Antifolate chemistry: Synthesis of 4-{N-[(6RS)-2-methyl-4-oxo- 3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino}benzoic acid via a (propargyl)Co2(CO)6+ complex

Article abstract of DOI:10.1039/b301989f

A new route to compound 3 (4-{N-[(6RS)-2-methyl-4-oxo-3,4,7,8- tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino}benzoic acid), a crucial intermediate for the synthesis of potent inhibitors of thymidylate synthase (TS), is described. In this sequence the C⁶-N¹⁰ bond was constructed first, by the reductive amination of 5-acetamido-6-bromoindan-1-one 6 with tert-butyl 4-aminobenzoate, then the cyclopenta[g]quinazolinone ring was formed and the propargyl group was introduced on the N¹⁰-position using the (propargyl)Co₂(CO)₆⁺ complex as the electrophilic propargyl reagent.

Full text of DOI:10.1039/b301989f

View Article Online / Journal Homepage / Table of Contents for this issue
Antifolate chemistry: synthesis of 4-{N-[(6RS )-2-methyl-4-oxo-
3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-
؉
ynyl)amino}benzoic acid via a (propargyl)Co2(CO)6 complex
Vassilios Bavetsias,* Rainer Clauss and Elisa A. Henderson
Cancer Research UK Centre for Cancer Therapeutics at The Institute of Cancer Research,
Chemistry Department, Cancer Research UK Laboratory, 15 Cotswold Road, Sutton, Surrey,
UK SM2 5NG. E-mail: vassilio@icr.ac.uk
Received 19th February 2003, Accepted 4th April 2003
First published as an Advance Article on the web 23rd April 2003
A new route to compound 3 (4-{N-[(6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-
(prop-2-ynyl)amino}benzoic acid), a crucial intermediate for the synthesis of potent inhibitors of thymidylate
synthase (TS), is described. In this sequence the C6–N 10 bond was constructed first, by the reductive amination of
5-acetamido-6-bromoindan-1-one 6 with tert-butyl 4-aminobenzoate, then the cyclopenta[g]quinazolinone ring was
formed and the propargyl group was introduced on the N 10-position using the (propargyl)Co2(CO)6ϩ complex as the
electrophilic propargyl reagent.
Introduction
Thymidylate synthase (TS) catalyses the conversion of
2Ј-deoxyuridine 5Ј-monophosphate (dUMP) to thymidine
5Ј-monophosphate (TMP) and this enzyme proved to be an
attractive target in anticancer drug design.1 The prototype
folate-based inhibitor of TS is CB3717 1, a compound that was
first synthesised at the Institute of Cancer Research, UK and
showed activity in clinical trials.2,3 Over the last two decades
a large amount of research in the antifolate area has been
directed towards the development of inhibitors of thymidylate
synthase (TS).4 As a result a number of molecules have reached
the stage of clinical trials, and Raltitrexed 25,6 has been
approved in various countries for the treatment of colorectal
cancer.
We have recently reported the synthesis of cyclopenta[g]-
quinazoline-based antifolates, a novel class of TS inhibitor.7
4-{N-[(6RS)-2-Methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta-
[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino}benzoic acid 3, the
key intermediate for the synthesis of this class of compounds,
was prepared from N-(4-{N-[(6RS)-2-methyl-4-oxo-3,4,7,8-
tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-ynyl)-
amino}benzoyl)--glutamic acid by the enzymatic cleavage of
its glutamyl residue.7,8 We now report an improved route to
4-aminobenzoate under classical conditions (i.e. TsOH, DME,
reflux/NaBH3CN, MeOH, AcOH, room temperature) resulted
in the formation of 7 in 35% yield. This yield was increased to
this key intermediate 3 in which the propargyl group was intro-
ϩ
duced in the penultimate step using the (propargyl)Co2(CO)6
complex as the electrophilic propargyl reagent.
81% when the reductive amination was performed using
decaborane in methanol.10 Cyanation of the aryl bromide 7 was
effected utilising the Rosenmund–von Braun reaction11 by
Results and discussion
heating 7 with copper() cyanide in 1-methyl-2-pyrrolidinone
The route to compound 3 is outlined in Scheme 1. This method-
ology differs significantly from the published route to 3.7,8
The oxo-functionality, required for the formation of the
C6–N10 bond via a reductive amination reaction, was intro-
duced in the initial steps of the synthesis whereas the cyclo-
penta[g]quinazoline ring was constructed after the formation of
the C6–N10 bond making this route simpler and more flexible.
