
tions of (O,O)/(N,O) and (N,O,O) with Cl and Cl P(O)O to
Table 2: (a) intermediates and products; (b) expanded view of inter-
mediates.
2
(
O) and (O,O)/(N,O), as in eqs 5-9 of the proposed reaction
scheme.
A further important point is that only O-substituted Phosphate
POCl produces higher levels of di- and trisubstituted phosphate
3
intermediates.
-
-
intermediates can react with Cl or Cl P(O)O to give product or
2
further intermediates on the reaction pathway; N-substituted inter-
mediates react indirectly via equilibration to the corresponding
O-substituted species.
Reactions were modeled on the basis of eqs 4 and 7-9 for two
different starting phosphate distributions resulting from (a) a
Full details of the kinetic model are given in the Supporting
Information. Rate constants for reactions of the various phos-
phate intermediates derived from quinazolone 7 in chloroben-
zene are listed in Table 2.
The reaction profiles are shown in Figures 4 and 5, which
include the NMR-derived species concentrations, together with
those calculated from the kinetic model using the rate constants
listed in Table 2.
“
normal” POCl addition at 20 °C over 30 min, followed by
3
heating to 70 °C, and (b) a dump-charge of POCl at 20 °C,
followed by heating to 70 °C. The former addition profile for
3
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ARTICLE
Scheme 3. Influence of Solvent on Dimer Formation
Table 3. Solvent Dependence of Dimer Formation in the
Chlorination of 7
a
a
solvent
% chloroquinazoline
% dimer
chlorobenzene
methoxybenzene
dimethyl ether
butyronitrile
>99
>99
98
<1
<1
2
97
3
acetonitrile
89
11
a
19
Yields are calculated from F NMR integrals.
Scheme 4. Influence of Base on Dimer Formation
Table 4. Influence of Base upon Dimer Formation in the
Chlorination of 12
Figure 5. Reaction profiles for phosphate-containing intermediates and
product for quinazolone 7 at 70 °C in chlorobenzene following rapid
addition of POCl at 20 °C (see text); [7] = 0.301 M, POCl (1.5 equiv),
a
a
base
% QCl
% dimer
3
3
diisopropylethylamine (1.5 equiv). Full lines are calculated using the rate
constants from Table 2: (a) intermediates and products; (b) expanded
view of intermediates.
diisopropylethylamine (80 °C)
tri-n-butylamine (20 °C)
triethylamine (80 °C)
99
99
94
88
1
1
6
triethylamine (20 °C)
12
The most obvious difference between the profiles in Figure 4
and 5 is to be seen in the behavior of (O), which initially increases
in Figure 4 (Figure (4a)) but falls continuously in Figure 5
a
19
Yields are calculated from F NMR integrals.
(
Figure 5b). This is a consequence of the initially higher levels of
latter feature is accommodated very well by the (chemically
-
di- and trisubstituted intermediates observed upon relatively
slow addition of POCl (Figure 4); the result is that initially its
sensible) reaction of the intermediates with both Cl
-
(decreasing during reaction) and Cl P(O)O (increasing),
3
2
rate generation from (O,O)/(N,O) exceeds its rate of reaction
with Cl to give product QCl.
as described in the model. An alternative postulate of nucleo-
philic catalysis of the substitution reactions by the tertiary
amine bases, involving rate-determining reaction between (O,
-
The good agreement between the experimentally derived
values and those calculated using the rate constants in Table 2,
especially given the relatively complicated reaction profiles for
the two different phosphate distributions, provides strong
support for the reaction scheme described in eqs 4-9. We
explored a number of possible alternative reaction sequences
but were unable to find any that gave similar agreement. Two
key features in particular must be accounted for by any
successful model: the first is the variation of the concentration
of the monosubstituted phosphate (O), which clearly reflects
both its reaction to products and its formation from the more
highly substituted intermediates during reaction; the second is
that the decrease in the (O,O)/(N,O) species is close to
exponential and far from the second-order curve that would
result from simple reaction of these species with chloride. This
O)/(N,O) and R N, also fits the observed reaction profiles.
