Synthesis of asymmetric halomesylate mustards with aziridineethanol/alkali metal halides: application to an improved synthesis of the hypoxia prodrug PR-104

Article abstract of DOI:10.1016/j.tet.2007.04.044

Aromatic asymmetric halomesylate mustards are efficiently prepared by reaction of activated aromatic chlorides with aziridineethanol/alkali metal halides, followed by mesylation of the haloalcohol. The reaction conditions are sufficiently mild to be compatible with a range of different substituents and protecting groups, including carboxylate and phosphate esters, and have been used in an improved synthesis of the anticancer bromomesylate mustard PR-104, now in clinical trials.

Full text of DOI:10.1016/j.tet.2007.04.044

Tetrahedron 63 (2007) 5470–5476
Synthesis of asymmetric halomesylate mustards with
aziridineethanol/alkali metal halides: application to an
improved synthesis of the hypoxia prodrug PR-104
*
Shangjin Yang, Graham J. Atwell and William A. Denny
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019,
Auckland Mail Centre, Auckland 1142, New Zealand
Received 2 February 2007; revised 26 March 2007; accepted 12 April 2007
Available online 20 April 2007
Abstract—Aromatic asymmetric halomesylate mustards are efficiently prepared by reaction of activated aromatic chlorides with aziridine-
ethanol/alkali metal halides, followed by mesylation of the haloalcohol. The reaction conditions are sufficiently mild to be compatible with
a range of different substituents and protecting groups, including carboxylate and phosphate esters, and have been used in an improved syn-
thesis of the anticancer bromomesylate mustard PR-104, now in clinical trials.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
bis(mesylate) mustard (4) with a limited amount of lithium
bromide, or conversely by reaction of the bis(bromo)
mustard (5) with a limited amount of silver mesylate. These
reactions give 6 directly, but the lack of selectivity leads to a
mixture of all three possible components 4–6 in both cases.6
The ratios of these can be influenced by the amount of
reagent used but careful chromatographic separation is still
required, and yields of the desired isolated pure 6 are gener-
ally only 30–40%.
(Hetero)aromatic asymmetric mustards have been described
for use as prodrugs for hypoxia (e.g., 1)1 and for ADEPT
(e.g., 2)2,3 and GDEPT (e.g., 3).4 We have recently reported
that halomesylate mustards (e.g., 3) are more selectively ac-
tivated than symmetric dihalomustards by cells expressing
the Escherichia coli nitroreductase NTR.4 We have been
particularly interested in halomesylates as hypoxia prodrugs,
and have recently taken the bromomesylate PR-104 (1) to
clinical trial5 (Fig. 1).
In this paper we report a new and more efficient method
(Scheme 2) for the preparation of halomesylate mustards
(IV) from relatively activated aromatic halides (I), using
commercially available aziridineethanol and alkali metal
halides (MX), and apply this to an improved synthesis of
the clinical drug 1 and analogues. The reaction presumably
follows the course shown in Scheme 2, with initial reaction
A key step in the synthesis of 1 is preparation of the bromo-
mesylate (6), which is reacted with di-tert-butyl diisopropyl-
phosphoramidite to give the phosphate triester (7), which is
treated with TFA to furnish 1 (Scheme 1).6 The desired
bromomesylate (6) can be obtained either by reaction of the
H
N
O
CO2H
NO2
NO2 O
CO2H
OMs
N
H
OH
H
N
OH
O2N
Br
OP(O)(OH)2
O2N
Cl
N
O
N
N
OMs
2
OMs
Cl
1
3
Figure 1.
Keywords: Aniline mustard; Asymmetric mustard synthesis; Aziridineethanol; PR-104.
* Corresponding author. Tel.: +64 9 373 7599x86626; fax: +64 9 373 7502; e-mail: s.yang@auckland.ac.nz
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.044

S. Yang et al. / Tetrahedron 63 (2007) 5470–5476
5471
NO2
NO2
NO2
i
ii
H
N
H
N
H
N
O2N
OH O2N
R
O2N
Br
OH
N
O
N
O
N
O
MsO
OMs
Br
OMs
Br
5
4
6: R=OH
iii
iv
7: R=OP(O)(OtBu)2
1: R=OP(O)(OH)2
Scheme 1. Reagents: (i) LiBr; (ii) AgOMs; (iii) i-Pr2NP(OtBu)2; (iv) TFA.
NO2
N
conversion to halomesylate mustards (IV) with methane-
sulfonyl chloride or (preferably) methanesulfonic anhydride
(which avoids traces of chloro impurities when other halo-
mesylates are prepared).
NO2
NO2
R
O
R
O
i
R
O
i
O2N
hal
O2N
X-
O2N
Cl
N+
OH
I
Y
II
2. Results and discussion
III: Y = OH
IV: Y = OMs
ii
The aziridineethanol reaction works best with highly acti-
vated haloaromatics. Table 1 shows the results of the reac-
tion of a series of chlorodinitrobenzamides and -benzoates
with aziridineethanol in the presence of lithium or sodium
metal halides. Preferable solvents were DMF, THF, 1,4-di-
oxane or 3-methyl-2-butanone.
Scheme 2. Reagents: (i) aziridineethanol/M+Xꢀ; (ii) (Ms)2O or MsCl.
to form an aziridinium intermediate, followed by ring open-
ing with halide anion (Xꢀ). This gives the asymmetric halo-
alcohols (III) in a single step as the major product in much
higher yields, without the need for separation of closely re-
lated products. It is compatible with a number of different
functional groups, and variation of the halogen in the alkali
metal halides (e.g., LiCl, LiBr, NaI) allows the preparation
of various haloalcohols from a single precursor and their
Thus reaction of 2-chloro-3,5-dinitrobenzamide (8) with
aziridineethanol gave the corresponding haloalcohols (9a–
9c) directly, in yields ranging from 70–90%, and these
were converted to the halomesylates (10a–10c) in good over-
all yields without the need for chromatographic purification.
