Selective phenol alkylation: An improved preparation of efaproxiral

Article abstract of DOI:10.1080/00397910600636527

An improved, two-step synthesis of efaproxiral, used in breast cancer therapy, is described, utilizing inexpensive commodity chemicals for starting materials. Selective amide formation and O-alkylation in the presence of multireactive functional groups is demonstrated, thus avoiding protection/deprotection steps. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600636527

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Selective Phenol Alkylation: An Improved
Preparation of Efaproxiral
Joanne E. Anderson a , Roman Davis a , Russ N. Fitzgerald a & Jannine M.
Haberman a
a GlaxoSmithKline Chemical Development, Research Triangle Park, North
Carolina, USA
Published online: 16 Feb 2007.
To cite this article: Joanne E. Anderson , Roman Davis , Russ N. Fitzgerald & Jannine M. Haberman (2006)
Selective Phenol Alkylation: An Improved Preparation of Efaproxiral, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:15, 2129-2133, DOI:
10.1080/00397910600636527
To link to this article: http://dx.doi.org/10.1080/00397910600636527
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Synthetic Communicationsw, 36: 2129–2133, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600636527
Selective Phenol Alkylation: An Improved
Preparation of Efaproxiral
Joanne E. Anderson, Roman Davis, Russ N. Fitzgerald,
and Jannine M. Haberman
GlaxoSmithKline Chemical Development, Research Triangle Park,
North Carolina, USA
Abstract: An improved, two-step synthesis of efaproxiral, used in breast cancer
therapy, is described, utilizing inexpensive commodity chemicals for starting
materials. Selective amide formation and O-alkylation in the presence of multi-
reactive functional groups is demonstrated, thus avoiding protection/deprotection
steps.
Keywords: Bargellini reaction, 2-bromo-2-methylpropanoic acid, efaproxiral,
selective alkylation
We recently published an article[1] on the alkylation of phenols with 2-bromo-
2-methylpropanoic acid that illustrates advantages over previous methods,
specifically control of exotherm, exposure safety, and methacrylate
polymer. One previous method required alkylation of an ester of 2-bromo-
2-methylpropanoic acid, followed by saponification, and this approach
resulted in formation of polyacrylates, which were not easily detected or
cleaned from the reactors. A second and older method, the Bargellini
reaction, required extremely large amounts of sodium hydroxide, resulting
in large waste streams, and complex exotherm control. As described in the
published article, the use of 2-bromo-2-methylpropanoate minimized poly-
acrylate formation, and whatever polymer did form was easily removed
because of its solubility in water.
Received in the USA January 23, 2006
Address correspondence to Roman Davis, GlaxoSmithKline Chemical Develop-
ment, 5 Moore Drive, Research Triangle Park, NC 27709, USA. Fax: 919-315-8735;
E-mail: roman.d.davis@gsk.com
2129