Most significantly, the propargyl group was introduced in the
penultimate step under mild conditions utilising the (propar-
gyl)Co2(CO)6ϩ complex as the electrophilic propargyl synthon.
In this synthetic sequence (Scheme 1) 5-acetamido-6-bromo-
indane 4 was used as the starting material. Oxidation of 4 with
CrO3 in acetic acid9 gave a mixture of two regioisomers 5 and 6;
the desired ketone 6 was isolated by column chromatography in
43% yield. Reductive amination of the ketone 6 with tert-butyl
(NMP) at 140 ЊC. In the next step, the indane derivative 8 was
cyclised to the cyclopenta[g]quinazolin-4-one 9 in 83% yield by
treatment with H2O2, NaOH in EtOH–H2O. It was envisaged
that the introduction of the N 10-propargyl substituent could be
achieved by using a cobalt-complexed propargyl cation as the
electrophilic propargyl synthon. It is known that cobalt-com-
plexed propargyl cations react with a variety of nucleophiles12
including primary or secondary amines.13 Indeed the tetrafluoro-
borate salt 12, prepared by treatment of the dicobalt hexa-
14
carbonyl complex 11 with propionic acid and HBF4 at
Ϫ20 ЊC, reacted smoothly with 9 at room temperature to afford
13 in high yield (76%) without the need to protect the N 3–H.
Decomplexation of 13 with Fe(NO3)3 in EtOH afforded the
N 10-propargylated derivative 14. In the final step the tert-butyl
group was removed with TFA to afford the desired product 3 as
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 9 4 3 – 1 9 4 6
1943

View Article Online
Scheme 1 Reagents and conditions: (a), CrO3 AcOH, 55 ЊC; (b), tert-butyl 4-aminobenzoate, TsOH, DME, molecular sieves, reflux/NaBH3CN,
AcOH, MeOH, room temp. or tert-butyl 4-aminobenzoate, decaborane, MeOH, room temp.; (c) CuCN, NMP, 140 ЊC; (d), H2O2, NaOH, EtOH–
H2O, 55 ЊC; (e), Co2(CO)8, CH2Cl2, room temp.; (f ), propionic acid, HBF4, Ϫ20 ЊC; (g), DIEA, CH2Cl2, room temp.; (h), Fe(NO3)3, EtOH, room
temp.; (i), CH2Cl2/TFA.
a racemic mixture. Chiral HPLC (column: Astec cyclobond
BETA; mobile phase: 83% 25 mM Na2HPO4/25 mM
NaH2PO4–17% CH3CN; flow 1 ml minϪ1; λ = 230 nM) indicated
two peaks for compound 3 in a ratio of 1 : 1.
Synthesis
5-Acetamido-6-bromoindan-1-one 6. This compound was
prepared as described in ref. 9: Purification of the crude prod-
uct by column chromatography using a gradient of ethyl acetate
in dichloromethane (10 to 20%) afforded in order of elution:
a. 5-Acetamido-6-bromoindan-1-one as a white solid which
was further purified by trituration with ethyl acetate–hexane
(1 : 4, v/v): 2.60 g (43%), mp 162–164 ЊC (Found: C, 49.18; H,
3.65; N, 5.13; Br, 29.89; C11H10BrNO2 requires C, 49.28; H,
3.76; N, 5.22; Br, 29.80%); νmax (film)/cmϪ1 3234 (w), 1702 (s),
1662 (s), 1526 (s); δH (CDCl3) 2.30 (1 H, s, Me), 2.71 (2 H, m,
2-H), 3.11 (2 H, t, J 5.6, 3-H), 7.93 (1 H, br s, CONH), 7.94,
8.60 (each 1 H, s, 4-H, 7-H); m/z (ESI) 268, 270 {(M ϩ H)ϩ,
100%, 95% respectively, bromine isotopic pattern}, 226 (25).
b. 5-Acetamido-6-bromoindan-3-one as a white solid which
was further purified by trituration with ethyl acetate–hexane
(1 : 4, v/v): 0.45 g, (8%), mp 219–220 ЊC (Found: C, 49.24; H,
3.67; N, 5.12; Br, 29.73; C11H10BrNO2 requires C, 49.28; H,
3.76; N, 5.22; Br, 29.80%); νmax (film)/cmϪ1 3276 (w), 1700 (s),
1663 (s), 1605 (s); δH (CDCl3) 2.26 (3 H, s, Me), 2.71 (2 H, m,
2-H), 3.10 (2 H, t, J 5.6, 1-H), 7.60 (1 H, br s, CONH), 7.72,
8.62 (each 1 H, s, 4-H, 7-H); m/z (ESI) 268, 270 {(M ϩ H)ϩ,
100%, 95% respectively, bromine isotopic pattern}, 188 (90).
