Synthesis of chiral β-methyl tryptamine-derived GnRH antagonists

Article abstract of DOI:10.1016/S0040-4039(01)01288-6

The stereospecific formation of 2-aryl-β-methyl tryptamine derivatives 15 and 16 from chiral 4-chloro-1-(3,5-dimethylphenyl)-3-methylbutanones is described. These intermediates were further manipulated into the GnRH antagonists 1b and 1c in five steps.

Full text of DOI:10.1016/S0040-4039(01)01288-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6459–6461
Synthesis of chiral b-methyl tryptamine-derived GnRH
antagonists
Joseph P. Simeone,* Robert L. Bugianesi, Mitree M. Ponpipom, Mark T. Goulet, Mark S. Levorse
and Ranjit C. Desai
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Received 26 April 2001; revised 19 June 2001; accepted 26 June 2001
Abstract—The stereospecific formation of 2-aryl-b-methyl tryptamine derivatives 15 and 16 from chiral 4-chloro-1-(3,5-
dimethylphenyl)-3-methylbutanones is described. These intermediates were further manipulated into the GnRH antagonists 1b and
1c in five steps. © 2001 Elsevier Science Ltd. All rights reserved.
During the course of our investigation into the develop-
ment of potent non-peptide gonadotropin releasing
hormone antagonists,1a–c we became interested in the
synthesis of 2-aryl-b-methyl tryptamine derivatives. We
found that the introduction of a methyl group b to the
tryptamine nitrogen provided increased potency and
selectivity over the non-substituted analogs, when eval-
uated in our screening protocol.2 This discovery
prompted us to develop a stereospecific synthesis of the
tryptamine core, preferably with the 2-aryl group
intact, to facilitate further SAR studies (Fig. 1).
tional group at the 5-position to further elaborate the
molecule.
Using this methodology, we were able to prepare the
racemic compound 1a (Scheme 1). Starting from com-
mercially available 2-methylcyclopropane carboxylic
acid 2, treatment with oxalyl chloride followed by
N,O-dimethylamine hydrochloride, yielded the Weinreb
amide 3. This was then converted to the ketone 4 via
reaction with the lithium derivative of 5-bromo-m-
xylene. With the ketone in hand, the next step was the
formation of the indole core. Reaction with the previ-
ously prepared ethyl 2-(4-hydrazinophenyl)-2-methyl-
propanoate 54 in the presence of concentrated HCl and
n-butanol gave a 4:1 mixture of the b- and a-methyl
isomers 6 and 7. These were readily separated by
silica-gel chromatography.5 Reductive alkylation of
tryptamine 6 with 4-pyridin-4-ylbutanal6 resulted in the
secondary amine 8 which was protected as the CBZ-
carbamate before elaboration of the ‘left-hand’ side of
the molecule. Saponification of the ethyl ester was
achieved by refluxing overnight in a solution of water
and 0.5N KOH in methanol. The PyBOP reagent was
The original synthesis3 of 2-aryl tryptamine intermedi-
ates was designed to allow a facile modification of the
aryl group. The tryptamine nitrogen was protected as a
phthalimide, bromination at the 2-position of the indole
was accomplished using pyridine hydrobromide perbro-
mide, and the aryl group was introduced via a modified
Suzuki coupling procedure. However, the focus of our
efforts eventually shifted to modifications of other parts
of the molecule. With this in mind, we turned toward a
Fischer indole approach to construct the tryptamine
with the aryl group in place and, in addition, a func-
R
H
N
N
1a: R = CH3 (rac.)
O
N
1b: R = (S)-CH3
1c: R = (R)-CH3
N
H
1a-c
Figure 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01288-6