Table 1. Preparation of halomesylate mustards (IV) from dinitrobenzamide halides (I)
NO2
NO2
NO2
R2
R3
R2
R3
R2
R3
R1
R1
X
R1
X
Cl
N
N
OH
OMs
III
IV
I
R1
R2
H
R3
X
I
III
IV
Yield (%)
I/III
I/IV
(# steps)ref
NO2
CONH2
Cl
Br
I
8
9a
9b
9c
10a
10b
10c
92
87
70
90
74
45
15 (3)1,10
24 (3)1,10
NO2
H
CONH(CH2)2OTHP
Cl
Br
I
11
12a
12b
12c
13a
13b
13c
97/37a
80
63
95/36a
76
62
40 (2)1
40 (2)1
19 (2)6
NO2
NO2
NO2
H
CONH(CH2)2OP(O)(OtBu)2
t
CO2 Bu
Cl
Cl
14
17
20
15
18
16
19
90a
61a
H
63
56
CONH2
H
Cl
Br
I
21a
21b
21c
22a
22b
22c
43
32
12 (3)1,11
w10 (37)b
— (29)b
36b
28b
H
CO2Me
NO2
NO2
Cl
Br
I
23
26
24a
24b
24c
25a
25b
25c
63
36
58
50
28
53
t
CO2 Bu
H
Cl
27
28
51
45
a
Using 2-[(2-chloroethyl)amino]ethanol as reagent for the first step.
Subsequent reaction of 21a with LiBr or NaI (see text).
b

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S. Yang et al. / Tetrahedron 63 (2007) 5470–5476
The mild reaction conditions allow the use of a variety of
different side chains off the carboxamide. In particular, the
THP ether (11) gave excellent yields of the haloalcohols
(12a–12c), which could be converted to the halomesylates
(13a–13c) (Table 1), of which 13b (which can easily be de-
protected with catalytic methanesulfonic acid in methanol)
is the key intermediate for an improved synthesis of the clin-
ical drug 1. In both of the above sets, the reactions to form the
iodoalcohols (9c, 12c) resulted in the lowest yields, because
of greater secondary reaction of the more reactive iodides
to form polar impurities. Exploring the limits of the reac-
tion, the phosphate triester (14), prepared from 2-chloro-
3,5-dinitro-N-(2-hydroxyethyl)benzamide6 with di-tert-butyl
diisopropylphosphoramidite, did not survive the aziridine-
ethanol reaction but did give a good yield of the chloroalco-
hol 15 when reacted with the open-chain precursor of
aziridineethanol, 2-[(2-chloroethyl)amino]ethanol (Table 1).
This reagent is not commercially available, but can be easily
prepared by known methods.7,8 The chloromesylate 16 was
prepared from 15 as above (Table 1). But even with 2-[(2-
chloroethyl)amino]ethanol, reactions to prepare the corre-
sponding bromo- or iodoalcohols were accompanied by
significant loss of the phosphate protecting group.
yields of 37% and 29%, respectively, from 20 (Scheme 4 and
Table 1).
Reaction of 3-chloro-2,6-dinitrobenzamide with aziridine-
ethanol was not successful, but the corresponding methyl
ester12 (23) gave the corresponding haloalcohols 24a–24c,
which were converted to the halomesylates 25a–25c in
good overall yield (Table 1). The corresponding tert-butyl
ester 26 gave similar yields of the chloroalcohol 27 and
the chloromesylate 28.
3. Conclusions
Aziridineethanol/alkali metal halides offer a straightforward
and high-yielding direct preparation of asymmetric halo-
mesylate mustards from activated aromatic halides. This
reaction has been used to provide an improved synthesis of
the hypoxia prodrug PR-104 (1). The reaction conditions
are sufficiently mild to be compatible with THP ether and
carboxylate ester protecting groups, and a phosphotriester
function.
The tert-butyl ester 17 also reacted with aziridineethanol to
give the chloroalcohol 18 in 63% yield, followed by mesyl-
ation to 19 (Table 1). Cleavage of this with TFA gave the acid
21, which was activated with oxalyl chloride and coupled
with 2-aminoethanol to give the amide 22 (Scheme 3).
4. Experimental
4.1. General procedures
Analyses were performed by the Microchemical Laboratory,
University of Otago, Dunedin, New Zealand. Melting points
were determined using an Electrothermal Model 9200 digi-
tal melting point apparatus, and are as read. NMR spectra
were measured on a Bruker DRX-400 spectrometer, and ref-
erenced to Me4Si. Mass spectra were recorded on a Varian
VG-70SE spectrometer at nominal 5000 resolution. HPLC
was carried out using a Bondclone 10 C18 reverse-phase sil-
ica gel column, with a Phillips PU4100 M gradient elution
pump and a Phillips PU 4120 diode array detector, and elut-
ing with the appropriate ratios of 95% MeCN/5% water (sol-
vent A) and 0.45 M ammonium formate buffer (solvent B;
pH 3.45).
NO2
NO2
ii
i
19
H
N
O2N
Cl
CO2H
OMs
O2N
Cl
OH
N
N
O
OMs
22
21
Scheme 3. Reagents: (i) TFA; (ii) (COCl)2, then H2N(CH2)2OH.
The 5-chloro-2,4-dinitrobenzamide (20) was less reactive,
giving (in DMF) a moderate (43%) yield of the chloroalco-
hol 21a, which could be converted in high yield to the chloro-
mesylate 22a by reaction with MsCl (Table 1). The overall
yield of 32% is compared favourably with previous work,1
which gave a 12% yield after chromatographic separation.
Reaction of 20 in the presence of LiBr gave a much poorer
yield of the bromoalcohol 21b (w10%), and 21b and the cor-
responding iodoalcohol 21c were better obtained by subse-
quent reaction of 21a with LiBr or NaI (in 86% and 68%
yields, respectively) (Scheme 4). This allowed the prepara-
tion of the bromo- and iodomesylates 22b and 22c in overall
4.2. Preparation of starting materials
4.2.1. Di(tert-butyl)2-[(2-chloro-3,5-dinitrobenzoyl)-
amino]ethyl phosphate (14). A solution of 2-chloro-3,5-di-
nitro-N-(2-hydroxyethyl)benzamide6 (2.00 g, 6.91 mmol) in
dry DMF (8 mL) and THF (12 mL) was treated at 10 ꢁC with
1H-tetrazole (0.77 g, 11.0 mmol) followed by di-tert-butyl
diisopropylphosphoramidite (95%, 2.62 g, 9.44 mmol). The
mixture was stirred at room temperature for 2 h under N2,
then treated with a solution of 70% aqueous H2O2 (1.8 mL)
in THF (2.0 mL) at 10 ꢁC for 30 min. The reaction was di-
luted with EtOAc, and the solution was washed with water,
dried and concentrated under reduced pressure below
30 ꢁC. The residue was purified by chromatography on silica
gel, eluting with EtOAc/petroleum ether (4:1), followed by
recrystallisation from EtOAc/diisopropyl ether, to give 14
NO2
O
NO2
O
NH2
NH2
O2N
X
O2N
Cl
N
N
1
(1.69 g, 51%) as a white solid: mp 98 ꢁC (dec); H NMR
OH
OH
i
21a
21b: X=Br
[(CD3)2SO] d 9.05–8.98 (m, 2H), 8.53 (d, J¼2.6 Hz, 1H),
4.00 (q, J¼6.1 Hz, 2H), 3.53 (q, J¼5.6 Hz, 2H), 1.43 (s,
18H); 13C NMR d 163.0, 148.5, 145.8, 139.8, 128.3, 125.8,
120.7, 81.5 (d, Jc-p¼7.1 Hz, 2), 61.2 (d, Jc-p¼6.4 Hz), 39.5
ii
21c: X=I
Scheme 4. Reagents: (i) LiBr; (ii) NaI.