In summary, a new, simpler, and more flexible route to com-
pound 3, a crucial intermediate for the synthesis of novel
inhibitors of TS, has been developed. In this route the N 10
-
propargyl substituent was introduced under mild conditions
utilising the (propargyl)Co2(CO)6ϩ complex as the electrophilic
propargyl synthon. It should be noted that an N 10 propargyl
substituent provides optimum TS binding in a variety of
classical quinazoline-based inhibitors of TS. Therefore, this
methodology may be applied for the introduction of an
N 10-propargyl substituent in other antifolates.
Experimental
Thin layer chromatography (TLC) was performed on pre-
coated sheets of silica 60F254 (Merck Art 5735) visualised under
UV light. Merck silica 60 (Art 15111) was used in low-pressure
column chromatography. Petrol refers to light petroleum
(bp 60–80 ЊC). Electrospray ionisation (ESI) mass spectra were
recorded using a TSQ 700 triple quadrupole mass spectrometer
(Finnigan MAT) fitted with an electrospray ionisation source
(Analytica). Proton NMR spectra were recorded using a Bruker
AC250 spectrometer at 250 MHz. Field strengths are expressed
in units of δ (ppm) relative to tetramethylsilane, and peak
multiplicities are designated as follows: s, singlet; d, doublet; dd,
doublet of doublets; dm, doublet of multiplets; t, triplet; q,
quartet, br s, broad singlet, m, multiplet. Melting points were
determined on a Kofler block and are uncorrected. Elemental
analyses were determined by C.H.N. Analysis Ltd., Leicester,
UK.
Tert-butyl
4-[N-(5-acetamido-6-bromoindan-1-yl)amino]-
benzoate 7. Method A. To a flask containing 5-acetamido-6-
bromoindan-1-one 6 (0.900 g, 3.36 mmol), 4-toluenesulfonic
acid monohydrate (0.045 g), and tert-butyl 4-aminobenzoate
(0.972 g, 5.04 mmol) was added 1,2-dimethoxyethane (dried by
distillation over CaH2; 48 cm3). An azeotropic distillation
apparatus (Aldrich)15 containing molecular sieves (3 Å) was
fitted to the reaction flask that was placed in an oil bath
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 9 4 3 – 1 9 4 6
1944

View Article Online
preheated to 60 ЊC. The temperature was raised to 110 ЊC and
stirring was continued at this temperature for 7 h under argon.
The reaction mixture was then allowed to cool to room temper-
ature, then a solution of sodium cyanoborohydride (0.336 g) in
anhydrous methanol (11 cm3) was added followed immediately
by acetic acid (0.6 cm3). The black reaction mixture was stirred
at room temperature for 24 h under argon; then partitioned
between ethyl acetate (170 cm3) and saturated aqueous sodium
bicarbonate (100 cm3). The aqueous layer was extracted with
more ethyl acetate (2 × 100 cm3); the organic extracts were
combined, dried (MgSO4) and concentrated in vacuo to leave a
dark oily residue. Purification by column chromatography on
elution with ethyl acetate–hexane (1 : 1, v/v) afforded the title
compound 7 as a white solid: 0.520 g (35%).
