Enantiospecific and regioselective opening of 2-alkyl nosylaziridines by indoles mediated by boron trifluoride. Application to a practical synthesis of a GnRH antagonist

Article abstract of DOI:10.1016/j.tetasy.2003.08.038

An efficient, high yield process for the synthesis of a GnRH antagonist has been developed. We have demonstrated that under boron trifluoride mediation, nosyl aziridines will react with 2-arylindole derivatives to afford β-substituted tryptamines in an enantiospecific process with remarkably high regioselectivity. The scope of the reaction was explored with several 2-substituted nosyl aziridines. The key reaction was developed expressly for the GnRH antagonist program and has been demonstrated on 40 kilogram scale.

Full text of DOI:10.1016/j.tetasy.2003.08.038

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3503–3515
Enantiospecific and regioselective opening of 2-alkyl
nosylaziridines by indoles mediated by boron trifluoride.
Application to a practical synthesis of a GnRH antagonist
Roger N. Farr,a,* Ramon J. Alabaster,b John Y. L. Chung,a Bridgette Craig,a John S. Edwards,b
Andrew W. Gibson,b Guo-Jie Ho,a,† Guy R. Humphrey,a Simon A. Johnsonb and E. J. J. Grabowskia
aDepartment of Process Research, Merck Research Laboratories, Rahway, NJ 07065-0900, USA
bDepartment of Process Research, Merck Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK
Received 2 May 2003; accepted 29 August 2003
Abstract—An efficient, high yield process for the synthesis of a GnRH antagonist has been developed. We have demonstrated that
under boron trifluoride mediation, nosyl aziridines will react with 2-arylindole derivatives to afford b-substituted tryptamines in
an enantiospecific process with remarkably high regioselectivity. The scope of the reaction was explored with several 2-substituted
nosyl aziridines. The key reaction was developed expressly for the GnRH antagonist program and has been demonstrated on 40
kilogram scale.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
In order to enable further study of the pharmacological
properties of our lead compound, we desired a practi-
cal, chromatography-free synthesis suitable for prepara-
tion of bulk quantities of GnRH 1.
Gonanotropin releasing hormone (GnRH) is
a
decapeptide secreted from the hypothalumus and stimu-
lates the production of the pituitary hormones luteiniz-
ing hormone and follicle-stimulating hormone. By
inhibiting the production of luteinizing hormone,
GnRH antagonists can achieve suppression of gonadal
steroid hormones to castrate levels. This offers thera-
peutic benefit for the management of several pathologi-
cal states exacerbated by these hormones such as
hormone-dependent cancers, endometriosis and preco-
cious puberty.1,2 We have reported our extensive inves-
tigation of non-peptide GnRH antagonists3–5 as well as
the syntheses of our drug candidates.6–9 To date, our
lead compounds containing a 2-arylindole core and
b-methyl tryptamine side chain are the most selective as
well as potent. Previous syntheses (Scheme 1, routes
1–2) relied upon either the Larock indole synthetic
approach6 (route 1) or the more classic Fisher indole
approach7 (route 2) to afford the chiral tryptamine
core. In both cases, the chiral moiety was obtained
through linear multistep syntheses (4 and 5 steps,
respectively). The 4-pyridylethyl sidechain was then
incorporated after an additional 3–4 steps.
The chiral tryptamine core posed an interesting syn-
thetic challenge. We envisaged the most convergent
synthetic disconnection would be to prepare the
tryptamine from a 2-arylindole and an activated (S)-2-
methyl aziridine derivative (Scheme 1, route 3).
Although the aziridine literature has been recently
reviewed,10,11 the regio- and enantioselective opening of
a 2-substituted activated aziridine at the more hindered
position was unprecedented.12,13
2. Results
2.1. BF3-catalyzed addition
In order to investigate the Lewis acid catalyzed opening
of nitrophenylsulfonyl (nosyl) aziridines, 2-phenylindole
1 and methyl aziridine 2b14 were chosen as model
substrates (Table 1). After examining a variety of Lewis
acids, BF3-etherate was shown to be the most effective.
A dichloromethane solution of 2-phenylindole 1 was
sequentially treated with 1.1 equivalents of aziridine 2b
and BF3-etherate. After stirring at room temperature
* Corresponding author. Tel.: (732) 594-3062; fax: (732) 594-1499;
e-mail: roger farr@merck.com
–
† Current address: Millennium Pharmaceuticals Inc. 35 Landsdowne
St. Cambridge, Mass. 02139, USA.
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.08.038

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R. N. Farr et al. / Tetrahedron: Asymmetry 14 (2003) 3503–3515
Scheme 1.
Table 1. Aziridine activation model study
R
Aziridine (ee)a
Rxn time (h)
Assay yield (%)
Crude (ee)
Isolated (ee)b
1
2
3
4
5
H-2a
18
24
48
72
51
96
48
–
–
CH3-2b
Bn-2c
iPr-2d
Ph-2e
>99%
>99%
>99%
>99%
>99%
Complex
Complex
90%
>99%
>99%
–
@20% conversion
66
1 min
92%
a Both the chiral and racemic aziridines were prepared and analyzed by chiral HPLC or SFC.
b All products were synthesized and fully characterized (1H NMR, 13C NMR, elemental analysis).
for 24 h, the desired product 3b was obtained in 96%
assay yield.15 Evaluation of the crude reaction mixture16
showed remarkable regioselectivity and the enantiospe-
cificity was 99.4%.
We were encouraged by this unprecedented result and
decided to explore quickly the generality of the nosyl
aziridine opening. To evaluate the effect of the R group
on the aziridine ring, we prepared a short series of

R. N. Farr et al. / Tetrahedron: Asymmetry 14 (2003) 3503–3515
3505
nosyl aziridines 2a–e (Table 1). Unsubstituted nosyl
2.2. Nosyl aziridine synthesis
aziridine 2a17 (R=H, entry 1) was employed in the
BF3-mediated reaction with 2-phenylindole 1 to afford
the desired product 3a in modest yield (51%). 2-Benzyl
nosyl aziridine 2c18 was sluggish under the standard
reaction conditions. A reaction time of 48 h was
required to afford the desired product 3c in 48% yield.
The reaction enantiospecificity was impressive with the
isolated solid being greater than 99% ee.
Initially, we began our study by preparing nosyl
aziridine 2b via a cyclo-dehydration22 of the corre-
sponding amino alcohol 7b (Scheme 3) to afford
aziridine 8. The methyl aziridine 8 was then added to
the respective nosyl chloride23 and the products were
isolated by crystallization. An experimental observation
led to an improved procedure. When the amino alco-
hols were treated with 1.1 equivalents of nosyl chloride
in the presence of triethylamine, the sulfonamide was
formed cleanly with 10% of the desired nosyl aziridines
as a byproduct. Using 2.1 equivalents of nosyl chloride
in the presence of triethylamine, resulted in the clean
formation of the target compounds in high yield.14,24
This procedure worked well for lab scale runs, however,
nosyl aziridines 2a–f were shown to be unstable in the
presence of triethylamine. Therefore, this process was
unsuitable for large scale synthesis.
The a-branched derivative 2d19 (R=isopropyl, entry 4,
Table 1) was extremely sluggish under the reaction
conditions. Despite efforts to improve the reaction
profile, the reaction mixture was complex and only 20%
conversion20 was achieved after 72 h. Our next sub-
strate 2e21 (R=Ph, entry 5) also exhibited a pro-
nounced effect when subjected to our Lewis acid
catalyzed reaction. After adding neat BF3-etherate to a
mixture of 2-phenylindole 1 and nosyl aziridine 2e in
dichloromethane, the reaction was extremely exother-
mic. By cooling the reaction mixture to−20°C and
adding the Lewis acid over 10 min, the desired product
3e was obtained in 66% yield. Analysis of the crude
reaction mixture showed that the product was obtained
with 90% ee.
A two-step protocol was adopted for large-scale pro-
duction of nosyl aziridine 2b. -Alaninol 7b was treated
L
with two equivalents of nosyl chloride in pyridine. Bis
nosylated compound 9 was generated in situ and
cyclization was then achieved employing diisopropyl-
ethylamine in a two-step through process. This modifi-
cation obviates the stability issues seen with tri-
ethylamine. This sequence was demonstrated on 23 kg
scale with an isolated yield of 86% for the two step
process.
Applying these reaction conditions to the substrates
required for the synthesis of GnRH 1, aryl indole 4 was
allowed to react with aziridine 2b to afford a crystalline
product 5 in 92% isolated yield (Scheme 2). Dinitrono-
syl aziridine 2f also reacted smoothly to afford the
desired crystalline product 6 in 85% isolated yield. Both
of these products were >99.5% ee. The stereochemistry
was determined by direct comparison of a known inter-
mediate obtained via the Larock indole approach previ-
ously reported.6 With this key reaction in place, we
were ready to turn our attention to the development of
our total synthesis.
2.3. Indole synthesis
The synthesis of arylindole 4 was achieved without
incident (Scheme 4). Commercially available 4-nitro-
phenylacetic acid 10 was treated with catalytic sulfuric
acid in refluxing methanol to afford the methyl ester 11
in 97% isolated yield. Dimethylation of ester 11 was
Scheme 2. Key BF3 catalyzed addition reaction. Reagents and conditions: (a) BF3-OEt2, toluene, 20°C, 24 h, 92%; (b) BF3-OEt2,
toluene, 20°C, 24 h, 85%.

