3946
S. Yang, W. A. Denny / Tetrahedron Letters 50 (2009) 3945–3947
Table 1
the careful fractional crystallisation of isomer mixtures required
was a potential drawback for large-scale synthesis.
Comparison of methods for the preparation of 1
A completely different approach to the synthesis of 1 (Scheme
4) was prompted by a publication13 showing that 3,4-dimethyl-
benzoic acid (9) could be brominated directly to give 2,5-dibro-
mo-3,4-dimethylbenzoic acid (12) as the main product. We
found that the 5-Br group in 12 activated the 2-Br to allow regio-
selective coupling with anilines or phenols, and moreover was eas-
Method
No. of steps
Overall yield (%)
Reference
Sandmeyer (Scheme 1)
Modified isatin (Scheme 2)
Nitration (Scheme 3)
7
6
6
4
15
30
25
51
7
10
12
This work
Dibromination (Scheme 4)
ily removed by hydrogenation. Thus bromination of
9 with
bromine and silver nitrate, as reported, gave the 2,5-dibromo
derivative 12 in good yield after a single crystallisation from etha-
nol.14 Coupling of 12 with 2-hydroxyphenylacetic acid using the
previously reported method7 gave bromo diacid 13, which was
cyclodehydrated with concd H2SO4 to bromoxanthenone 14,15
which was purified by crystallisation. Hydrogenation of 14 gave
1 in an overall yield of 51% in four steps (Table 1). The last two
steps in the process can be reversed, hydrogenating 13 to give
the known7 diacid 7, which is then cyclodehydrated to 1 in similar
overall yield.16 Alternatively, bromination of 9 with NBS in sulfuric
acid, which was successfully used for 5,8-dibromoquinoline,17 gave
a similar result18 thus avoiding the use of expensive silver nitrate.
Traces of dibromo isomers and of monobromo and tribromo impu-
rities in this preparation of 12 did not couple, allowing the prepa-
ration of pure 7 by the above route.
In conclusion, an efficient and general synthesis of 5,6-dimeth-
ylxanthenone-4-acetic acid (ASA404, DMXAA) is developed using
3,4-dimethylbenzoic acid as starting material. This four-synthetic
step process employs relatively inexpensive reagents, does not in-
volve any heterogeneous, low-temperature or exothermic reac-
tions and produces only crystalline intermediates, making it
easily scalable.
as for
Scheme 1
ii
i
1
Me
NH
Me
NH2
Me
NH
Me
OAc
NOH
Me
Me
2
3
O
O
8
OAc
Scheme 2. Improved isatin synthesis. Reagents and conditions: (i) (AcO)2CHCOCl,
KHCO3, CH2Cl2, À10 °C to 20 °C, 30 min; (ii) NH2OHÁHCl, EtOH, H2O, reflux, 2 h, 83%
over two steps.
CO2H
O2N
6
CO2H
CO2H
i
Me
NH2
5
Me
+
5
ii
2
Me
Me
Me
H2N
Me
CO2H
Me
10a: 6-NO2
9
10b:
10c:
2-NO2
5-NO2
11
Me
Scheme 3. Nitration route. Reagents and conditions: (i) fuming HNO3, À5 °C, 5 min,
94% (ii) H2, Pd, C, 20 °C, 10 h, 98%.
References and notes
isatin 4 and its subsequent hydrolysis to give 5. Not unexpectedly
for a substrate with an ortho electron-donating group,9 the first
step gave 3 as a crude product of low purity, limiting the overall
yield of 1 in the seven-step process to about 15% (Table 1). A later10
improved method for the preparation of 5 by the acylation of 2
with 2,2-diacetoxyacetyl chloride and in situ hydrolysis of the
aldehyde diacetate 8 to the aldehyde (Scheme 2) improved the
overall yield of 1 to about 30% in a six-step process (Table 1).
A second alternative route to 5 via the reported11 direct nitra-
tion of 3,4-dimethylbenzoic acid (9), followed by reduction, was
also explored12 (Scheme 3). The initial mixture of the three nitro
isomers (10a–10c; ratio 1:2:1) obtained was purified by crystalli-
sation to give a 3.4:1 mixture of 10b and 10c only. Hydrogenation
of this mixture, followed by crystallisation gave 5 in 42% overall
yield from 9, resulting in an overall yield of 1 of about 25% in six
steps (Table 1). While this was broadly comparable to Scheme 2,
1. Rehman, F.; Rustin, G. Exp. Opin. Inv. Drugs 2008, 17, 1547–1551.
2. Ching, L. M.; Cao, Z.; Kieda, C.; Zwain, S.; Jameson, M. B.; Baguley, B. C. Br. J.
Cancer 2002, 86, 1937–1942.
3. Tozer, G. M.; Kanthou, C.; Baguley, B. C. Nat. Rev. Cancer 2005, 5, 423–435.
4. Pawel, V. AACR-NCI-EORTC Meeting Proceedings 2006. (Abstract 40).
5. McKeage, M. J. Expert Opin. Inv. Drugs 2008, 17, 23–29.
6. Li, J.; Jameson, M. B.; Baguley, B. C.; Pili, R.; Baker, S. D. Clin. Cancer Res. 2008, 14,
2102–2110.
7. Rewcastle, G. W.; Atwell, G. J.; Zhuang, L.; Baguley, B. C.; Denny, W. A. J. Med.
Chem. 1991, 34, 217–220.
8. Popp, F. D. Adv. Heterocycl. Chem. 1975, 18, 1–58.
9. Taylor, A. J. Chem. Res. (M) 1980, 4154–4171.
10. Rewcastle, G. W.; Sutherland, H. S.; Weir, C. A.; Blackburn, A. G.; Denny, W. A.
Tetrahedron Lett. 2005, 46, 8719–8721.
11. Courtin, A.; Von Tobel, H. R. Helv. Chim. Acta 1980, 63, 385–394.
12. Atwell, G. J.; Yang, S.; Denny, W. A. Eur. J. Med. Chem. 2002, 37, 825–828.
13. Ledochówski, Z.; Stefan´ ska, B. Roczniki Chem.: Ann. Soc. Chim. Polonorum 1966,
40, 291–300.
14. Procedure for dibromination: A solution of 3,4-dimethylbenzoic acid (9) (3.0 g,
20 mmol) in acetic acid (60 mL) was treated with 65% nitric acid (13 mL),
O
Br
iv
Me
iv
O
CO2H
iii
Me
14
X
CO2H
X
Br
CO2H
iii
1
ii
Me
Me
O
CO2H
Me
Me
CO2H
Me
13
9
: X=H
i
12: X=Br
O
Me
7
CO2H
Scheme 4. Dibromination route. Reagents and conditions: (i) Br2, AcOH, HNO3, AgNO3, 20 °C, 16 h, 75%; or NBS, H2SO4, 20 °C, 16 h, 80%; (ii) 2-hydroxyphenylacetic acid, Cu,
TDA-1, 85 °C, 4 h, 68%; (iii) H2SO4, water (9:1), 80 °C, 10 min, 95%; (iv) H2, Pd, C, 99%.