solvents were removed in vacuo and the residue was suspended
in water (∼40 cm3). The pH of this mixture was adjusted to
∼5 with 1 N hydrochloric acid. The white precipitate was
collected by filtration, washed with water, dried in vacuo over
P2O5, then it was triturated with ether, collected by filtration
and dried in vacuo. The title compound 9 was obtained as a
white solid 1.11 g (83%), mp 277–281 ЊC (it melts with decom-
position), (Found: C, 70.22; H, 6.43; N, 10.65; C23H25N3O3
requires C, 70.57; H, 6.44; N, 10.73%); δH (DMSO-d6) 1.50 (9
H, s, C(CH3)3), 2.31 (3 H, s, Me), 1.87, 2.55 (each 1 H, m, 7-H),
2.97 (2 H, m, 8-H), 5.15 (1 H, m, 6-H), 6.77 (2 H, d, J 8.6, 3Ј,5Ј-
H), 6.91 (1 H, d, J 8.70, N10–H), 7.44, 7.87 (each 1 H, s, 5-H,
9-H), 7.66 (2 H, d, J 8.75, 2Ј,6Ј-H); m/z (ESI) 783 {(2M ϩ H)ϩ,
100%}, 392 {(M ϩ H)ϩ, 30%}, 199 (90).
Method B. To a nearly clear solution of 5-acetamido-6-bro-
moindan-1-one 6 (0.964 g, 3.60 mmol) in anhydrous methanol
(70 cm3) was added tert-butyl 4-aminobenzoate (0.733 g, 3. 8
mmol) followed by decaborane (0.130 g, 1.08 mmol); a clear
solution was obtained after stirring for approximately 0.5 h.
The reaction mixture was stirred at room temperature overnight
before being concentrated in vacuo. Purification by column
chromatography and elution with a gradient of ethyl acetate in
hexane (35 to 40%), afforded a gummy residue which was fur-
ther purified by trituration with dichloromethane–hexane (1 : 4,
v/v). The title compound 7 was obtained as a white solid: 1.32 g
(81%) mp 153 ЊC (Found: C, 59.36; H, 5.62; N, 6.31; Br, 17.96;
C22H25BrN2O3 requires C, 59.33; H, 5.66; N, 6.29; Br, 17.94%);
νmax (film)/cmϪ1 1700 (s), 1684 (s), 1654 (s), 1604 (s); δH (CDCl3)
1.57 (9 H, s, C(CH3)3), 2.25 (3 H, s, Me), 1.91, 2.63 (each 1 H,
m, 2-H), 2.95 (2 H, m, 3-H), 5.03 (1 H, t, J 6.60, 1-H), 6.64 (2 H,
d, J 8.75, 3Ј,5Ј-H), 7.60 (1 H, br s, CONH), 7.49, 8.25 (each 1 H,
s, 4-H, 7-H), 7.85 (2 H, d, J 8.75, 2Ј,6Ј-H); m/z (ESI) 467, 469
{(M ϩ Na)ϩ, 100%, 95% respectively, bromine isotopic
pattern}, 252, 254 (35).
Dicobalt hexacarbonyl propargyl alcohol complex 11. This
is a known compound13 and in this study was prepared accord-
ing to Nicholas’ methodology:14 To a round bottom flask
charged with Co2(CO)8 (5.12 g, 15.0 mmol) under argon in a
well ventilated hood was added anhydrous dichloromethane
(170 cm3) followed by a solution of propargyl alcohol (0.840 g,
15.0 mmol) in anhydrous dichloromethane (20 cm3). The deep
red reaction mixture was stirred at room temperature for 7 h
under argon, then it was filtered through a thin layer of neutral
alumina. The filtrate was concentrated in vacuo to give a red
residue. Purification by column chromatography, on elution
with 40% diethyl ether in hexane, afforded the title compound
11 as a red solid 4.10 g (80%); δH (CDCl3) 1.83 (1 H, t, J 6.0,
OH, exchanges with D2O), 4.80 (2 H, d, J 6.0, CH2), 6.08 (1 H,
s, C–H).
(Propargyl)Co2(CO)6؉BF4؊ 12. This is a known compound13
and in this study was prepared according to Nicholas’ method-
ology:14 To a round bottom flask charged with the dicobalt
hexacarbonyl complex 11 (1.60 g, 4.7 mmol) under argon was
added (syringed via a septum) propionic acid (2.2 cm3). The
reaction mixture was cooled to Ϫ20 ЊC and then a solution of
HBF4 in diethyl ether (54% w/w, 2.05 cm3) was slowly syringed
into the reaction mixture via a septum. The reaction mixture
was stirred at Ϫ20 ЊC for 40 min, then pre-cooled diethyl ether
(50 cm3) was added. Trituration afforded a red precipitate that
was collected by filtration, washed with plenty of dry diethyl
ether and dried in vacuo over P2O5: 1.71 g (90%). This was
immediately used in the next reaction without any further
purification.