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R. N. Farr et al. / Tetrahedron: Asymmetry 14 (2003) 3503–3515
Scheme 3. Nosyl aziridine syntheses. Reagents and conditions: (a) Ph3P(OEt)2, Ref. 20; (b) toluene, 1 M aq NaOH, corresponding
nosyl chloride, 2b 90%, 2f, 92%; (c) 4-Nitrosulfonyl chloride, pyridine; (d) iPr2NEt, EtOAc, 86% for two-step process.
Scheme 4. Synthesis of 2-phenyl indole 4. Reagents and conditions: (a) H2SO4, MeOH, reflux, 97%; (b) CH3I, NaOtBu, DMF,
10°C, 97%; (c) 10% Pd/C, HCO2K, EtOH, 95%; (d) ICl, pH 5–5.5 with aq NaOH, EtOH; (e) HCl (g), 97%, 81% for four-step
process; (f) MEBYNOL, PdCl2, CuI, PPH3, Et2NH, THF, 100%; (g) NaOtBu, heptane, 95%; (h) PdCl2, CuI, PPh3, Et3N, THF,
reflux, 100%; (i) CuI, DMF, toluene, 134°C, 88%.

R. N. Farr et al. / Tetrahedron: Asymmetry 14 (2003) 3503–3515
3507
achieved by treating the ester in dimethylformamide
duced in 95% assay yield.
with three successive charges of sodium t-butoxide/
methyl iodide. Following an aqueous workup, the
product was obtained as a solution in isopropyl acetate
in 97% assay yield. After solvent switch to ethanol, the
mixture was treated with 1.8 weight% of 10% Pd/C and
potassium formate at 65°C. The transfer hydrogenation
was complete to afford amine 12 which was used as is
in the next step. Under careful pH control,25 the iodina-
tion using iodine monochloride afforded iodoaniline 13
which was isolated as the hydrochloride salt in 97%
yield. This sequence was run and resulted in the isola-
tion of 49.7 kg of hydrochloride salt 13. Typical iso-
lated yields for the four-step process was 85–90%.
Iodoaniline 13 was treated with triethylamine, catalytic
quantities of copper(I) iodide, palladium chloride and
triphenylphosphine at 70°C29 in aqueous toluene. The
xylyl acetylene 16 was then added into the mixture. By
running the reaction in this way, the reaction is essen-
tially instantaneous. This allowed the acetylene to be
titrated in to reach the reaction endpoint and prevent
the reagent from accumulating and dimerizing. The
yield was quantitative and the product used as is in the
next step. Indole formation was achieved using a mod-
ification of the procedure originally reported by
Castro.30 A toluene solution of aniline 17 was diluted
with DMF, treated with copper(I) iodide and heated to
134°C. After 3 h, desired indole 4 was then isolated as
a crystalline solid in 88% yield.
The known xylyl acetylene 1626 was prepared according
to a modification of a published procedure27 employing
2-methyl-3-butyn-2-ol (MEBYNOL), an extremely
inexpensive and safe acetylene synthon.28 Aryl bromide
14 was allowed to react with MEBYNOL in the pres-
ence of diethyl amine, catalytic quantities of copper(I)
iodide, palladium chloride and triphenylphosphine. The
heptane reaction mixture was then treated with sodium
t-butoxide and charcoal. The acetone byproduct was
distilled and the desired xylyl acetylene 16 was pro-
2.4. Endgame optimization
Our initial strategy (Scheme 5) to incorporate the 4-
pyridyl ethyl sidechain was via the Fukuyama
approach31,32 utilizing the Mitsunobu reaction. Dinitro-
sulfonamide 6 was allowed to react with pyridyl ethanol
18 under the conditions developed by Fukuyama et al.
Scheme 5. Preliminary endgame synthesis. Reagents and conditions: (a) DEAD, PPh3, THF, 20°C, 84%; (b) NaOH, MeOH, reflux;
(c) HOBT, EDC, Et3N, THF, 80% for two steps; (d) DEAD, PPh3, THF, 0–20°C; (e) HSCH2COOH, LiOH, DMF, 20°C.

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R. N. Farr et al. / Tetrahedron: Asymmetry 14 (2003) 3503–3515
Dinitrosulfonamide 6 required three equivalents of
pyridyl ethanol 18 to achieve reaction completion.33
The product 19 was isolated in 84% yield. Dinitrosul-
fonamide 19 proved to be too labile to utilize in our
synthesis since we were unable to hydrolyze the methyl
ester moiety without competitive removal of the dini-
trosulfonyl group.34 For this reason we continued for-
ward with the synthesis employing the mono
nitrosulfonamide 5.
pyridylethanol 18 and there were supply issues with
this reagent as well as removing the byproducts from
the crude reaction mixture.
3. The denosylation resulted in moderate yield and
by-product rejection issues in the final product.
4. The lack of crystalline late stage intermediates.
Following the BF3 catalyzed aziridine opening, methyl
ester 5 could be crystallized yet suffered from poor
recovery (75–80%). Hydrolysis of the methyl ester 5
gave the corresponding acid which had proven reluc-
tant to crystallize. We explored the preparation of
amine salts of the acid and found that the tributylamine
salt 23 could be obtained directly in 95% isolated yield
with excellent impurity rejection (Scheme 6). The salt is
not hygroscopic, stable to storage, and represents a key
purification/hold point for a large-scale synthetic cam-
paign. We then surmised that the nosyl group could be
removed to generate the primary amine, which could
then be added directly to 4-vinyl pyridine. This would
hopefully allow us to circumvent the shortcomings of
our initial strategy.
Following hydrolysis of methyl ester 5, peptide cou-
pling was achieved using 1-(3-dimethylaminopropyl)-3-
ethylcardodiimide hydrochloride (EDC) and bicyclic
amine 2035 (Scheme 5). The desired amide 21 was
isolated in 80% assay yield and used as is in the next
step. The installation of the pyridyl ethyl sidechain
went smoothly to afford penultimate compound 22.
Without purification, removal of the nosyl group utiliz-
ing thioglycolic acid32 gave GnRH1 in 72% assay yield
for the two step process. Following an aqueous
workup, the desired bulk drug was crystallized, recrys-
tallized from ethyl acetate and isolated in 58% yield for
the three step process.
With salt 23 in hand, the amide 21 formation was
reinvestigated. Breaking the salt and treatment of the
acid with thionyl chloride in isopropyl acetate resulted
in clean conversion to the acid chloride. Addition of the
crude acid chloride solution to the amine tosylate 20 in
acetonitrile/triethylamine afforded amide 21 in excellent
At this point in the program, several issues with the
chemistry needed to be addressed prior to further scale-
up.
1. The EDC peptide coupling utilized expensive
reagents and the yields were modest.
2. The Mitsunobu reaction required excess of
Scheme 6. Reagents and conditions: (a) NaOH, ETOH, reflux; (b) Bu3N, IPAC, 20°C, 97% for two-step process; (c) Isopropyl
acetate, aq citric acid; (d) DMF, SOCl2, isopropyl acetate; (e) Et3N, ACN, 97% for two-step process; (f) C12H25SH, EtOH, 96%;
(g) AcOH, toluene, 70°C, 78%.