2130
J. E. Anderson et al.
To further investigate the scope, utility, and limitations of the reaction,
we selected 2-(4-f2-[(3,5-dimethylphenyl)amino]-2-oxoethylgphenoxy)-2-
methylpropanoic acid, efaproxiral (Fig. 1), with its attendant complexity of
phenol versus amide versus active methylene alkylation, as a target of
synthesis.
We selected efaproxiral as an opportune target to demonstrate this
selective chemistry, because efaproxiral, the active pharmaceutical ingredient
in Allos Therapeutics’ Efaproxyn, is completing Phase III clinical trials for
treatment of brain metastasis originating from breast cancer. Although
certain tumors survive radiation damage, due to hypoxia (oxygen star-
vation), 2,3-diphosphoglycerate (2,3-DPG) increases the susceptibility
of tumors to radiation damage by reducing the oxygen-binding affinity of
hemoglobin. 2,3-DPG is unable to cross the red-blood-cell membrane.
The 2,3-DPG agonist, 2-(4-f2-[(3,5-dimethylphenyl)amino]-2-oxoethylgphe-
noxy)-2-methylpropanoic acid, efaproxiral, is able to cross the red-blood-
cell membrane and is therefore an improvement over 2,3-DPG at unloading
oxygen from hemoglobin.[2] In effect, efaproxiral is designed to make
tumors more responsive to radiation therapy by increasing the amount of
oxygen in tumor cells. The therapy agent does not have to enter the tumor
to be effective but is administered with supplemental oxygen. Because of
the large quantities of therapy agent required for Phase III multicenter trials
and the likely large tonnage required at launch, a simple, high purity, and
environmentally benign process was essential.
Anilide formation in the presence of many other functional groups, such
as phenol, in either reaction partner requires protection.[3] As we sought to
avoid protection or deportation steps in our synthesis, we rejected typical
stoichiometric activation reagents. Although other methods were successful
for the direct coupling of N-(3,5-dimethylphenyl)-2-(4-hydroxyphenyl)-
acetamide (e.g., trichlorotriazine,[4] benzotriazole reagents[5]), by far the
simplest way to prepare this anilide was to heat a mixture of 3,5-dimethylani-
line, 4-hydroxyphenylacetic acid, and catalytic boric acid under azeotropic
water-elimination conditions (Dean–Stark trap) for 18–20 h in toluene
(Scheme 1). For other examples of boric acid–catalyzed amide couplings,
see Scheme 1.[6] The putative mixed anhydride, stabilized via hydrogen
bonding, regenerates the catalytically active boric acid (Fig. 2). Once
the reaction was complete, as judged by the disappearance of
Figure 1. Efaproxiral.

Improved Preparation of Efaproxiral
2131
Scheme 1.
4-hydroxyphenylacetic acid, the mixture was cooled and the resulting solid
isolated by filtration. Interestingly, the presence of catalytic boric acid drasti-
cally reduced the reaction time and temperature compared to previously
reported conditions, which had required 3 days under Dean–Stark conditions
in xylenes.[7] Although other acids are likely to catalyze this reaction, the low
cost, safety, and ease of removal of boric acid makes it an especially attractive
catalyst.
Reaction of N-(3,5-dimethylphenyl)-2-(4-hydroxyphenyl)acetamide with
2-bromo-2-methylpropanoic acid under the conditions previously described
(NaOH, 2-butanone) provided a single product in high yield and purity
(Scheme 2). We demonstrated spectroscopically that this single product was
alkylated exclusively at the phenol and was unequivocally the desired 2-(4-
f2-[(3,5-dimethylphenyl)amino]-2-oxoethylgphenoxy)-2-methylpropanoic
acid. Through multiple bond correlations, NMR data confirm the presence of
the protonated amide. Infrared bands consistent with a phenol moiety were not
observed in the product spectrum, confirming alkylation at this site.
EXPERIMENTAL
All masses and volumes, except those defined by molar ratios, are
approximate.
HPLC reaction monitoring and analysis was conducted on a Luna C18(2)
column of 50 mm ꢀ 2 mm, 3 mm, at 408C, with a flow rate of 1 mL/min, and
UV visualization at 220 nm; mobile phase A: H2O (0.05%), mobile phase B:
CH3CN (0.05%); gradient: 0–95% B over 8 min.
Figure 2. Mixed anhydride.