S. Yang et al. / Tetrahedron 63 (2007) 5470–5476
5473
(d, Jc-p¼8.5 Hz), 29.3 (d, Jc-p¼4.3 Hz, 6). Anal. Calcd for
C17H25ClN3O9P: C, 42.38; H, 5.23; N, 8.72; P, 6.43. Found:
C, 42.67; H, 5.22; N, 9.02; P, 6.36%.
4.3.4. 2-[(2-Chloroethyl)(2-hydroxyethyl)amino]-3,5-di-
nitro-N-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]benz-
amide (12a). From 2-chloro-3,5-dinitro-N-[2-(tetrahydro-
2H-pyran-2-yloxy)ethyl]benzamide6 (11) as a yellow solid
1
4.2.2. tert-Butyl 3-chloro-2,6-dinitrobenzoate (26). A mix-
ture of 3-chloro-2,6-dinitrobenzoic acid11 (3.00 g, 12 mmol),
tert-butyl acetate (20 mL, 150 mmol) and 70% HClO4
(0.8 mL) was stirred at 35 ꢁC for 6 h, then poured into excess
satd aqueous NaHCO3. The mixture was extracted with
CH2Cl2 and the organic phase was washed with satd aqueous
NaHCO3 andwater,driedandevaporatedtodryness.Theresi-
due was crystallised from hexane to give 26 (2.51 g, 68%) as
a white solid: mp 109–110 ꢁC; 1H NMR [(CD3)2SO] d 8.43
(d, J¼8.9 Hz, 1H), 8.22 (d, J¼8.9 Hz, 1H), 1.49 (s, 9H).
Anal. Calcd for C11H11ClN2O6: C, 43.65; H, 3.66; N, 9.26.
Found: C, 43.93; H, 3.68; N, 9.30%.
(97% yield): mp (EtOAc/petroleum ether) 106–108 ꢁC; H
NMR [(CD3)2SO] d 9.07 (t, J¼5.4 Hz, 1H), 8.70 (d,
J¼2.8 Hz, 1H), 8.33 (d, J¼2.8 Hz, 1H), 5.15 (t, J¼5.6 Hz,
1H), 4.62 (t, J¼3.7 Hz, 1H), 3.78 (m, 4H), 3.58–3.43 (m,
8H), 3.14 (m, 2H), 1.80–1.40 (m, 6H); 13C NMR d 165.7,
146.8, 143.7, 139.7, 133.9, 128.4, 123.1, 98.0, 64.8, 61.5,
57.8, 54.3, 53.3, 41.4, 39.5, 30.1, 24.9, 19.1. Anal. Calcd
for C18H25ClN4O8: C, 46.91; H, 5.47; N, 12.16. Found: C,
47.08; H, 5.43; N, 12.21%.
4.3.5. 2-[(2-Bromoethyl)(2-hydroxyethyl)amino]-3,5-di-
nitro-N-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]benz-
amide (12b). From 11 as a yellow solid (80% yield): mp
(EtOAc/heptane) 121–123 ꢁC; 1H NMR [(CD3)2SO] d 9.06
(t, J¼5.4 Hz, 1H), 8.70 (d, J¼2.8 Hz, 1H), 8.33 (d,
J¼2.8 Hz, 1H), 5.15 (t, J¼5.5 Hz, 1H), 4.62 (t, J¼3.5 Hz,
1H), 3.78 (m, 2H), 3.63–3.43 (m, 10H), 3.15 (m, 2H), 1.80–
1.40 (m, 6H); 13C NMR d 165.7, 146.6, 143.8, 139.8, 134.0,
128.4, 123.0, 98.0, 64.8, 61.5, 57.9, 54.1, 53.4, 39.5, 30.1,
29.8, 24.9, 19.1. Anal. Calcd for C18H25BrN4O8: C, 42.79;
H, 4.99; N, 11.09. Found: C, 42.82; H, 4.96; N, 11.03%.
4.3. Aziridineethanol reaction: general conditions
A slurry of aromatic chloride (1 equiv) and either LiCl
(0.5 equiv), LiBr (17 equiv) or NaI (17 equiv) in solvent (3-
methyl-2-butanone unless otherwise mentioned for specific
products) was cooled to below 5 ꢁC. Aziridineethanol
(2.5 equiv) was added over 10 min to the stirred mixture,
which was kept below 20 ꢁC overnight. Water was added,
and the reaction mixture was extracted three times with
EtOAc. The combined organic layers were washed with
water and with a 10% aqueous solution of the appropriate so-
dium halide, dried and concentrated under reduced pressure.
The concentrate was passed through a short column of silica
gel, eluting with EtOAc/heptane, to provide product. The fol-
lowing compounds were prepared by this method.
4.3.6. 2-[(2-Hydroxyethyl)(2-iodoethyl)amino]-3,5-dini-
tro-N-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]benz-
amide (12c). From 11 as a yellow foam (63% yield); H
1
NMR (CDCl3) d 8.63 (d, J¼2.8 Hz, 1H), 8.56 (d, J¼
2.8 Hz, 1H), 8.24 (br, 1H), 4.54 (m, 1H), 4.48 (m, 1H),
3.93 (m, 2H), 3.84 (m, 1H), 3.70 (m, 6H), 3.54 (m, 1H),
3.30 (m, 2H), 3.18 (m, 2H), 1.90–1.40 (m, 6H); 13C NMR
d 165.7, 146.7, 144.4, 140.9, 134.5, 129.2, 123.5, 101.6,
67.0, 65.4, 58.0, 55.0, 53.7, 40.7, 31.3, 25.1, 21.2, 0.3;
HRMS (FAB) calcd for C18H26IN4O8 [M+H]+ m/z
553.0795; found 533.0797.