R. N. Farr et al. / Tetrahedron: Asymmetry 14 (2003) 3503–3515
3509
1
yield (>97% on 15 kg scale). Removal of the nosyl
group to give penultimate amine 24 was investigated.
Using the published procedure32 employing thioglycolic
acid resulted in byproduct formation complicating
purification. However, we found 1-dodecanethiol was
remarkably effective at removing the nosyl group. The
reagent is inexpensive, has minimal odor, and the
byproducts are neutral.36 Following de-protection, the
penultimate amine 24 was extracted into aqueous acid
and the neutral byproducts were readily removed. Fol-
lowing pH adjustment with sodium hydroxide, amine
24 was then extracted into toluene, dried via azeotropic
distillation, and used as is in the next step. The assay
yield was 96%.
house, N.J. H and 13C NMR spectra were collected at
400 and 100 MHz, respectively. All reactions were run
under a nitrogen atmosphere and all reagents were used
as supplied by manufacturer unless otherwise noted.
Flash chromatography was carried out using Merck
Kieselgel 60 (23–400 mesh). Assay yields were obtained
by HPLC analysis from crude reaction mixtures. All
assays were calculated using the purified products as
standards. Enantiomeric purity was determined by
supercritical fluid chromatography (SFC) using a Chi-
ralpak AD column (4.6 mm×25 cm) with a mobile
phase of 4% methanol in carbon dioxide for 4 min then
ramp to 40% methanol @ 2% per min with a 3 min
hold at 40% methanol, outlet pressure of 200 bar, flow
rate of 1.5 mL/min, and column temperature of 35°C.
Addition of amine 24 to 4-vinyl pyridine was then
investigated. 4-Vinyl pyridine is inexpensive and avail-
able on large scale. Addition of amines to 4-vinyl
pyridine was known37,38 and following a screening
study, we developed an optimized reaction condition.
The toluene solution of penultimate amine 24 was
treated with acetic acid and 4 vinyl pyridine and the
mixture was heated to 80°C for 2 h to afford the
product (GnRH 1) in 78% assay yield. The mixture was
cooled to room temperature and subjected to an
aqueous extraction. The bulk drug was then crystallized
from ethyl acetate and isolated in 70% yield on 10
kilogram scale. The yield for the four-step through
process was typically 65% (isolated yield). The final
product was 99.5% ee.
4.2. Preparation of aziridines
The known aziridines 2a–e were prepared on 50 mmol
scale using published procedures.24 The racemic
aziridine 2d and (S)-aziridine 2f have not been reported
previously. The preparation of 2f and the physical and
spectroscopic data of these compounds are given below.
4.2.1. 2-Isopropyl-1-[(4-nitrophenyl)sulfonyl]aziridine 2d.
Mp=102.6–103.5°C (heptane/methyl chloride); 1H
NMR (CDCl3) l 8.42 (d, J=9.1, 2H), 8.17 (d, J=9.2,
2H), 2.70 (m, 2H), 2.23 (d, J=4.3, 1H), 1.50 (m, 1H),
0.94 (d, J=6.9, 3H), 0.84 (d, J=6.7, 3H). 13C NMR
(CDCl3) l 150.6, 144.1, 129.3, 124.2, 47.0, 33.5, 30.0,
19.5, 19.0. Anal. calcd for C11H14N2O4S: C, 48.88; H,
5.22; N, 10.36. Found: C, 48.98; H, 5.11; N, 10.33.
3. Conclusion
We have developed a large scale, economical and
efficient process for the synthesis of the GnRH antago-
nist GnRH-1. The key step of the synthesis, a BF3-cat-
4.2.2. (2S)-1-[(2,4-Dinitrophenyl)sulfonyl]-2-methylazirid-
ine 2f. A two-phase mixture of (2S)-2-methylaziridine22
(2.0 g, 35.0 mmol) in IPAC (50 mL) and 1 M potassium
bicarbonate (53 mL, 53.0 mmol) was treated with a
solution of 2,4-dinitrobenzene- sulfonyl chloride (9.4 g,
35.0 mmol) in IPAC (94 mL) at 20–25°C. After 2 h, the
lower aqueous layer was removed and the organics
washed with water (50 mL) and concentrated. Crystal-
lization from MTBE/IPA provided the title compound
2f (8.90 g, 89%) as an off-white solid, mp=124.3–
alyzed reaction between
a
nosyl aziridine and
2-arylindole, resulted in unprecedented regio- and enan-
tioselectivity in >90% yield. A brief exploration of the
scope of the Lewis acid-catalyzed reaction illustrated
that the reaction is amenable to the synthesis of other
tryptamine sidechains.
In addition, the synthesis utilized a palladium-catalyzed
coupling between an iodo aniline derivative and a
phenyl acetylene to give the required phenyl indole in
excellent yield. A simple procedure to obtain the
desired nosyl aziridines has been developed. The
endgame is remarkably straightforward with all
reagents being inexpensive, and providing crystalline
late stage intermediates with high yielding processes.
This chemistry has been demonstrated on appreciable
scale.
1
128.3°C (IPA/MTBE); H NMR (CDCl3) l 8.56 (m,
2H), 8.45 (m, 1H), 3.18 (m, 1H), 2.97 (dd, 0.5, 7.1, 1H),
2.33 (d, J=5.0, 1H), 1.38 (d, J=5.6, 3H). 13C NMR
(CDCl3) l 150.2, 148.6, 137.8, 132.8, 126.6, 119.8, 39.5,
37.4, 16.9. Anal. Calcd for C9H9N3O6S: C, 37.63; H,
3.16; N, 14.63. Found: C, 38.00; H, 3.20; N, 14.23.
4.3. General procedure A. Gram scale preparation of
indolesulfonamides 3a–c,f
Boron trifluoride etherate (0.61 mL, 4.81 mmol) was
added over a period of 10 min to a solution of phenyl
indole (4.92 mmol) and aziridine 2a–c,f (3.28 mmol) in
methylene chloride (10 mL) at 20°C. The solution was
stirred for 18 h. and quenched with 5% aqueous
NaHCO3 solution (10 mL). Concentration of the
organic layer and chromatography on silica gel (hex-
ane/methylene chloride) afforded the title compounds.
4. Experimental
4.1. General
Melting points are uncorrected and were determined
using an open-air apparatus. Combustion analyses were
performed by Quantitative Technologies, Inc., White-