6460
J. P. Simeone et al. / Tetrahedron Letters 42 (2001) 6459–6461
O
O
O
b
a
+ EtO2C
OMe
OH
N
NHNH2
2
4
5
3
R1
NH2
R2
H
N
EtO2C
c
d
EtO2C
N
N
H
N
H
6 R1=CH3, R2=H
7 R1=H, R2=CH3
8
CBZ
N
N
e,f,g
h
1a
O
N
N
H
9
Scheme 1. Reagents and conditions: (a) (1) ClCOCOCl, DMF, benzene, 0°C, (2) N,O-dimethylamine hydrochloride, Et3N, 0°C to
rt, 62%; (b) 5-bromo-m-xylene, 1.6 M n-BuLi, THF, −78°C, 81%; (c) phenylhydrazine 5, HCl, n-butanol, reflux, 16% 6, 4% 7; (d)
4-pyridin-4-ylbutanal, MgSO4, CHCl3, 0 to −10°C, 75%; (e) CBZCl, K2CO3, H2O, THF, 0°C, 80%; (f) 0.5N KOH/CH3OH, H2O,
reflux, 97%; (g) Et2N, PyBOP, Et3N, CH2Cl2, rt, 75%; (h) H2, 10% Pd/C, CH3OH, 97%.
the Fischer indole conditions in combination with
phenylhydrazine to give rise to our desired
tryptamines with the methyl stereocenter fixed.
used to couple the carboxylic acid with diethylamine.
Finally, deprotection of carbamate through
hydrogenolysis of the CBZ protecting group led to the
5
9
desired tryptamine 1a.
Starting from (R)-3-bromo-2-methyl-1-propanol 10,
one carbon homologation to the nitrile 11 was achieved
via SN2 displacement of the bromide with sodium cya-
nide in DMF (Scheme 2). A two-step ‘one-pot’ lac-
tonization procedure9 was then used whereby the nitrile
was hydrolyzed with sodium hydroxide in aqueous
ethanol, followed by cyclization of the acid through the
action of PTSA in benzene.
At this time, we discovered that a variation of the
Fischer indole synthesis could be used to obtain 2-aryl
tryptamines directly in moderate yields. Using a model
system involving the reaction of 4-chlorobutyrophe-
none with 4-nitrophenyl hydrazine, we were able to
obtain 2-phenyl-5-nitro tryptamine in 40% yield. This
result was contrary to the findings of Grandberg7 and
later Sannicolo8 who both found that only tetra-
hydopyridazine products could be obtained from the
reaction of phenyl hydrazines with 4-chlorobutyrophe-
nones. Based on this result, we set out to prepare a
4-chlorobutyrophenone substituted with a chiral methyl
group at the 3-position. This could then be subjected to
The Claisen condensation of lactone 12 with methyl
3,5-dimethyl benzoate was at first problematic. The
published procedure10 called for a 3:2 excess of lactone
to ester. This ratio resulted in sodium methoxide medi-
ated degradation of the lactone leading to low yields of
O
O
(R)
(S)
O
O
a
b
c
HO
Br
HO
O
CN
O
(S)
(S)
12
10
11
13
NH2
(S)
Cl
EtO2C
d
e
(S)
N
H
14
15
16 (R) enantiomer
from 10(S) (not shown)
Scheme 2. Reagents and conditions: (a) NaCN, DMF, 80°C, 88%; (b) (1) NaOH, EtOH, reflux, (2) PTSA, benzene, reflux, 61%;
(c) NaOMe, methyl 3,5-dimethyl benzoate, dioxane, reflux; (d) conc. HCl, dioxane, reflux, 87% for two steps; (e) phenylhydrazine
5, HCl, t-butanol, reflux, 16%.