4.3.1. 2-[(2-Chloroethyl)(2-hydroxyethyl)amino]-3,5-di-
nitrobenzamide (9a). From 2-chloro-3,5-dinitrobenz-
amide6 (8) (in THF) as a yellow solid (92% yield): mp
(EtOAc/petroleum ether) 96–100 ꢁC; 1H NMR [(CD3)2SO]
d 8.69 (d, J¼2.8 Hz, 1H), 8.43 (s, 1H), 8.35 (d, J¼2.8 Hz,
1H), 8.10 (s, 1H), 5.15 (t, J¼5.6 Hz, 1H), 3.77 (m, 2H),
3.54 (m, 4H), 3.14 (m, 2H); 13C NMR d 167.6, 146.7,
143.8, 139.7, 134.1, 128.2, 123.1, 57.8, 54.3, 53.6, 41.4.
Anal. Calcd for C11H13ClN4O6$0.5H2O: C, 38.66; H, 4.13;
N, 16.40. Found: C, 38.37; H, 4.42; N, 15.68%.
4.3.7. tert-Butyl 2-[(2-hydroxyethyl)(2-chloroethyl)-
amino]-3,5-dinitrobenzoate (18). From tert-butyl 2-chloro-
3,5-dinitrobenzoate9 (17) (in DMF) as a yellow solid (63%
yield): mp (EtOAc/petroleum ether) 106–107 ꢁC; 1H NMR
[(CD3)2SO] d 8.73 (d, J¼2.8 Hz, 1H), 8.44 (d, J¼2.8 Hz,
1H), 4.58 (t, J¼5.4 Hz, 1H), 3.75 (t, J¼6.7 Hz, 2H), 3.55
(q, J¼5.7 Hz, 2H), 3.46 (t, J¼6.7 Hz, 2H), 3.19 (t, J¼
5.9 Hz, 2H), 1.60 (s, 9H). Anal. Calcd for C15H20ClN3O7:
C, 46.22; H, 5.17; N, 10.78; Cl, 9.10. Found: C, 46.50;
H, 5.23; N, 10.66; Cl, 9.05%.
4.3.2. 2-[(2-Bromoethyl)(2-hydroxyethyl)amino]-3,5-di-
nitrobenzamide (9b). From 8 as a yellow solid (87% yield):
mp (EtOAc/petroleum ether) 138–140 ꢁC; 1H NMR
[(CD3)2SO] d 8.69 (d, J¼2.8 Hz, 1H), 8.43 (s, 1H), 8.35
(d, J¼2.8 Hz, 1H), 8.10 (s, 1H), 5.15 (t, J¼5.6 Hz, 1H),
3.61 (m, 4H), 3.53 (m, 2H), 3.14 (m, 2H); 13C NMR
d 167.6, 146.4, 143.8, 139.8, 134.2, 128.2, 123.0, 57.8,
54.1, 53.6, 29.8. Anal. Calcd for C11H13BrN4O6: C, 35.0;
H, 3.5; N, 14.9. Found: C, 35.0; H, 3.5; N, 14.6%.
4.3.8. 5-[(2-Chloroethyl)(2-hydroxyethyl)amino]-2,4-di-
nitrobenzamide (21a). From 5-chloro-2,4-dinitrobenz-
amide11 (20) (in DMF) as a yellow solid (43% yield): mp
(EtOAc/petroleum ether) 131–134 ꢁC; 1H NMR [(CD3)2SO]
d 8.48 (s, 1H), 8.10 (s, 1H), 7.75 (s, 1H), 7.35 (s, 1H), 4.76
(vbr s, 1H), 3.83 (t, J¼5.9 Hz, 2H), 3.75 (t, J¼5.9 Hz, 2H),
3.56 (t, J¼5.4 Hz, 2H), 3.36 (t, J¼5.5 Hz, 2H); 13C NMR
d 166.3, 147.3, 137.4, 136.9, 135.0, 124.3, 119.8, 58.1, 54.1,
52.5, 41.3. Anal. Calcd for C11H13ClN4O6: C, 39.71; H,
3.94; N, 16.84. Found: C, 39.79; H, 3.95; N, 16.61%.
4.3.3. 2-[(2-Hydroxyethyl)(2-iodoethyl)amino]-3,5-dini-
trobenzamide (9c). From 8 as a yellow solid (70% yield):
mp (EtOAc/petroleum ether) 152–155 ꢁC; 1H NMR
[(CD3)2SO] d 8.69 (d, J¼2.8 Hz, 1H), 8.41 (s, 1H), 8.34
(d, J¼2.8 Hz, 1H), 8.10 (s, 1H), 5.13 (t, J¼5.6 Hz, 1H),
3.53 (m, 4H), 3.35 (m, 2H), 3.13 (m, 2H); 13C NMR
d 167.5, 146.1, 143.8, 139.8, 134.2, 128.2, 123.0, 57.8,
54.8, 53.7, 2.07. Anal. Calcd for C11H13IN4O6: C, 31.15;
H, 3.09; N, 13.21. Found: C, 31.45; H, 2.99; N, 12.91%.
4.3.9. Methyl 3-[(2-chloroethyl)(2-hydroxyethyl)amino]-
2,6-dinitrobenzoate (24a). From methyl 3-chloro-2,6-di-
nitrobenzoate12 (23) (in DMF) as a yellow oil (63% yield);

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S. Yang et al. / Tetrahedron 63 (2007) 5470–5476
1H NMR [(CD3)2SO] d 8.25 (d, J¼9.7 Hz, 1H), 7.63 (d,
J¼9.7 Hz, 1H), 4.79 (t, J¼5.2 Hz, 1H), 3.87 (s, 3H), 3.80
(t, J¼5.5 Hz, 2H), 3.72 (t, J¼5.5 Hz, 2H), 3.54 (q,
J¼5.3 Hz, 2H), 3.36 (t, J¼5.5 Hz, 2H); 13C NMR d 163.2,
147.8, 136.54, 134.5, 128.0, 126.3, 122.0, 58.1, 54.7, 53.8,
53.8, 41.3. HRMS (FAB) calcd for C12H1535ClN3O7
[M+H]+ m/z 347.0520; found 347.0521.