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R. N. Farr et al. / Tetrahedron: Asymmetry 14 (2003) 3503–3515
4.3.1. 4-Nitro-N-[2-(2-phenyl-1H-indol-3-yl)ethyl]benz-
enesulfonamide 3a. The general procedure A was used
with aziridine 2a to afford the title compound 3a in
51% yield as an orange crystalline solid: mp=166.5–
−20°C, allowed to warm to 0°C over 10 min and
quenched with 5% aqueous NaHCO3 solution (10 mL).
Concentration of the organic layer and chromatogra-
phy on silica gel (30% hexane/methylene chloride)
afforded the title compound 1e as a yellow, amorphous
1
167.5°C (ethyl acetate/hexane); H NMR (d-DMSO) l
1
8.32 (m, 3H), 8.00 (d, J=8.5, 2H), 7.30–7.62 (m, 7H),
6.90–7.13 (m, 2H), 3.18 (d, J=7.3, 2H), 3.03 (d, J=7.4,
2H); 13C NMR (d-DMSO) l 149.3, 146.3, 135.9,
134.72, 132.6, 128.8, 128.4, 127.8, 127.7, 127.5, 124.4,
121.6, 118.9, 118.2, 111.2, 107.8, 43.3, 25.4. Anal. calcd
for C22H19O4N3S: C, 62.70; H, 4.54; N, 9.97. Found: C,
62.48; H, 4.57; N, 9.80.
solid (0.81 g, 50%): H NMR (d-DMSO) l 11.29 (s,
1H), 8.26 (d, J=8.6, 3H), 7.83 (d, J=8.6, 2H), 7.40–
7.60 (m, 6H), 6.80–7.20 (m, 7H), 4.55 (m, 1H), 3.85 (m,
1H), 3.65 (m, 1H); 13C NMR (d-DMSO) l 149.2, 146.1,
142.4, 136.3, 136.0, 132.7, 128.7, 128.6, 128.3, 127.8,
127.7, 127.6, 126.7, 126.1, 124.2, 121.2, 120.0, 118.9,
111.5, 111.1, 46.5, 42.2. Anal. calcd for C28H23N3O4S:
C, 67.59; H, 4.66; N, 8.45. Found: C, 67.87; H, 4.63; N,
8.30.
4.3.2. 4-Nitro-N-[(2S)-2-(2-phenyl-1H-indol-3-yl)prop-
yl]benzenesulfonamide 3b. The general procedure A was
used with aziridine 2b to afford the title compound 3b
in 86% yield as an orange crystalline solid: mp=215.3–
4.3.7.
4-Nitro-N-[2-phenyl-2-(2-phenyl-1H-indol-3-yl)-
ethyl]benzenesulfonamide (RS)-3e. Using the procedure
outlined for 3e, phenyl indole (1.00 g, 5.17 mmol) and
aziridine (RS)-2e (1.85 g, 6.09 mmol) afforded the title
compound (RS)-3e as a yellow amorphous solid (1.30
g, 51%). Anal. calcd for C28H23N3O4S: C, 67.59; H,
4.66; N, 8.45. Found: C, 67.35; H, 4.77; N, 8.30.
1
215.9°C (ethyl acetate/hexane); H NMR (d-DMSO) l
8.25 (m, 3H), 7.80 (d, J=8.2, 2H), 7.29–7.62 (m, 7H),
6.9–7.13 (m, 2H), 3.20–3.45 (br, 3H), 1.37 (br, 3H); 13C
NMR (d-DMSO) l 149.2, 146.4, 136.4, 134.9, 132.9,
128.8, 128.6, 127.6, 126.4, 124.2, 121.1, 119.8, 118.6,
113.0, 111.5, 48.3, 31.7, 18.5. Anal. calcd for
C23H21N3O4S: C, 63.43; H, 4.86; N, 9.65. Found: C,
63.08; H, 4.81; N, 9.48.
4.4. Large scale synthesis
4.4.1. Methyl 4-nitrophenylacetate 11.39 A slurry of 4-
nitrophenylacetic acid (10.0 kg, 55.2 mol) in methanol
(50 L) was stirred to obtain solution at 20°C. Concen-
trated sulfuric acid (1.0 L) was added over about 5 min
and the mixture stirred at 40°C for 2 h. The solution
was cooled to 25°C and seeded with methyl ester
product (0.5 g) to induce crystallization. The resultant
slurry was cooled to 5°C and aged 30 min. The slurry
was filtered and washed with methanol, yielding the
title compound 11 as a white solid (10.3 kg, 96%).
4.3.3. 4-Nitro-N-[2-(2-phenyl-1H-indol-3-yl)propyl]benz-
enesulfonamide, (RS)-3b. The general procedure A was
used with aziridine (RS)-2b to afford the title com-
pound (RS)-3b in 90% yield as a yellow-orange crys-
talline solid: mp=219.8–220.5°C (ethyl acetate/hexane);
Anal. calcd for C23H21N3O4S: C, 63.43; H, 4.86; N,
9.65. Found: C, 63.23; H, 4.87; N, 9.51.
4.3.4. 4-Nitro-N-[(2r)-3-phenyl-2-(2-phenyl-1H-indol-3-yl)-
propyl]benzene-sulfonamide 3c. The general procedure A
was used with aziridine (R)-2c to afford the title com-
pound 3c in 48% yield as a yellow crystalline solid:
mp=173.1–175.1°C (methylene chloride/hexane). 1H
NMR (d-DMSO) l 11.02 (s, 1H), 8.24 (m, 3H), 7.80 (d,
J=8.3, 2H), 7.70 (d, J=7.7, 1H), 7.34 (m, 3H), 7.22 (d,
J=7.7, 1H), 6.96–7.16 (m, 7H), 6.70 (m, 2H), 3.05–3.48
(m, 5H); 13C NMR (d-DMSO) l 149.1, 146.3, 140.2,
136.4, 136.2, 132.7, 128.7, 128.6, 128.1, 127.8, 127.5,
126.4, 125.7, 124.1, 121.0, 119.8, 118.6, 111.5, 110.3,
46.9, 39.2, 37.6. Anal. calcd for C29H25N3O4S: C, 68.09;
H, 4.93; N, 8.21. Found: C, 67.83; H, 4.97; N, 8.08.
4.4.2. Methyl 2-(4-aminophenyl)-2-methylpropanoate
12.40 Sodium t-butoxide (2.5 kg, 26.0 mol) was added
in one portion to DMF (50.0 L) at 0°C. The cloudy
solution was re-cooled to 5°C. Methyl-4-nitrophenylac-
etate 11 (5.0 kg, 25.6 mol) was added in one portion.
The purple slurry was cooled to 5°C. Methyl iodide (1.6
L, 25.7 M) was added over about 1 h maintaining the
reaction temperature 0–10°C. On complete addition the
slurry was aged for 15 min and a second charge of
sodium t-butoxide (2.5 kg, 26.0 mol) was added.
Methyl iodide (1.6 M, 25.7 M) was added over about
40 min maintaining the batch temperature 5–10°C. The
slurry was aged 20 min at 5–10°C and a third charge of
sodium t-butoxide (0.25 kg, 2.60 mol) was added fol-
lowed by methyl iodide (0.3 L, 4.8 M). Water (50 L)
containing acetic acid (0.83 L) was added over 20 min
at 5–10°C followed by isopropyl acetate (20 L). The
phases were well mixed and the lower aqueous layer
removed and extracted with IPAC (10 L). The organics
were combined and washed with 0.5N hydrochloric
acid (2×10 L) and 5% aqueous brine (10 L). The
organics were concentrated to an oil and ethanol (25 L)
added. To the solution was added a slurry of 10%
palladium on carbon (50% water wet, 200 g) in water
(1.0 L). The resultant slurry was stirred and warmed to
45°C. A solution of potassium formate (10.35 kg, 123
mol) in water (28 L) was added over about 2 h. On
4.3.5. 4-Nitro-N-[(3-phenyl-2-(2-phenyl-1H-indol-3-yl)-
propyl]benzenesulfonamide, (RS)-3c. The general proce-
dure A was used with aziridine (RS)-2c to afford the
title compound (RS)-3b in 50% yield as a yellow crys-
talline solid: mp=173.7–175.4°C (methylene chloride/
hexane). Anal. calcd for C29H25N3O4S: C, 68.09; H,
4.93; N, 8.21. Found: C, 67.80; H, 5.08; N, 8.00.
4.3.6. 4-Nitro-N-[(2R)-2-phenyl-2-(2-phenyl-1H-indol-3-
yl)ethyl]benzenesulfonamide 3e. A solution of phenyl
indole (1.00 g, 4.92 mmol) and aziridine (R)-2e (1.00 g,
3.28 mmol) in methylene chloride (10 mL) was cooled
to −20°C under a nitrogen atmosphere. Boron trifl-
uoride etherate (0.61 mL, 4.81 mmol) was added over a
period of 10 min. The solution was aged for 10 min at