3
The steric bulk of the amines would, however, make this very
unlikely, and indeed, the reactions showed no rate acceleration
upon addition of extra base.
The initial distribution of phosphates depends upon the
substitution pattern of the parent quinazolone as well as the
mode of addition of POCl , but in all cases a surprisingly strong
3
tendency to form di- and trisubstituted intermediate phosphates
was observed. We note, for example, that for the 5-fluoroquina-
zolone, 7, the proportion of the simple monosubstituted deriva-
tive (O), 8, corresponds to only 23% of the total quinazolone,
even following rapid addition of POCl to the quinazolone/base
3
mixture. Alkoxy-substituted quinazolones, however, form a high-
er proportion of the monosubstituted analogues of 8, up to
1
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ARTICLE
Scheme 5. Quinazolone Chlorination with POCl3
6
5-70% under similar reaction conditions, and overall also give
preferred, particularly those of higher polarity, such as anisole
rise to a lower proportion of N-phosphorylated intermediates.
Dimer Formation. The optimized reaction conditions ap-
plied to the 5-fluoroquinazolone, 7, namely direct addition of
and chlorobenzene; avoid CH CN. (4) Good selectivity
3
with respect to dimer formation and conversion of intermedi-
ates to product requires (i) g1.0 equiv of R N to ensure
3
POCl (1.2-1.5 equiv) over 30-60 min to a slurry of 7 and
that conditions remain basic throughout POCl addition and
3
3
diisopropylethylamine (1.2-1.5 equiv) at 15-20 °C in chloro-
benzene (5-40 vol), followed by warming to 70-90 °C,
afforded the chloroquinazolone with only ∼0.5% dimer. The
final outcome of the reaction was, however, sensitive to the
nature of both the solvent and the base, despite the fact the
almost complete absence of dimer immediately following phos-
phorylation. This is illustrated by the following examples: the
influence of solvent on the chlorination of 7 (Scheme 3) and the
influence of base on the chlorination of 12 (Scheme 4). The
results are summarized in Tables 3 and 4.
(ii) g1.0 equiv of POCl to enable intermediates to funnel
3
effectively to product.
The conditions have been applied successfully to a range of
alkoxy- and fluoro-substituted quinazolones at laboratory and
kilogram scales. It was noticeable that for the alkoxy-substituted
quinazolones, e.g., 6,7-dimethoxyquinazolin-4(3H)-one, there was
less separation between the rates of phosphorylation and the
subsequent chlorination, with some product formation at 20 °C,
but this did not affect the outcome. The conditions described
may also be expected to be relevant to the chlorination of related
systems, such as pyrimidones.
The most pronounced solvent effect on the degree of dimer
formation occurred with acetonitrile as solvent (Table 3). We
may speculate that this is related to a lower degree of ion-pairing
formation in this more polar solvent and that the resulting higher
level of free chloride more readily promotes the reverse reaction
’ EXPERIMENTAL SECTION
Materials. 5,7-Difluoroquinazolone and inorganic chemicals were
high-purity commercial reagents used without further purification.
A typical chlorination reaction with POCl with quinazolone in
3
anisole is described for preparation of 4-chloro-5,7-difluoroquinazoline.
The chloroquinazoline is not isolated; instead, it is coupled with the
appropriate aniline to give the corresponding anilide.
Preparation of 4-Chloro-5,7-difluoroquinazoline. To a
cooled (10 °C) slurry of 5,7-difluoroquinazolone (20 g, 0.109 mol, 1.0
molar equiv) and DIPEA (24.90 mL, 0.143 mol, 1.3 molar equiv) in
-
at phosphorus, giving increased levels of QO during reaction.