4.5. Preparation of 2-[(2-bromoethyl)-2,4-dinitro-6-({[2-
(tetrahydro-2H-pyran-2-yloxy)ethyl]amino}carbonyl)-
anilino]ethyl methanesulfonate (13b): example of
mesylation with methanesulfonic anhydride
A solution of 12b (98% pure) (51.5 g, 102 mmol) in dry
CH2Cl2 (300 mL) containing dry pyridine (21.4 mL,
265 mmol) was cooled to 0 ꢁC and treated over a 5 min pe-
riod with a solution of methanesulfonic anhydride (97%,
23.8 g, 137 mmol) in CH2Cl2 (80 mL). The mixture was
stirred at 20 ꢁC for 1.5 h, then 10% aqueous KHCO3
(200 mL) was added and the mixture was stirred vigorously
for 30 min, then concentrated under reduced pressure to re-
move all of the CH2Cl2. The oil that precipitated was sepa-
rated from the remaining liquid, rinsed with water and
dissolved in EtOAc (300 mL). The EtOAc solution was
washed with water (2ꢂ), dried and filtered through a short
column of silica gel. The eluate was concentrated to 100 mL
and shaken with excess hexane (250 mL). The precipitated
oil was separated from the mother liquor and dried to give
4.3.10. Methyl 3-[(2-bromoethyl)(2-hydroxyethyl)-
amino]-2,6-dinitrobenzoate (24b). From 23 (in DMF) as
a yellow oil (36% yield); 1H NMR [(CD3)2SO] d 8.24
(d, J¼9.4 Hz, 1H), 7.62 (d, J¼9.4 Hz, 1H), 4.79 (vbr s,
1H), 3.78 (s, 3H), 3.77 (t, J¼6.2 Hz, 2H), 3.65 (t, J¼
6.1 Hz, 2H), 3.53 (t, J¼5.4 Hz, 2H), 3.36 (t, J¼5.3 Hz,
2H); 13C NMR d 163.2, 147.6, 136.4, 134.5, 128.1,
126.3, 121.9, 58.1, 53.8, 53.6, 52.5, 29.7. HRMS (FAB)
calcd for C12H1579BrN3O7 [M+H]+ m/z 392.0093; found
392.0093.
4.3.11. Methyl 3-[(2-hydroxyethyl)(2-(iodoethyl)amino]-
2,6-dinitrobenzoate (24c). From 23 (in DMF) as a yellow
gum (58% yield); 1H NMR [(CD3)2SO] d 8.24 (d,
J¼9.7 Hz, 1H), 7.59 (d, J¼9.7 Hz, 1H), 4.79 (t, J¼5.2 Hz,
1H), 3.87 (s, 3H), 3.71 (t, J¼7.2 Hz, 2H), 3.53 (q,
J¼5.1 Hz, 2H), 3.40–3.33 (m, 4H); 13C NMR d 163.2,
147.2, 136.3, 134.5, 128.1, 126.3, 121.8, 58.1, 53.8, 53.5
(2), 2.2. HRMS (FAB) calcd for C12H15IN3O7 [M+H]+ m/z
439.9955; found 439.9960.
1
13b as yellow foam (56.4 g, 95%) (98% pure); H NMR
(CDCl3) d 8.62 (d, J¼2.8 Hz, 1H), 8.53 (d, J¼2.8 Hz, 1H),
7.29 (br, 1H), 4.55 (m, 1H), 4.37 (m, 2H), 3.90 (m, 2H),
3.78 (m, 1H), 3.73–3.49 (m, 9H), 3.01 (s, 3H), 1.90–1.48 (m,
6H); 13C NMR d 165.0, 145.9, 145.6, 142.1, 136.4, 128.5,
122.8, 100.5, 67.1, 66.3, 64.2, 55.4, 52.1, 40.5, 37.5, 31.0,
29.0, 25.2, 20.6; HRMS (FAB) calcd for C19H2879BrN4O10S
[M+H]+ m/z 583.0710; found 583.0712. The following
compounds were prepared similarly.
4.3.12. tert-Butyl 3-[(2-chloroethyl)(2-hydroxyethyl)-
amino]-2,6-dinitrobenzoate (27). From 26 (in DMF) as
a yellow gum (51% yield); 1H NMR [(CD3)2SO] d 8.20 (d,
J¼9.6 Hz, 1H), 7.58 (d, J¼9.6 Hz, 1H), 4.78 (t, J¼5.2 Hz,
1H), 3.81–3.74 (m, 2H), 3.74–3.66 (m, 2H), 3.53 (q,
J¼5.3 Hz, 2H), 3.34 (t, J¼5.5 Hz, 2H), 1.50 (s, 9H); 13C
NMR d 160.9, 147.4, 137.1, 134.8, 127.8, 126.6, 121.7,
84.5, 58.1, 53.8, 52.5, 41.2, 27.0 (3). HRMS (FAB) calcd
for C15H2135ClN3O7 [M+H]+ m/z 390.1068; found
390.1063.
4.5.1. 2-[2-(Aminocarbonyl)(2-bromoethyl)-4,6-dinitro-
anilino]ethyl methanesulfonate (10b). From 9b as a yellow
solid (85% yield): mp (EtOAc/petroleum ether) 153–
1
154 ꢁC; H NMR [(CD3)2SO] d 8.74 (d, J¼2.8 Hz, 1H),
8.33 (d, J¼2.8 Hz, 1H), 8.19 (s, 1H), 7.99 (s, 1H), 4.29
(m, 2H), 3.60 (m, 2H), 3.49 (m, 4H), 3.14 (s, 3H); 13C
NMR d 167.11, 145.75, 146.37, 140.92, 136.12, 127.24,
122.20, 67.53, 54.41, 51.16, 36.46, 29.73. Anal. Calcd for
C12H15BrN4O8S: C, 31.72; H, 3.33; N, 12.34; Br, 17.35.
Found: C, 32.00; H, 3.41; N, 12.22; Br, 17.71%.
4.4. Preparation of di(tert-butyl) 2-({2-[(2-chloro-
ethyl)(2-hydroxyethyl)amino]-3,5-dinitrobenzoyl}-
amino)ethyl phosphate (15): example of 2-[(2-chloro-
ethyl)amino]ethanol reaction
4.5.2. 2-[2-(Aminocarbonyl)(2-iodoethyl)-4,6-dinitroani-
lino]ethyl methanesulfonate (10c). From 9c as a yellow
solid (64% yield): mp (EtOAc/petroleum ether) 144–
1
147 ꢁC; H NMR [(CD3)2SO] d 8.73 (d, J¼2.8 Hz, 1H),
A suspension of 2-[(2-chloroethyl)amino]ethanol hydro-
chloride7,8 (1.0 g, 3.56 mmol), Et3N (2.0 mL, 14.3 mmol)
in 1,4-dioxane (50 mL) was cooled in an ice bath, and 14
(478 mg, 0.99 mmol) was added. The mixture was stirred
at room temperature overnight, then water (100 mL) was
added and the mixture was extracted with EtOAc
(3ꢂ100 mL). The combined organic layers were washed
with water, dried and concentrated under reduced pressure,
then passed through a short column of silica gel, eluting
with heptane/EtOAc (gradient from 1:1 to 0:1) to give 15
8.33 (d, J¼2.8 Hz, 1H), 8.16 (s, 1H), 7.97 (s, 1H), 4.28
(m, 2H), 3.49 (m, 4H), 3.32 (m, 2H), 3.14 (s, 3H); 13C
NMR d 167.1, 145.4, 145.3, 140.9, 136.1, 127.2, 122.1,
67.5, 55.6, 50.7, 36.5, 2.6. Anal. Calcd for C12H15IN4O8S:
C, 28.75; H, 3.01; N, 11.16. Found: C, 29.29; H, 3.37; N,
10.73%.