R. N. Farr et al. / Tetrahedron: Asymmetry 14 (2003) 3503–3515
3511
complete addition the reaction mixture was stirred at
60–70°C for 1 h. The slurry was cooled to 15°C and
filtered through a pad of solka-floc (100 g). The cake
was washed with 50% v/v aqueous ethanol (30 L) and
the filtrates combined. The solution was concentrated
under reduced pressure to remove about 20 L of distil-
late. The solution was extracted with IPAC (20 and 10
L) and the combined organics washed with 10%
aqueous brine solution (15 L). The organic layer was
separated and the solution assayed by HPLC. The title
compound 12 (4.5 kg, 95%) was obtained and used
without further purification. A small sample was con-
centrated and showed spectral data in accordance to
those previously reported.39
4.4.5. 1-Ethynyl-3,5-dimethylbenzene 16. To a solution
of butynol 15 (22.6 kg, 120.0 mol) in heptane (140 kg)
was added Darco G-60 (2.2 kg) and sodium t-butoxide
(2.20 kg, 22.9 mol). The slurry was warmed to reflux
and distilled to remove heptane (70 L) over a period of
2 h. Reaction progress was monitored by HPLC analy-
sis. The reaction mixture was cooled to 0°C and aged
for 2 h. The mixture was filtered through a pad of hyflo
and the cake washed with heptane (16 kg). The filtrate
and wash was combined. The title compound 16 (13.8
kg by HPLC assay) was obtained in 95% overall yield
from bromodimethylbenzene. The crude solution was
used without purification. A small sample was purified
using a small silica gel plug (toluene) to provide the
known 1-ethynyl-3,5-dimethylbenzene26 as a colorless
liquid.
4.4.3. Methyl 2-(4-amino-3-iodophenyl)-2-methylpropan-
oate. Hydrochloride 13. A solution of aniline 12 (14.0
kg, 72.5 mol) in ethanol (74 kg) was treated with
concentrated hydrochloric acid (ca. 20 mL) to adjust
pH from 7.7 to 5.7. A 5.2 M solution of iodine
monochloride in HCl (13.9 L, 72.3 mol) was added at
15–20°C while maintaining the reaction pH 5.0–5.5, by
addition of 14 wt% aqueous sodium hydroxide solu-
tion. On complete addition the reaction was aged 30
min at 15–20°C and quenched with a solution of
sodium thiosulfate pentahydrate (1.12 kg) in water (1.7
L). The pH was adjusted to 7–8 using additional
sodium hydroxide solution. The reaction mixture was
concentrated at reduced pressure (70 L removed). IPAC
(122 kg) and water (42 kg) were added with stirring.
The organic layer was washed with water (42 kg),
concentrated under reduced pressure to approximately
110 L. 4.4 M HCl in ethyl acetate (25.0 L, 110 mol) was
added to the IPAC solution over 30 min at 20–25°C.
The resultant thick slurry was stirred for 2 h, filtered
and the cake washed with IPAC (2×25 L). The product
was dried in vacuo at 35°C to afford the title com-
pound 13 (25.1 kg, 97%) as a white solid, mp=165–
4.4.6. Methyl 2-{4-amino-3-[(3,5-dimethylphenyl)ethyn-
yl]phenyl}-2-methyl-propanoate 17. To
a slurry of
iodoaniline hydrochloride 13 (34.0 kg, 95.4 mol) in
toluene (142 kg) and water (83 kg) was added triethyl-
amine (29.1 kg, 288.1 mol) at 20–25°C. A mixture of
palladium chloride (168 g, 0.95 mol), triphenylphos-
phine (763 g, 2.91 mol) and copper(I) iodide (362 g,
1.91 mol) was added in one portion. The mixture was
warmed to 70°C and a solution of alkyne 16 in heptane
(97.0 kg at 13.1 wt% purity, 105.9 mol) added over 1 h.
HPLC analysis indicated complete reaction 30 min
after complete addition. The reaction mixture was
cooled to 25°C and the lower aqueous layer separated.
The organic layer was washed sequentially with 5%
aqueous ammonium hydroxide solution (2×18 L) and
water (18 L) and concentrated at reduced pressure to a
final volume of 128 L. The batch was assayed by
HPLC. The title compound 17 (29.2 kg by solution
assay) was obtained in 95% yield. The solution was
used ‘as is’ in the following step. A small sample was
taken and crystallized from hexane, for analytical pur-
poses, to give the title compound 17 as a crystalline
1
166.5°C. H NMR (d-DMSO) l 9.12 (br.s, 3H), 7.65
1
solid: mp=97.5–98.5°C (hexane); H NMR (CDCl3) l
(m, 1H), 7.26 (m, 2H), 3.58 (s, 3H), 1.45 (s, 6H). 13C
NMR (d-DMSO) l 176.4, 141.9, 139.0, 136.7, 127.3,
120.9, 89.8, 52.6, 45.8, 26.7, 26.6. Anal. calcd for
C11H15ClINO2: C, 37.15; H, 4.25; N, 3.94. Found: C,
36.82; H, 4.11; N, 3.78.
7.36 (d, J=2.3, 1H), 7.18 (m, 2H), 7.12 (dd, J=2.3, 8.4,
1H), 6.99 (m, 1H), 6.69 (d, J=8.4, 1H), 4.24 (br.s, 2H),
3.66 (s, 3H), 2.33 (s, 6H), 1.56 (s, 6H). 13C NMR
(CDCl3) l 177.4, 146.4, 137.9, 134.1, 130.2, 129.2,
129.2, 127.3, 122.8, 114.3, 108.0, 95.0, 85.3, 52.2, 45.5,
26.5, 21.1. Anal. calcd for C21H23NO2: C, 78.47; H,
7.21; N, 4.36. Found: C, 78.22; H, 7.31; N, 4.19.
4.4.4. 4-(3,5-Dimethylphenyl)-2-methylbut-3-yn-2-ol 15.
To a solution of bromo-dimethylbenzene (22.2 kg,
120.0 mol), diethylamine (23.5 kg, 321.3 mol), and
2-methyl-3-butyn-2-ol (14.4 kg, 171.2 mol) in heptane
(30.0 kg) at 20°C was added a mixture of palladium
chloride (213 g, 1.20 mol), triphenylphosphine (934 g,
3.56 mol) and copper(I) iodide (222 g, 1.17 mol). The
mixture was warmed to reflux over 1 h and aged for 5
h. Reaction progress was monitored by HPLC analysis.
The reaction mixture was cooled to 40°C and heptane
(40 kg) added. The batch was concentrated at reduced
pressure to remove approximately 70 L distillate. The
mixture was cooled to 5°C, aged for 1 h, and filtered.
The filter cake was washed with heptane (2×31 kg). The
filtrate and wash were combined (22.6 kg by HPLC
assay, 100% yield) and used without further
purification.
4.4.7. Methyl 2-[2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-
methylpropanoate 4. To a solution of the acetylene 17
(29.1 kg, 90.6 mol) in toluene was added DMF (109 kg)
and copper(I) iodide (8.60 kg, 45.2 mol). The slurry was
warmed to reflux (134°C) and aged for 4 h. The mixture
was cooled to 60°C and toluene (45 kg) added. The
mixture was cooled to 5°C and aged for 1 h. The
undissolved copper salts were removed by filtration
through solka flok and the cake washed with toluene
(44 kg). The combined filtrate and wash were washed
sequentially with 5% aqueous ammonium hydroxide
(2×63 kg) and water (63 kg). The washed organic layer
was concentrated at reduced pressure to about 200 L.
Silica gel (60–200 mesh, 25 kg) was added to the
solution. The slurry was stirred for 30 min at 20°C and