Tert-butyl
4-[N-(5-acetamido-6-cyanoindan-1-yl)amino]-
benzoate 8. To a solution of 7 (1.170 g, 2.62 mmol) in 1-methyl-
2-pyrrolidinone (NMP) (13 cm3) was added copper() cyanide
(0.400 g, 4.70 mmol). The reaction mixture was placed in an oil-
bath preheated to 140 ЊC and stirred at this temperature for 1 h
and 40 min. The reaction mixture was allowed to cool to room
temperature, then poured into a mixture of aqueous ammonia
(d = 0.88 g cmϪ3, 12 cm3) and ice (∼34 cm3) and the resulting
brown mixture was stirred at room temperature for ∼10 min.
The brown solid was collected by filtration washed with plenty
of water, then dissolved in dichloromethane (100 cm3). The
mixture was stirred at room temperature for 10 min, dried
(MgSO4), and concentrated in vacuo. Purification by column
chromatography and elution with 35% ethyl acetate in hexane,
afforded a crispy solid that was reprecipitated from ethyl acet-
ate–hexane. The title compound 8 was obtained as a white
solid: 0.714 g, (70%) mp 173–174 ЊC (Found: C, 70.35; H, 6.44;
N, 10.62; C23H25N3O3 requires C, 70.57; H, 6.44; N, 10.73%);
νmax (film)/cmϪ1 2224 (w), 1700 (s), 1684 (s), 1653 (s), 1604 (s);
δH (CDCl3) 1.58 (9 H, s, C(CH3)3), 2.28 (3 H, s, Me), 1.96, 2.67
(each 1 H, m, 2-H), 3.04 (2 H, m, 3-H), 4.23 (1 H, d, J 8.31,
N–H), 5.06 (1 H, q, J 7.50, 1-H), 6.65 (2 H, d, J 8.75, 3Ј,5Ј-H),
7.60 (1 H, br s, CONH), 7.54, 8.32 (each 1 H, s, 4-H, 7-H), 7.87
(2 H, d, J 8.75, 2Ј,6Ј-H); m/z (ESI) 783 {(2M ϩ H)ϩ, 100%,},
414 {(M ϩ Na)ϩ, 55%}, 199 (15).
Dicobalt hexacarbonyl complex 13. To a round bottom flask
containing the tetrafluoroborate salt 12 (1.44 g, 3.5 mmol) was
added anhydrous dichloromethane (dried by distillation over
P2O5; 100 cm3). The nearly clear red dark solution was stirred
at room temperature for a few minutes under argon, then 9
(1.04 g, 2.66 mmol) was added in one portion; a clear solu-
tion was obtained after approximately 2 min. Stirring was
continued at this temperature for 5 min then diisopropylethyl-
amine (0.92 cm3, 5.32 mmol) was added and the reaction
mixture was stirred at room temperature for 45 min under
argon. The reaction mixture was partitioned between ethyl
acetate (300 cm3) and brine (120 cm3). The organic layer was
washed with 10% aqueous citric acid (100 cm3), brine (100 cm3),
dried (Na2SO4), and concentrated in vacuo. Purification by
column chromatography and elution with ethyl acetate in
dichloromethane (60 to 70%) gave 13 as a red solid 1.45 g
(76%), mp >150 ЊC (with decomposition, red crystals turn
black); δH (CDCl3) 1.58 (9 H, s, C(CH3)3), 2.53 (3 H, s, 2-Me),
2.32, 2.60 (each 1 H, m, 7-H), 3.05, 3.20 (each 1 H, m, 8-H),
4.55 (2 H, AB system, J 17.2, N10–CH2), 5.63 (1 H, t, J 8.6,
6-H), 5.96 (1 H, s, propargyl complex C–H), 6.93 (2 H, d, J 8.9,
3Ј,5Ј-H), 7.58, 8.00 (each 1 H, s, 5-H, 9-H), 7.90 (2 H, d, J 8.9,
2Ј,6Ј-H), 10.58 (1 H, s, N3–H); m/z (ESI) 716 {(M ϩ H)ϩ, 80%},
231 (100), 199 (70).