4.5.3. 2-[(2-Iodoethyl)-2,4-dinitro-6-({[2-(tetrahydro-2H-
pyran-2-yloxy)ethyl]amino}carbonyl)anilino]ethyl
methanesulfonate (13c). From 12c as a yellow foam (99%
yield); 1H NMR (CDCl3) d 8.62 (d, J¼2.8 Hz, 1H), 8.52 (d,
J¼2.8 Hz, 1H), 7.21 (br, 1H), 4.55 (m, 1H), 4.35 (m, 2H),
3.90 (m, 2H), 3.80 (m, 1H), 3.70–3.5 (m, 7H), 3.30 (m,
2H), 3.00 (s, 3H), 1.90–1.50 (m, 6H); 13C NMR d 165.0,
145.7, 142.0, 136.3, 128.2, 122.8, 100.6, 66.9, 66.5, 64.3,
56.7, 51.6, 40.5, 37.6, 31.0, 25.2, 20.6, 0.7; HRMS (FAB)
calcd for C19H28IN4O10S [M+H]+ m/z 631.0571; found
631.0575.
1
as a yellow foam (510 mg, 90%); H NMR [(CD3)2SO]
d 8.94 (t, J¼5.5 Hz, 1H), 8.71 (d, J¼2.8 Hz, 1H), 8.34 (d,
J¼2.8 Hz, 1H), 5.13 (t, J¼5.6 Hz, 1H), 4.02 (m, 3H), 3.77
(m, 2H), 3.55 (m, 6H), 3.14 (m, 2H), 1.42 (s, 18H); 13C
NMR d 266.0, 146.9, 143.7, 139.6, 133.6, 128.3, 123.2,
81.6, 64.0, 59.6, 54.3, 53.3, 41.5, 29.3. HRMS (FAB) calcd
for C21H3535ClN4O10S [M+H]+ m/z 569.1779; found
569.1772.

S. Yang et al. / Tetrahedron 63 (2007) 5470–5476
5475
4.5.4. 2-[5-(Aminocarbonyl)(2-bromoethyl)-2,4-dinitro-
anilino]ethyl methanesulfonate (22b). From21basayellow
solid (96% yield), identical (1H NMR, 13C NMR, HPLC)
with compound prepared previously by an alternate route.11
539.1206. The following compounds were similarly
prepared.
4.6.1. 2-[2-(Aminocarbonyl)(2-chloroethyl)-4,6-dinitro-
anilino]ethyl methanesulfonate (10a). From 9a (in THF)
as a yellow solid (98% yield): mp (EtOAc/petroleum ether)
155–157 ꢁC; 1H NMR [(CD3)2SO] d 8.74 (d, J¼2.7 Hz, 1H),
8.34 (d, J¼2.7 Hz, 1H), 8.19 (s, 1H), 7.99 (s, 1H), 4.29 (m,
2H), 3.73 (m, 2H), 3.48 (m, 4H), 3.15 (s, 3H); 13C NMR
d 167.11, 145.98, 146.34, 140.84, 136.05, 127.26, 122.22,
67.49, 54.35, 51.34, 41.36, 36.46. Anal. Calcd for
C12H15ClN4O8S: C, 35.1; H, 3.7; N, 13.7; Cl, 8.5. Found:
C, 35.7; H, 3.9; N, 13.6; Cl, 8.7%.
4.5.5. 2-[5-(Aminocarbonyl)(2-iodoethyl)-2,4-dinitroani-
lino]ethyl methanesulfonate (22c). From 21c as a yellow
solid (97% yield), identical (1H NMR, 13C NMR, HPLC)
with compound prepared previously by an alternate route.11
4.5.6. Methyl 3-[(2-bromoethyl)-[2-[(methylsulfonyl)oxy]-
ethyl]amino]-2,6-dinitrobenzoate (25b). From 24b as a
yellow oil (77% yield): H NMR [(CD3)2SO] d 8.24 (d,
1
J¼9.4 Hz, 1H), 7.62 (d, J¼9.4 Hz, 1H), 4.79 (vbr s, 1H),
3.78 (s, 3H), 3.77 (t, J¼6.2 Hz, 2H), 3.65 (t, J¼6.1 Hz,
2H), 3.53 (t, J¼5.4 Hz, 2H), 3.36 (t, J¼5.3 Hz, 2H); 13C
NMR d 163.2, 147.6, 136.4, 134.5, 128.1, 126.3, 121.9,
58.1, 53.8, 53.6, 52.5, 29.7. HRMS (FAB) calcd for
C12H1579BrN3O7 [M+H]+ m/z 392.0093; found 392.0093.
4.6.2. 2-[(2-Chloroethyl)-2-(6-tert-butoxy-8,8-dimethyl-
6-oxido-5,7-dioxa-2-aza-6-phosphanon-1-anoyl)-4,6-di-
nitroanilino]ethyl methanesulfonate (16). From 15 as
1
a yellow foam (68% yield); H NMR [(CD3)2SO] d 8.94
(t, J¼5.6 Hz, 1H), 8.75 (d, J¼2.8 Hz, 1H), 8.34 (d,
J¼2.8 Hz, 1H), 4.28 (t, J¼5.4 Hz, 2H), 4.02 (q, J¼6.2 Hz,
2H), 3.74–3.43 (m, 8H), 3.13 (s, 3H), 1.43 (s, 18H); 13C
NMR d 265.6, 146.2, 145.3, 140.8, 135.6, 127.5, 122.4,
81.7, 67.5, 64.2, 54.3, 51.3, 41.4, 36.5, 29.5. HRMS (FAB)
calcd for C22H3735ClN4O12PS [M+H]+ m/z 647.1555; found
647.1555.