3512
R. N. Farr et al. / Tetrahedron: Asymmetry 14 (2003) 3503–3515
1
filtered through a bed of silica gel (60–200 mesh, 25
kg). The cake was washed with toluene (300 kg). The
filtrates were combined and concentrated at reduced
pressure (40°C) to a volume of 60 L. Heptane (40 kg)
was added and the solution seeded with indole 4 (5.0
g). The resultant slurry was aged at 20°C for 1 h,
heptane (140 kg) added and the slurry cooled to 5°C
for 2 h. The product was isolated by filtration to afford
the title compound 4 (25.65 kg, 88% yield) as a crys-
talline solid; mp=118.5–120°C. 1H NMR (CDCl3) l
8.39 (br.s, 1H), 7.63 (d, J=0.6, 1H), 7.34 (d, J=8.5,
1H), 7.31 (d, J=0.5, 2H), 7.20 (dd, J=8.5, 1.7, 1H),
7.00 (m, 1H), 2.41 (s, 6H), 1.70 (s, 6H). 13C NMR
(CDCl3) l 178.0, 138.8, 138.5, 136.6, 135.5, 132.5,
129.5, 129.3, 123.1, 120.4, 117.1, 110.8, 99.9, 52.2, 46.4,
27.0, 21.4. Anal. calcd for C21H23NO2: C, 78.47; H,
7.21; N, 4.36. Found: C, 78.51; H, 7.27; N, 4.23.
as an orange crystalline solid; mp=156.0–157.5°C. H
NMR (CDCl3) l 8.04 (br.s, 1H), 8.00 (m, 2H), 7.64
(m, 2H), 7.45 (d, J=1.8, 1H), 7.21 (d, J=8.5, 1H),
7.15 (dd, J=1.8, 8.5, 1H), 7.06 (s, 1H), 7.02 (s, 2H),
4.43 (m, 1H), 3.70 (s, 3H), 3.52 (m, 2H), 3.26 (m, 1H),
2.39 (s, 6H), 1.63 (s, 3H), 1.61 (s, 3H), 1.44 (d, J=7.1,
3H). 13C NMR (CDCl3) l 177.6, 149.4, 145.8, 138.7,
136.8, 136.4, 134.8, 132.3, 130.2, 127.5, 126.3, 126.2,
123.7, 120.6, 116.0, 112.1, 111.1, 52.2, 48.1, 46.4, 31.8,
27.1, 26.9, 21.4, 18.8. Anal. calcd for C30H33N3O6S: C,
63.93; H, 5.90; N, 7.45. Found: C, 63.67; H, 5.87; N,
7.40.
4.4.10. N-{(2S)-2-[5-[2-(2-Azabicyclo[2.2.2]oct-2-yl)-1,1-
dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-
yl]propyl}-4-nitrobenzenesulfonamide 21. Procedure A
from ester 5. A sodium hydroxide solution (5 M, 1.92
L, 9.6 mol) and water (8.0 L) was added to a solution
of ester 5 (4.10 kg, 7.28 mol) in methanol (23 L). The
mixture was heated at reflux for 8 h. The mixture was
concentrated under reduced pressure to approximately
20% volume. Water (10 L) was added, the pH adjusted
to 9.5–10 with 6H HCl. Ethyl acetate (20 L) was added
and the pH adjusted to 2 with 6N HCl. The organic
layer was washed with water (10 L), concentrated
under reduced pressure and acetonitrile (40 L) added.
The solution was concentrated to approximately 20 L.
HOBT (1.56 kg, 10.2 mol) and EDC (2.10 kg, 10.9
mol) was added at 20°C and aged for 1 h. Amine 20
(1.34 kg, 8.7 mol) and triethylamine (5.10 L, 36.4 mol)
were added and the mixture aged for 2 h. The mixture
was concentrated under reduced pressure to remove
acetonitrile. Ethyl acetate (20 L) was added and the
solution washed sequentially with water (15 L), 0.5 M
NaHCO3 (2×12 L), 1.0 M citric acid (12 L) and water
(12 L). The batch was assayed by HPLC. The title
compound 21 (3.63 kg, 78%) was obtained. The crude
solution was concentrated to an oily residue, dissolved
in THF (20 L) and used without further purification. A
portion of the product was chromatographed on silica
gel (methylene chloride/ethyl acetate) to afford the title
4.4.8. (2S)-2-Methyl-1-[(4-nitrophenyl)sulfonyl]aziridine
2b. A solution of
L-alaninol (8.33 kg, 110.9 mol) in
pyridine (35.1 kg) was added to a slurry of 4-nitroben-
zene sulfonyl chloride (57.7 kg, 260.4 mol) in acetoni-
trile (67.0 kg) at 0–10°C over 1 h. The reaction mixture
was aged at 3–5°C for 2 h. Ethyl acetate (192 kg) and
water (85 kg) were added and the mixture stirred for
10 min. The lower aqueous layer was removed and the
organics washed with 1 M citric acid (2×50 kg) and
water (43 kg). The organic solution was cooled to 10°C
and treated with water (43 kg). Diisopropylethylamine
(22.7 kg, 175.6 mol) was added at 10–20°C over 30
min. The reaction was stirred at 20°C for 30 min. The
lower aqueous layer was removed and extracted with
ethyl acetate (37 kg). The combined organics were
washed with 1 M citric acid (2×50 kg) and water (2×43
kg). The solution was concentrated under reduced
pressure to about 100 L. Isopropanol (total of 100 L)
was added with concomitant distillation, at constant
volume, under reduced pressure to remove ethyl ace-
tate. The resultant slurry was cooled to 0–5°C aged for
1 h and filtered. The cake was washed with iso-
propanol (27 kg) and dried in vacuo at 25°C to afford
the title compound 2b (22.94 kg, 86%) as a white
crystalline solid. The isolated solid had identical spec-
tral and physical properties as those previously
reported.14
1
compound 21 as a colorless foam: H NMR (CDCl3)
(5:1 mixture of rotamers, data for major rotamer) l
8.50 (s, 1H), 8.04 (m, 2H), 7.70 (m, 2H), 7.30 (m, 2H),
7.10 (m, 2H), 4.77 (m, 1H), 3.53 (m, 1H), 3.40 (m, 3H),
3.23 (m, 1H), 2.37 (s, 6H), 1.83 (m, 1H), 1.60 (s, 3H),
1.56 (s, 3H), 1.40 (d, J=7.0, 3H), 1.11–1.62 (m, 8H).
13C NMR (CDCl3) l 175.7, 149.4, 146.1, 138.0, 136.9,
134.9, 132.4, 130.0, 127.7, 126.7, 126.4, 123.9, 119.4,
116.1, 111.9, 111.4, 50.1, 48.0, 46.5, 45.7, 31.9, 29.4,
28.1, 26.1, 25.7, 25.4, 24.1, 24.0, 21.3, 18.7. HRMS
calcd for C36H42N4O5S (M+H+): 643.2954. Found
643.2953.
4.4.9. Methyl 2-[2-(3,5-dimethylphenyl)-3-(1S)-1-methyl-
2-{[(4-nitrophenyl)- sulfonyl]amino}ethyl)-1H-indol-5-yl]-
2-methylpropanoate 5. Boron trifluoride etherate (5.46
kg, 38.5 mol) was added, at 20–25°C, to a solution of
the indole 4 (11.2 kg, 35.0 mol) and (S) aziridine 2b
(10.2 kg, 42.1 mol) in toluene (43.2 kg) over 1 h. The
mixture was aged at 20–25°C for 12 h. The reaction
was quenched into a stirred mixture of ethyl acetate
(63 kg) and 2 M KHCO3 (70 kg). The organic layer
was washed with water (40 kg) and concentrated at
reduced pressure to approximately 20% volume. Etha-
nol (100 kg) was added and the solution concentrated
to a final volume of 65 L. The solution was assayed by
HPLC. The title compound 5 (18.1 kg, 92% assay
yield) was obtained and used without further purifica-
tion in the subsequent step. A small sample was crys-
tallized from methanol to provide analytically pure 5
4.4.11. N-{(2S)-2-[5-[2-(2-Azabicyclo[2.2.2]oct-2-yl)-1,1-
dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-
yl]propyl}-4-nitrobenzenesulfonamide 21. Procedure B
from tributylammonium salt 23. A slurry of the tri-
butylamine salt 24 (14.7 kg, 20.1 mol) in IPAC
(60 L) was stirred with 2 M aqueous citric acid (23 L)
for 30 min at 20°C. The lower aqueous layer was
separated and the organics washed sequentially with 2
M citric acid (11 L) and water (2×8 L). The IPAC