J. P. Simeone et al. / Tetrahedron Letters 42 (2001) 6459–6461
6461
the coupled product 13. When we switched the ratio to
2:1 ester to lactone and used freshly prepared sodium
methoxide in the same excess, we realized an 87% yield
of chloroketone 14 after acid-catalyzed ring opening.
An attempt was made to perform both transformations
in a ‘single pot’ but this was complicated by our
inability to separate the excess ester from the chloro-
ketone product.
2. Walsh, T. F.; Toupence, R. B.; Young, J. R.; Huang, S.
X.; Ujjainwalla, F.; DeVita, R. J.; Goulet, M. T.;
Wyvratt, Jr., M. J.; Fisher, M. H.; Lo, J.-L.; Ren, N.;
Yudkovitz, J. B.; Yang, Y. T.; Cheng, K.; Smith, R. G.
Bioorg. Med. Chem. Lett. 2000, 10, 443–447 and refer-
ences cited therein.
3. Chu, L.; Fisher, M. H.; Goulet, M. T.; Wyvratt, M. J.;
Fisher, M. H. Tetrahedron Lett. 1997, 38, 3871.
4. Ashton, W. T.; Sisco, R. M.; Yang, Y. T.; Lo, J. L.;
Yudkovitz, J. B.; Cheng, K.; Goulet, M. T. Bioorg. Med.
Chem. Lett. 2001, 11, 1723–1726.
5. Chromatography was performed using 100:1 silica
gel:compound and eluting initially with 3 column vol-
umes of methylene chloride, followed by 5%
methanol:methylene chloride until both isomers eluted.
6. Ashton, W. T.; Sisco, R. M.; Yang, Y. T.; Lo, J. L.;
Yudkovitz, J. B.; Gibbons, P. H.; Mount, G. R.; Ren, R.
N.; Butler, B. S.; Cheng, K.; Goulet, M. T. Bioorg. Med.
Chem. Lett. 2001, 11, 1729–1731.
The chloroketone 14 was condensed with phenyl-
hydrazine 5 under the Fischer indole conditions to give
rise to the target 2-aryl-tryptamine 15. Although the
yields11 for this step in the process are only modest, this
method allowed us to prepare sufficient quantities of
both enantiomers12 in a timely fashion. From here, we
followed the same procedure used for the racemic com-
pound, as outlined above, to obtain optically pure 1b.
The entire process was repeated for the synthesis of the
(R) enantiomer 1c.
7. Grandberg, I. I. Khim. Geterotsikl. Soedin. 1974, 579–590
and references cited therein.
8. Sannicolo, F.; Benincori, T.; Brenna, E. J. Chem. Soc.,
Perkin Trans. 1991, 2139–2145.
9. Solladie, G.; Moghadam, F. M. J. Org. Chem. 1982, 47,
91–94.
10. Sato, M.; Tagawa, H.; Kosasayama, A.; Uchimara, F.;
Kojima, H.; Yamasaki, T.; Sakurai, T. Chem. Pharm.
Bull. 1978, 11, 3296–3305.
In summary, we have prepared racemic and optically
active b-methyl substituted tryptamine derivatives mak-
ing use of a novel synthesis of both enantiomers of
4-chloro-1-(3,5-dimethylphenyl)-3-methylbutan-1-one
and a modified Fischer indole synthesis. These deriva-
tives were transformed into the desired targets 1a–c in
five steps.
11. Several different modifications of the reaction conditions
were examined in an attempt to minimize the tetra-
hydropyridazine product. In all cases, yields of
tryptamines varied from 10 to 40%, depending on the
nature of the substituent at the 5-position.
12. Tryptamines 6, 15, and 16 were separately analyzed on a
Chiralcel ODR column in 1:1 CH3CN:1.0N NaClO4 at
25°C. Under these conditions, the racemate 6 showed
baseline resolution of both enantiomers, whereas analysis
of both enantiomers 15 and 16 revealed none of the
opposite enantiomer present.
References
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Y. T.; Cheng, K.; Smith, R. G.; Fisher, M. H.; Wyvratt,
M. J.; Goulet, M. T. Bioorg. Med. Chem. Lett. 2001, 11,
509–513; (b) Chu, L.; Lo, J.-L.; Yang, Y. T.; Cheng, K.;
Smith, R. G.; Fisher, M. H.; Wyvratt, M. J.; Goulet, M.
T. Bioorg. Med. Chem. Lett. 2001, 11, 515–517; (c) Lin, P.;
Marino, D.; Goulet, M. T.; Fisher, M. H.; Wyvratt, M. J.;
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