It should be emphasized that in all cases reported in Tables 3
and 4, reaction mixtures at completion of phosphorylation were
essentially completely free of dimer. Thus, dimer formation
occurred during the conversion of phosphates to the product
chloroquinazoline. This presumably arises from some reversi-
-
bility of the phosphorylation reaction by reaction of Cl at P at
-
higher temperatures to regenerate QO , which can then couple
3
anisole (140 mL, 7 rel vol) was added POCl (12.3 mL, 0.132 mols, 1.2
with the (O)-phosphate to give dimer. In keeping with this, it was
molar equiv) over 30 min, keeping the reaction temperature 20 °C. The
mixture was stirred at 20 °C for 1 h, heated to 95 °C, and held at 95 °C
for 2.5 h. The mixture is sampled for reaction completion by quenching
the analytical sample with pyrrolidine and analyzing by HPLC. Gen-
erally, 98-99% (HPLC area %) conversion with ∼ <2% starting
material is obtained.
HPLC Method for 4-Chloro-5, 7-difluoroquinazolone. Zorbax
SB-C18, 1.8 μm (50 ꢁ 4.6 mm), gradient as in Table 5.
confirmed that the use of larger excesses of POCl reduced dimer
3
formation in all cases, presumably by competitively converting
-
any QO generated to (O)-phosphate. Use of aromatic solvents,
such as chlorobenzene or anisole, and bases, such as tributyla-
mine and diisopropylethylamine, whose hydrochlorides are
soluble at reaction temperatures, minimizes the problem.
’
SUMMARY
a
We describe a general method for cleanly converting quina-
Table 5
zolones (QOH) to 4-chloroquinazolines, illustrated in Scheme 5.
The key concept underlying Scheme 5 is the separation of two
distinct reaction phases, governed by control of reaction tem-
time/min
% water
% ACN
% TFA (1%)
0
85
70
45
45
85
5
20
45
45
5
10
10
10
10
10
perature. This allows a convenient, direct addition of POCl and
1.0
3
leads to greatly reduced dimer 6 formation and very high overall
yields (>95% in all cases studied). The hold time following
8
8
9
.0
.90
.0
POCl addition is necessary to ensure complete phosphorylation
3
of QOH prior to heating. Important points may be summarized
a
Run time = 9 min; post time = 2 min; flow rate = 1.5 mL/min; injection
as follows: (1) An initial fast reaction between POCl and QOH
3
volume = 5 μL; column temperature = 30 °C; wavelength = 240 nm.
Sample preparation: In a 25 mL volumetric flask, quench 25 μL of the
reaction mixture with 0.5 mL of pyrrolidine. Fill to volume with ACN or
1:1 aqueous ACN; 5,7-fluoroquinazolone, rt, 2.22 min; 5,7-difluoro-
4-(pyrrolidin-1-yl)quinazoline, rt, 2.57 min.
under strongly basic conditions at < 25 °C to prepare phosphate
intermediates is followed by warming to induce turnover to QCl
product. (2) The base must have a pK g 9 (aqueous pK );
a
a
diisopropylethylamine is preferred. (3) Aromatic solvents are
1
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ARTICLE
’
ASSOCIATED CONTENT
S
Supporting Information. Kinetic model, NMR spectra,
b
and HPLC chromatograms for the phosphorylation of 7-fluoro-
5
-(propan-2-yloxy)quinazolin-4-(3H)-one 12 and the formation
of 4-chloro-5-fluoroquinazolone, 13 and 4-chloro-5,7-difluoro-
quinazoline. This material is available free of charge via the
Internet at http://pubs.acs.org.
’
AUTHOR INFORMATION
Corresponding Author
*E-mail: lai.chan@astrazeneca.com.
’
REFERENCES
(1) Noble, M. E. M.; Endicott, J. A.; Johnson, L. N. Science 2004, 303,
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(
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(
(
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(
(
(
5) Tanner, J. E. J. Chem. Phys. 1970, 52, 2523.
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a a
references cited therein.
8) For example, reaction of related 5,7-difluoroquinazolin-4-ol with
the less reactive P-Cl species (PhO) P(O)Cl forms initially predomi-
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(
2
(
1
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