R. N. Farr et al. / Tetrahedron: Asymmetry 14 (2003) 3503–3515
3513
solution was concentrated to a final volume of approx-
imately 50 L (Kf <200 ug/mL). Thionyl chloride (2.40
L, 32.9 mol) and DMF (100.0 mL) were added and the
solution stirred at 25–30°C for 2 h. The solution was
concentrated under reduced pressure at constant vol-
ume while adding IPAC (total of 50 L added and
distilled). The solution of acid chloride in IPAC was
added over 20 min to a stirred mixture of amine 21
(7.82 kg, 24.6 mol) and triethylamine (9.50 L, 68.2 mol)
in acetonitrile (12.0 L) at 20–25°C. The mixture was
stirred for 2 h and water (25 L) added. The organic
layer was separated and washed with 2 M citric acid (20
L). The organic layer was concentrated under reduced
pressure and solvent switched into toluene (final volume
58 L). Assay by HPLC indicated that the reaction
afforded the title compound (12.6 kg) in 97% overall
yield. Purification of a small aliquot, by passing
through a short silica gel plug, provided a colorless
(13.4 kg, 72.3 mol) was added to the solution at 20–
25°C over 15 min. The resultant slurry was aged at
20°C for 30 min, cooled to 5°C and aged for 1 h.
Filtration afforded the title compound as a yellow
crystalline solid (43.1 kg, 99.3 wt% purity, 87% yield);
1
mp=117–120°C. H NMR (CDCl3) l 8.32 (s, 1H), 7.96
(d, J=8.8, 2H), 7.63 (d, J=8.8, 2H), 7.56 (s, 1H), 7.20
(dd, J=1.4, 8.6, 1H), 7.10 (d, J=8.6, 1H), 7.0 (s, 2H),
3.49 (dd, J=10.2, 13.0, 1H), 3.40 (dd, J=5.8, 13.0,
1H), 3.23 (m, 1H), 2.74 (m, 6H), 2.38 (m, 6H), 1.59 (s,
3H), 1.57 (s, 3H), 1.50 (m, 6H), 1.40 (d, J=7.1, 3H),
1.30 (m, 6H), 0.91 (t, J=7.3, 9H). Anal. calcd for
C41H58N4O6S: C, 67.00; H, 7.95; N, 7.62. Found: C,
66.80; H, 8.10; N, 7.90.
4.4.14.
dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-
yl]propan-1-amine 24. To solution of the
(2S)-2-[5-[2-(2-Azabicyclo[2.2.2]oct-2-yl)-1,1-
a
1
foam with identical by H and 13C NMR spectral data
benzenesulfonamide 21 (12.4 kg by HPLC assay, 19.3
mol) in toluene (58 L total volume), at 55°C was added
dodecanethiol (9.20 L, 38.6 mol) and tetra-
butylammonium bromide (124.0 g, 0.39 mol). A solu-
tion of lithium hydroxide (3.0 kg, 71.4 mol) in water (21
L) was added and the mixture stirred at 55–60°C for 30
min. The reaction mixture was cooled to 35°C and the
aqueous layer discarded. Ethanol (12 L) and 2 M citric
acid (12 L) were added and the mixture stirred for 30
min at 35°C. The lower aqueous layer was separated
and washed with toluene (18 L). Toluene (30 L) was
added and the pH adjusted to 13–14 with 50% sodium
hydroxide solution (4.2 L) at 50°C. The organic layer
was washed with water (2×18 L) and concentrated
under reduced pressure to obtain a dry solution of
amine in toluene. Assay by HPLC indicated that the
reaction afforded the title compound 24 (8.51 kg) in
96% yield. The dry product solution was used without
further purification. A small aliquot was taken and
purified by chromatography on silica gel (ethyl ace-
tate:ethanol, 2:1) to afford the title compound 24 as a
colorless foam. 1H NMR (CDCl3) (4:1 mixture of
rotamers, data for major rotamer) l 8.70 (s, 1H), 7.50
(s, 1H), 7.30 (d, J=8.4, 1H), 7.14 (s, 2H), 7.07 (d,
J=7.0, 1H), 7.02 (s, 1H), 3.44 (br.s, 2H), 3.16 (m, 1H),
2.93 (m, J=5.9, 12.1, 1H), 2.37 (s, 6H), 1.75 (m, 1H),
1.60 (s, 6H), 1.45 (d, J=6.8, 3H), 1.40–1.60 (m, 7H),
1.32 (m, 2H), 1.15 (m, 2H). 13C NMR (CDCl3) l 176.0,
138.1, 137.3, 136.8, 135.0, 133.3, 129.5, 127.3, 126.7,
119.0, 116.6, 114.4, 111.1, 50.6, 50.1, 47.9, 46.5, 45.6,
42.5, 35.4, 28.8, 28.6, 28.4, 25.9, 25.4, 24.1, 21.4, 18.9.
HRMS Calcd for C30H38N3O (M+H+): 458.3172.
Found 458.3170.
to the compound isolated from procedure A above.
4.4.12. N-{(2S)-2-[5-[2-(2-Azabicyclo[2.2.2]oct-2-yl)-1,1-
dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-
yl]propyl}-4-nitro-N-(2-pyridin-4-ylethyl)benzene-sulfon-
amide 22. To a solution of the nitrobenzenesulfonamide
21 (3.60 kg, 5.61 mol) in dry THF (20 L) was added
triphenylphosphine (5.88 kg, 22.4 mol). DEAD (3.70 L,
22.4 mol) and pyridylethanol 18 (3.50 kg, 22.4 mol)
were added simultaneously over 2 h at 20–40°C. The
mixture was allowed to stir at room temperature
overnight. A small aliquot (100 mL) was removed,
concentrated to an oil and partitioned between ethyl
acetate (50 mL) and water (50 mL). The organic layer
was concentrated and chromatographed on silica gel
(methylene chloride/ethyl acetate) to afford the title
1
compound 22 as an orange amorphous solid; H NMR
(CDCl3) (5:1 mixture of rotamers, data for major
rotamer) l 8.63 (s, 1H), 8.32 (d, J=5.8, 2H), 8.10 (d,
J=8.7, 2H), 7.60 (d, J=8.7, 2H), 7.48 (s, 1H), 7.32 (d,
J=8.3, 1H), 7.10 (d, J=8.3, 1H), 7.01 (s, 3H), 6.47 (d,
J=5.8, 2H), 3.84 (m, 1H), 3.66 (m, 1H), 3.45 (m, 3H),
3.03 (m, 1H), 2.90 (m, 1H), 2.61 (m, 1H), 2.40 (m, 1H),
2.33 (s, 6H), 1.84 (m, 1H), 1.62 (s, 3H), 1.57 (s, 3H),
1.42 (d, J=7.1, 3H), 1.11–1.65 (m, 8H). 13C NMR
(CDCl3) l 175.6, 149.6, 149.5, 146.8, 145.5, 138.6,
138.1, 136.5, 135.0, 132.5, 130.0, 127.8, 126.9, 126.3,
123.9, 123.7, 119.4, 116.2, 113.2, 111.5, 52.7, 50.1, 48.6,
46.6, 45.7, 34.2, 30.8, 27.0, 26.4, 25.5, 25.4, 24.1, 24.0,
21.3, 19.1. Anal. calcd for C43H49N5O5S: C, 69.10; H,
6.60; N, 9.36. Found: C, 68.90; H, 6.87; N, 9.03.
4.4.13.
2-[2-(3,5-Dimethylphenyl)-3-((1S)-1-methyl-2-
{[(4-nitrophenyl)sulfonyl]amino}ethyl)-1H-indol-5-yl]-2-
methylpropanoic acid—tributylammonium salt 23. A
solution of ester 5 (37.8 kg, 67.1 mol) in ethanol (100
L), at 50°C, was added to a mixture of water (234 kg)
and 48% sodium hydroxide (29.1 kg, 249 mol) at 85–
88°C. The reaction mixture was heated at reflux for a
further 1 h. The cooled solution was added to a two-
phase mixture of IPAC (220 L) and 1M aqueous citric
acid at 10–20°C over 1 h. The organic layer was washed
with water (2×24 L) and concentrated at reduced pres-
sure to a final volume of ca. 170 L. Tri-n-butylamine
4.4.15.
(2S)-2-[5-[2-(2-Azabicyclo[2.2.2]oct-2-yl)-1,1-
dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-
yl]-N-(2-pyridin-4-ylethyl)propan-1-amine 1. (Prepara-
tion of GnRH 1 from 24). A solution of the amine 24
(8.45 kg, 18.5 mol) and 4-vinyl pyridine (7.84 kg,
74.0 mol) in toluene (35 L), at 55°C, was treated with
acetic acid (2.80 kg, 46.2 mol) in one portion. The
mixture was warmed to 80°C for 2 h, cooled to 50°C
and washed with 2 M aqueous sodium hydroxide solu-
tion (20 L) and water (2×15 L). The toluene solution
was concentrated under reduced pressure and flushed