Tert-butyl 4-{N-[(6RS )-2-methyl-4-oxo-3,4,7,8-tetrahydro-
6H-cyclopenta[g]quinazolin-6-yl]amino}benzoate 9. A mixture
of 8 (1.33 g, 3.40 mmol), ethanol (15 cm3), and water (3.1 cm3)
was cooled in an ice-bath, then 30% aqueous H2O2 solution
(2.8 cm3) was added followed by granulated sodium hydroxide
pellets (0.230 g, 5.78 mmol). The reaction mixture was stirred at
∼0 ЊC for 10 min, then it was placed in an oil bath preheated to
55 ЊC and stirred at this temperature for 40 min. The reaction
mixture was allowed to cool to room temperature, then the
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 9 4 3 – 1 9 4 6
1945

View Article Online
Tert-Butyl 4-{N-[(6RS )-2-methyl-4-oxo-3,4,7,8-tetrahydro-
6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino}benz-
oate 14. To a solution of the complex 13 (1.40 g, 1.96 mmol) in
ethanol (200 cm3) was added Fe(NO3)3 (26 g). The clear solu-
tion was stirred at room temperature for 10 min then a second
portion of Fe(NO3)3 (∼15 g) was added. The reaction mixture
was stirred at room temperature for a further 10 min then a
final portion of Fe(NO3)3 (∼10 g) was added; the nearly clear
solution turned dark red. Stirring was continued at room tem-
perature for an extra 15 min, the reaction mixture was then
partitioned between ethyl acetate (700 cm3) and dilute brine
(200 cm3). The organic (not clear) layer was washed with more
brine (3 × 150 cm3), dried (Na2SO4), and concentrated in vacuo
to leave a brown solid. Purification by column chromatography
and elution with 5% methanol in chloroform, afforded a solid.
Trituration with dichloromethane–hexane gave the title com-
pound 14 as an off white solid, 0.565 g (67%), mp 244–246 ЊC;
(Found: C, 72.60; H, 6.37; N, 9.67; C26H27N3O3 requires C,
72.71; H, 6.34; N, 9.78%); δH (DMSO-d6) 1.50 (9 H, s, C(CH3)3),
s, N3–H); m/z (ESI) 747 {(2M ϩ H)ϩ, 100%}, 374 {(M ϩ H)ϩ,
70%}, 199 (20%). Chiral HPLC (column: Astec cyclobond
BETA; mobile phase: 83% 25mM Na2HPO4–25 mM
NaH2PO4–17% CH3CN; flow 1 ml minϪ1; λ = 230 nm): two
peaks in a ratio of approximately 1 : 1; retention times: 621, 680
seconds.
Acknowledgements
This work was supported by grants from the Cancer Research
Campaign. We thank Prof. A. L. Jackman for encouragement
and support throughout this project and Dr Ted McDonald for
chemical discussions at the final part of the project.
References
1 Antifolate Drugs in Cancer Therapy, ed. A. L. Jackman,
Humana Press, Totowa, New Jersey, 1999.
2 (a) T. R. Jones, A. H. Calvert, A. L. Jackman, S. J. Brown, M. Jones
and K. R. Harrap, Eur. J. Cancer, 1981, 17, 11; (b) R. C. Jackson,
A. L. Jackman and A. H. Calvert, Biochem. Pharmacol., 1983, 32,
3783.
3 A. H. Calvert, D. L. Alison, S. J. Harland, B. A. Robinson, A. L.
Jackman, T. R. Jones, D. R. Newell, Z. H. Siddick, E. Wiltshaw,
T. J. McElwain, I. E. Smith and K. R. Harrap, J. Clin. Oncol., 1986,
4, 1245.
4 For recent reviews see: (a) A. Gangjee, E. Elzein, M. Kothare and
A. Vasudevan, Curr. Pharm. Des., 1996, 2, 263; (b) V. Bavetsias
and A. L. Jackman, Curr. Med. Chem., 1998, 5, 265.
5 A. L. Jackman, G. A. Taylor, W. Gibson, R. Kimbell, M. Brown,
A. H. Calvert, I. R. Judson and L. R. Hughes, Cancer Res., 1991, 51,
5579.
6 A. L. Jackman, D. C. Farrugia, W. Gibson, R. Kimbell, K. R.
Harrap, T. C. Stephens, M. Azab and F. T. Boyle, Eur. J. Cancer,
Part A, 1995, 31, 1277.