4.5.7. Methyl 3-[(2-iodoethyl)[2-[(methylsulfonyl)oxy]-
ethyl]amino]-2,6-dinitrobenzoate (25c). From 24c as a
yellow gum (92% yield): H NMR [(CD3)2SO] d 8.30 (d,
1
J¼9.6 Hz, 1H), 7.72 (d, J¼9.6 Hz, 1H), 4.30 (t, J¼5.2 Hz,
2H), 3.88 (s, 3H), 3.71 (t, J¼5.2 Hz, 2H), 3.62 (t,
J¼7.1 Hz, 2H), 3.36 (t, J¼7.1 Hz, 2H), 3.14 (s, 3H); 13C
NMR d 162.9, 146.9, 138.0, 136.2, 128.3, 125.9, 123.4,
66.7, 53.9, 53.7, 49.4, 36.6, 2.4. HRMS (FAB) calcd for
C13H17IN3O9S [M+H]+ m/z 517.9730; found 517.9734.
4.6.3. tert-Butyl 2-[(2-chloroethyl)[2-[(methylsulfonyl)-
oxy]ethyl]amino]-3,5-dinitrobenzoate (19). From 18 as
a yellow solid (89% yield): mp (EtOAc/petroleum ether)
1
95–96 ꢁC; H NMR [(CD3)2SO] d 8.80 (d, J¼2.8 Hz, 1H),
4.5.8. tert-Butyl 3-[(2-chloroethyl)[2-[(methylsulfonyl)-
oxy]ethyl]amino]-2,6-dinitrobenzoate (28). From 27 as
a yellow gum (88% yield): 1H NMR [(CD3)2SO] d 8.26 (d,
J¼9.5 Hz, 1H), 7.70 (d, J¼9.5 Hz, 1H), 4.30 (t, J¼5.2 Hz,
2H), 3.76 (t, J¼6.2 Hz, 2H), 3.68 (t, J¼5.2 Hz, 2H), 3.62
(t, J¼6.2 Hz, 2H), 3.15 (s, 3H), 1.50 (s, 9H); 13C NMR
d 160.6, 147.0, 138.9, 136.7, 128.0, 126.1, 123.5, 84.8,
66.8, 52.9, 50.0, 41.4, 36.6, 27.0 (3). HRMS (FAB) calcd
for C16H2335ClN3O9S [M+H]+ m/z 468.0844; found
468.0829.
8.52 (d, J¼2.8 Hz, 1H), 4.29 (t, J¼5.5 Hz, 2H), 3.73 (t,
J¼6.8 Hz, 2H), 3.49 (t, J¼5.5 Hz, 2H), 3.45 (t, J¼6.8 Hz,
2H), 3.12 (s, 3H), 1.60 (s, 9H). Anal. Calcd for
C16H22ClN3O9S: C, 41.07; H, 4.74; N, 8.98; Cl, 7.58. Found:
C, 41.25; H, 4.83; N, 8.93; Cl, 7.71%.
4.6.4. 2-[5-(Aminocarbonyl)(2-chloroethyl)-2,4-dinitro-
anilino]ethyl methanesulfonate (22a). From 21a as a
yellow solid (74% yield), identical (1H NMR, 13C NMR,
HPLC) with compound prepared previously by an alternate
route.11
4.6. 2-[(2-Chloroethyl)-2,4-dinitro-6-({[2-(tetrahydro-
2H-pyran-2-yloxy)ethyl]amino}carbonyl)anilino]ethyl
methanesulfonate (13a): example of mesylation with
MsCl
4.6.5. Methyl 3-[(2-chloroethyl)[2-[(methylsulfonyl)-
oxy]ethyl]amino]-2,6-dinitrobenzoate (25a). From 24a as
a yellow oil (80% yield); H NMR [(CD3)2SO] d 8.31 (d,
1
J¼9.5 Hz, 1H), 7.74 (d, J¼9.5 Hz, 1H), 4.31 (t, J¼5.2 Hz,
2H), 3.88 (s, 3H), 3.78 (t, J¼6.3 Hz, 2H), 3.70 (t,
J¼5.2 Hz, 2H), 3.64 (t, J¼5.9 Hz, 2H), 3.14 (s, 3H); 13C
NMR d 163.0, 147.5, 138.1, 136.2, 128.3, 125.9, 123.6,
66.7, 54.8, 53.9, 49.8, 36.6. HRMS (FAB) calcd for
C13H1735ClN3O9S [M+H]+ m/z 426.0374; found 426.0372.
A stirred solution of 12a (210 mg, 0.46 mmol) in dry CH2Cl2
(10 mL) was cooled in an ice bath at 0 ꢁC and then treated
with Et3N (0.2 mL, 1.44 mmol), followed by MsCl
(0.10 mL, 1.29 mmol) dropwise. The mixture was stirred
for 10 min at 0 ꢁC, then satd NaHCO3 (10 mL) was added,
and after a further 30 min the aqueous phase was extracted
with CH2Cl2 (2ꢂ20 mL). The combined organic phases
were dried, concentrated under reduced pressure and filtered
through a short column, eluting with EtOAc/petroleum ether
(1:1) to give 13a (240 mg, 98%) as a yellow foam; 1H NMR
(CDCl3) d 8.62 (d, J¼2.8 Hz, 1H), 8.55 (d, J¼2.8 Hz, 1H),
7.31 (t, J¼5.4 Hz, 1H), 4.55 (m, 1H), 4.37 (m, 2H), 3.90
(m, 2H), 3.70 (m, 7H), 3.53 (m, 3H), 3.01 (s, 3H), 1.86–
1.45 (m, 6H); 13C NMR d 165.1, 146.0, 145.6, 142.1,
136.4, 128.7, 122.8, 100.4, 67.2, 66.2, 64.1, 55.2, 52.3,
41.7, 40.5, 37.5, 30.9, 25.2, 20.5; HRMS (FAB) calcd
for C19H2835ClN4O10S [M+H]+ m/z 539.1215; found
4.6.6. 2-[5-(Aminocarbonyl)(2-bromoethyl)-2,4-dinitro-
anilino]ethyl methanesulfonate (21b). A slurry of 21a
(110 mg, 0.33 mmol) in dry 3-methyl-2-butanone (15 mL)
and LiBr (2.0 g) was heated under reflux for 5 h. The reac-
tion mixture was cooled, then water (50 mL) was added,
and the mixture was extracted with EtOAc (3ꢂ50 mL).