2132
J. E. Anderson et al.
Scheme 2.
All temperatures are uncorrected. Starting materials, reagents, and
solvents were purchased from bulk commercial sources and used without
further purification.
N-(3,5-Dimethylphenyl)-2-(4-hydroxyphenyl)acetamide
A mixture of 4-hydroxyphenylacetic acid (0.26 mol, 40 g, 1.0 equiv), 3,5-
dimethylaniline (0.31 mol, 39 mL, 1.2 equiv), boric acid (0.02 mol, 1.6 g,
0.1 equiv), and toluene (0.5 L) was heated under reflux with water elimination
via a Dean–Stark trap for 18 h. The resulting mixture was cooled, and the
solid was collected by filtration, washed sequentially with toluene
(2 ꢀ 0.2 L) and water (2 ꢀ 0.2 L), and dried in vacuo at 50–558C to give
56–62 g (86–95%) of N-(3,5-dimethylphenyl)-2-(4-hydroxyphenyl)aceta-
mide. (Spectroscopic data were consistent with previously reported literature
data: see Ref. 7.)
2-(4-f2-[(3,5-Dimethylphenyl)amino]-2-oxoethylgphenoxy)-2-
methylpropanoic Acid
A
mixture of N-(3,5-dimethylphenyl)-2-(4-hydroxyphenyl)acetamide
(0.2 mol, 49 g) and 20–40 mesh NaOH (1.1 mol, 44 g) in 2-butanone (0.5 L)
was stirred and heated to 508C. After 1–2 h, a solution of 2-bromo-2-methyl-
propanoic acid (0.34 mol, 57 g, 1.7 equiv) in 2-butanone (0.1 L) was added
over approximately 1 h. The mixture was stirred at 508C, until N-(3,5-
dimethylphenyl)-2-(4-hydroxyphenyl)acetamide had been consumed
(typically 2–3 h). Water (0.3 L) was added, and the biphasic mixture was
cooled to 15–258C. After separation of the aqueous (lower) layer, which
contained no product as sodium salt, the organic (upper) layer was diluted
with ethyl acetate (0.4 L), and the mixture acidified to pH , 3 with 1 M
HCl (0.3 L). The organic phase was washed with water (0.3 L) and concen-
trated to 0.2 L under reduced pressure. A 1:1 mixture of toluene and
heptane (0.3 L) was added to the solution. (Toluene–heptane as antisolvent

Improved Preparation of Efaproxiral
2133
resulted in more robust crystallization than either toluene or heptane alone.)
The resulting suspension was cooled to 0–58C, and stirred for 30–60 min.
The solid was collected by filtration, washed with heptane, and dried in
vacuo at 80–958C to give 54–57 g (79–84%) of 2-(4-f2-[(3,5-dimethylphe-
nyl)amino]-2-oxoethylgphenoxy)-2-methylpropanoic acid. Mp 138–1398C;
1H NMR (400 MHz, DMSO): d 13.03 (s, 1H, CO2H), 9.98 (s, 1H, NH),
7.23 (s, 2H, ArH), 7.21 (d, 2H, J ¼ 8.0 Hz, ArH), 6.79 (d, 2H, J ¼ 8.0 Hz,
ArH), 6.69 (s, 1H, ArH), 3.53 (s, 2H, CH2Ar), 2.23 [s, 6H, Ar(CH3)2], 1.51
[s, 6H, C(CH3)2]; 13C NMR (100 MHz, DMSO): d 175.3, 169.4, 154.2,
139.3, 137.8, 130.0, 129.4, 124.9, 118.5, 117.1, 78.5, 42.7, 25.2, 21.3. Anal.
calcd. for C20H23NO4: C, 70.36; H, 6.79; N, 4.10. Found: C, 70.38; H, 6.89;
N, 4.21.
ACKNOWLEDGMENT
The authors thank Mark S. Saulter for providing residual boron results and
Hamid R. Shafiei for HPLC assistance.
REFERENCES
1. Davis, R.; Fitzgerald, R. N.; Guo, J. Synthesis 2004, 12, 1959.
2. Kleinberg, L.; Grossman, S. A.; Carson, K.; Lesser, G.; O’Neill, A.; Pearlman, J.;
Phillips, P.; Herman, T.; Gerber, M. Jour. of Clin. Oncology 2002, 3149.
3. Kelly, S. E.; LaCour, T. G. Synthesis 1983, 1012.
4. Rayle, H. L.; Fellmeth, L. Org. Proc. Res. Dev. 1999, 3, 172.
5. Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60, 2447.
6. Tang, P. Org. Synth. 2004, 81, 262.
7. Grella, M. P.; Danso-Danquah, R.; Safo, M. K.; Joshi, G. S.; Kister, J.; Marden, M.;
Hoffman, S. J.; Abraham, D. J. J. Med. Chem. 2000, 43, 4726.