7 V. Bavetsias, J. H. Marriott, C. Melin, R. Kimbell, Z. S. Matusiak,
F. T. Boyle and A. L. Jackman, J. Med. Chem., 2000, 43, 1910.
8 J. H. Marriott, S. Neidle, Z. Matusiak, V. Bavetsias, A. L. Jackman,
C. Melin and F. T. Boyle, J. Chem. Soc., Perkin Trans. 1, 1999, 1495.
9 C.-S. Li, W. C. Black, C.-C. Chan, A. W. Ford-Hutchinson,
J.-Y. Gauthier, R. Gordon, D. Guay, S. Kargman, C. K. Lau,
J. Mancini, N. Ouimet, P. Roy, P. Vickers, E. Wong, R. N. Young,
R. Zamboni and P. Prasit, J. Med. Chem., 1995, 38, 4897.
10 J. W. Bae, S. H. Lee, Y. J. Cho and C. M. Yoon, J. Chem. Soc., Perkin
Trans. 1, 2000, 145.
11 G. P. Ellis and T. M. Romney-Alexander, Chem. Rev., 1987, 87, 779.
12 K. M. Nicholas, Acc. Chem. Res., 1987, 20, 207 for a recent review
on the use of dicobalt-stabilised propargylic cations in synthesis, see:
B. J. Teobald, Tetrahedron, 2002, 58, 4133.
2.32 (3 H, s, 2-Me), 2.18, 2.55 (obscured by the DMSO peak)
᎐
(each 1 H, m, 7-H), 2.97 (1 H, m, 8-H), 3.14 (2 H, m, C᎐CH,
᎐
᎐
8-H), 3.96 (2 H, AB system, J 18.1, CH C᎐C), 5.75 (1 H, t,
᎐
2
J 8.2, 6-H), 6.98 (2 H, d, J 9.5, 3Ј,5Ј-H), 7.48, 7.76 (each 1 H, s,
5-H, 9-H), 7.74 (2 H, d, J 8.7, 2Ј,6Ј-H), 12.11 (1 H, s, N3–H);
m/z (ESI) 430 {(M ϩ H)ϩ, 90%}, 374 (55%), 231 (100), 199 (60).
N-[(6RS )-2-Methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta-
[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino}benzoic acid 3.
A
solution of 14 (0.245 g, 0.57 mmol) in dichloromethane (2 cm3)
and trifluoroacetic acid (10 cm3) was stirred at room temper-
ature for 1.5 hours, then the solvents were removed in vacuo.
The residue was triturated with diethyl ether and the precipitate
was collected by filtration, washed with diethyl ether and dried
in vacuo over P2O5 to afford the title compound as the trifluor-
acetate salt (0.255 g). Part of this material (0.067 g) was sus-
pended in water (6 cm3), and the pH was adjusted to ∼12 with
1 N aqueous sodium hydroxide. The pH of the clear solution
was adjusted to ∼4 with 1 N aqueous hydrochloric acid. The
white precipitate was collected by filtration, washed with water
and dried in vacuo over P2O5 to afford the title compound 3 as a
white solid (0.040 g) mp 305–307 ЊC (ref. 7: >325 ЊC); (Found:
C, 68.65; H, 4.97; N, 10.87; C22H19N3O3ؒ0.6H2O requires C,
68.78; H, 5.29; N, 10.93%); δH (DMSO-d6) 2.33 (3 H, s, 2-Me),
2.24, 2.50 (obscured by the DMSO peak) (each 1 H, m, 7-H),
2.97 (1 H, m, 8-H), 3.20 (1 H, m (obscured by H2O peak), 8-H),
13 K.-D. Roth and U. Muller, Tetrahedron Lett., 1993, 34, 2919.
14 K. L. Salazar and K. M. Nicholas, Tetrahedron, 2000, 56, 2211.
15 N. S. Barta, K. Paulvannan, J. B. Schwarz and J. R. Stille, Synth.
Commun., 1994, 24, 583.
᎐
᎐
3.13 (1 H, s, C᎐CH), 3.96 (2 H, AB system, J 19.0, CH C᎐C),
᎐
᎐
2
5.75 (1 H, t, J 8.3, 6-H), 7.01 (2 H, d, J 9.0, 3Ј,5Ј-H), 7.48, 7.78
(each 1 H, s, 5-H, 9-H), 7.80 (2 H, d, J 9.4, 2Ј,6Ј-H), 12.11 (1 H,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 9 4 3 – 1 9 4 6
1946