The combined organic layer was dried and concentrated
under pressure, then passed through a short column of silica
gel, eluting with heptane/EtOAc (1:1), to give 21b (107 mg,
86%) as a yellow solid: mp (EtOAc/petroleum ether) 144–
1
147 ꢁC; H NMR [(CD3)2SO] d 8.48 (s, 1H), 8.10 (s, 1H),

5476
S. Yang et al. / Tetrahedron 63 (2007) 5470–5476
7.76 (s, 1H), 7.33 (s, 1H), 4.76 (vbr s, 1H), 3.80 (t, J¼5.9 Hz,
2H), 3.69 (t, J¼5.9 Hz, 2H), 3.56 (t, J¼5.4 Hz, 2H), 3.36 (t,
J¼5.5 Hz, 2H); 13C NMR d 166.2, 147.1, 137.8, 137.4,
135.1, 124.3, 119.7, 58.1, 54.0, 52.5, 29.9. Anal. Calcd for
C11H13BrN4O6: C, 35.03; H, 3.47; N, 14.86. Found: C,
39.79; H, 3.95; N, 16.61%.
1.10 mmol) and DIPEA (142 mg, 1.10 mmol) in dioxane/
THF (1:1) (2 mL) at ꢀ5 ꢁC. The mixture was stirred at
0 ꢁC for a further 5 min, then poured into 0.1 N aqueous
MsOH (15 mL) and extracted with EtOAc (2ꢂ10 mL).
The combined organic phase was washed with water, dried
and evaporated under reduced pressure. Chromatography
on silica gel, eluting with EtOAc, followed by precipitation
of the product from a CH2Cl2 solution with hexane, gave 22
(272 mg, 82%) as a yellow gum, identical (1H NMR, HPLC)
with compound prepared previously by an alternative
route.12
4.6.7. 2-[5-(Aminocarbonyl)(2-iodoethyl)-2,4-dinitro-
anilino]ethyl methanesulfonate (21c). A slurry of 21a
(115 mg, 0.35 mmol) in dry 3-methyl-2-butanone (15 mL)
and NaI (2.0 g) was heated under reflux for 5 h. The reaction
mixture was cooled, then water (50 mL) was added, and the
mixture was extracted with EtOAc (3ꢂ50 mL). The com-
bined organic layer was dried and concentrated under pres-
sure, then passed through a short column of silica gel, eluting
with heptane/EtOAc (1:1), to give 21c (100 mg, 68%) as
a yellow solid: mp (EtOAc/petroleum ether) 144–147 ꢁC;
1H NMR [(CD3)2SO] d 8.47 (s, 1H), 8.10 (s, 1H), 7.76 (s,
1H), 7.30 (s, 1H), 4.76 (t, J¼5.3 Hz, 1H), 3.74 (t,
J¼7.1 Hz, 2H), 3.54 (m, 2H), 3.38 (m, 4H); 13C NMR
d 166.2, 146.7, 137.4, 136.8, 135.0, 124.2, 119.6, 58.1,
53.9, 53.4, 2.5. Anal. Calcd for C11H13IN4O6: C, 31.15; H,
3.09; N, 13.21. Found: C, 39.79; H, 3.95; N, 16.61%.
Acknowledgements
This work was supported by programme grant 01/276 from
the Health Research Council of NZ (G.J.A.) and by Proacta
Therapeutics Ltd (S.Y.).
References and notes
1. Denny, W. A.; Atwell, G. J.; Yang, S.; Wilson, W. R. PCT WO
2004033415 A1 (52 pp), 22nd April 2004.
4.6.8. 2-[(2-Chloroethyl)-2-[[(2-hydroxyethyl)amino]car-
bonyl]-4,6-dinitroanilino]ethyl methanesulfonate (22)
(Scheme 3). A solution of 19 (646 mg, 1.38 mmol) in TFA
(3 mL) was stirred at room temperature for 2 h, then concen-
trated almost to dryness under reduced pressure. It was then
partitioned between EtOAc and water, and the organic phase
was dried and evaporated under reduced pressure. Tritura-
tion of the oil with i-Pr2O and recrystallisation of the
resulting solid from EtOAc/hexane gave 2-[(2-chloroethyl)-
[(2-[(methylsulfonyl)oxy]ethyl]amino]-3,5-dinitrobenzoic
acid (21) (501 mg, 88%) as a yellow solid: mp 134–135 ꢁC;
1H NMR [(CD3)2SO] d 14.2 (vbr, 1H), 8.81 (d, J¼2.8 Hz,
1H), 8.60 (d, J¼2.8 Hz, 1H), 4.28 (t, J¼5.4 Hz, 2H), 3.71
(t, J¼6.8 Hz, 2H), 3.53–3.42 (m, 4H), 3.12 (s, 3H). Anal.
Calcd for C12H14ClN3O9S: C, 35.00; H, 3.43; N, 10.20;
Cl, 8.61. Found: C, 35.27; H, 3.46; N, 10.07; Cl, 8.89%.
2. Pedley, R. B.; Sharma, S. K.; Boxer, G. M.; Boden, R.;
Stribbling, S. M.; Davies, L.; Springer, C. J.; Begent, R. H. J.
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3. Springer, C. J.; Marais, R. M.; Spooner, R. PCT WO 0185960
A1 (45 pp), 15th November 2001.
4. Atwell, G. J.; Yang, S.; Pullen, S. M.; Hogg, A.; Pruijn, F. B.;
Patterson, A. V.; Wilson, W. R.; Denny, W. A. J. Med. Chem.
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G. J.; Yang, S.; Denny, W. A.; Wilson, W. R. Clin. Cancer
Res., submitted for publication.
6. Denny, W. A.; Atwell, G. J.; Yang, S.; Wilson, W. R.; Patterson,
A. V.; Helsby, N. A. PCT WO 2005042471 A1 (85 pp), 12th
May 2005.
7. Ross, W. C. J.; Wilson, J. G. J. Chem. Soc. 1959, 3617.
8. Aiko, I.; Saruwatari, K. Yakugaku Zasshi 1955, 75, 418.
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10. Friedlos, F.; Denny, W. A.; Palmer, B. D.; Springer, C. J.
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11. Palmer, B. D.; Wilson, W. R.; Cliffe, S.; Denny, W. A. J. Med.
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12. Palmer, B. D.; Wilson, W. R.; Anderson, R. F.; Boyd, M.;
Denny, W. A. J. Med. Chem. 1996, 39, 2518.
A suspension of 21 (300 mg, 0.73 mmol) in CH2Cl2 (5 mL)
was treated with oxalyl chloride (0.12 mL, 1.40 mmol) and
DMF (one drop), and stirred at room temperature for 1.5 h.
Evaporation of the volatiles under reduced pressure below
30 ꢁC, followed by azeotroping with benzene, gave the crude
acid chloride. A solution of this in DMF (1 mL) was added
dropwise to a stirred solution of 2-aminoethanol (67 mg,