3514
R. N. Farr et al. / Tetrahedron: Asymmetry 14 (2003) 3503–3515
with methanol (30 L) to remove residual toluene. Ethyl
acetate (70 L) was added and the batch concentrated to
45 L. The resultant slurry was aged at 20°C for 12h,
cooled to −5°C for 2 h and filtered. The cake was
washed with cold (0–5°C) ethyl acetate (15 L) and dried
in vacuo to afford the title compound GnRH 1 as a
white crystalline solid (7.30 kg, 70%). An analytically
pure sample was obtained by recrystallization from
4.4.18. Methyl 2-(2-(3,5-dimethylphenyl)-3-{(1S)-2-[[(2,4-
dinitrophenyl)sulfonyl](2 - pyridin - 4 - ylethyl)amino] - 1-
methylethyl}-1H-indol-5-yl)-2-methylpropanoate 19. To
a solution of the dinitrobenzenesulfonamide 6 (5.0 g,
8.22 mol) in dry THF (50 mL) was added
triphenylphosphine (4.30 g, 16.4 mmol). DEAD (2.60
mL, 16.4 mmol) and pyridylethanol 18 (1.90 mL, 16.4
mmol) were added simultaneously over 10 min at 0–
10°C. The mixture was concentrated to an oil and
partitioned between ethyl acetate (50 mL) and water
(50 mL). The organic layer was concentrated and chro-
matographed on silica gel (methylene chloride/ethyl
acetate) to afford the title compound 19 (4.93 g, 84%)
as an orange crystalline solid; mp=204.5–205°C
1
ethyl acetate: mp=110–111°C (ethyl acetate). H NMR
(CDCl3) (5:1 mixture of rotational isomers, data for
major rotamer) l 8.48 (s, 1H), 8.34 (m, 2H), 7.53 (s,
1H), 7.31 (d, J=8.4, 1H), 7.10 (m, 3H), 7.00 (s, 1H),
6.84 (m, 2H), 3.45 (m, 3H), 3.13 (m, 1H), 2.91 (m, 1H),
2.70 (m, 2H), 2.59 (m, 2H), 2.34 (s, 6H), 1.86 (m, 1H),
0.70–1.70 (m, 19H). 13C NMR (CDCl3) l 175.8, 149.5,
149.2, 138.2, 137.4, 136.6, 135.0, 133.0, 129.6, 126.5,
123.9, 119.0, 116.7, 114.5, 111.1, 55.1, 50.1, 49.5, 46.6,
45.6, 35.5, 31.4, 29.5, 28.1, 26.2, 25.7, 25.4, 24.1, 21.4,
19.3. Anal. calcd for C37H46N4O: C, 78.96; H, 8.24; N,
9.95. Found: C, 78.69; H, 8.30; N, 9.84.
1
(decomp). H NMR (CDCl3) l 11.11 (s, 1H), 8.62 (d,
J=2.3, 1H), 8.53 (d, J=5.8, 2H), 8.28 (d, J=5.7, 2H),
8.22 (dd, J=2.3, 8.7, H), 7.94 (d, J=8.8, 1H), 7.62 (m,
1H), 7.26 (d, J=8.6, 1H), 7.07 (m, 3H), 6.96 (s, 1H),
6.58 (m, 2H), 3.90 (m, 2H), 3.54 (s, 3H), 3.48 (m, 1H),
3.13 (m, 2H), 2.59 (m, 1H), 2.42 (m, 1H), 2.29 (s, 6H),
1.58 (s, 3H), 1.57 (s, 3H), 1.44 (d, J=7.1, 3H). 13C
NMR (CDCl3) l 177.4, 149.8, 149.7, 147.4, 146.8,
138.1, 137.1, 136.8, 135.6, 135.5, 132.9, 131.5, 129.7,
126.9, 126.8, 126.5, 124.2, 119.9, 119.8, 116.3, 112.6,
112.0, 52.2, 48.3, 46.4, 33.5, 30.5, 27.4, 27.2, 21.3, 19.1.
Anal. calcd for C37H39N5O8S: C, 62.26; H, 5.51; N,
9.81. Found: C, 62.17; H, 5.48; N, 9.77.
4.4.16.
(2S)-2-[5-[2-(2-Azabicyclo[2.2.2]oct-2-yl)-1,1-
dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-
yl]-N-(2-pyridin-4-ylethyl)propan-1-amine 1. (Prepara-
tion of GnRH 1 from 22). A solution of the sulfonamide
24 (4.18 kg, 5.60 mol) and lithium hydroxide (2.40 kg,
57.2 mol) in DMF (18 L) at 20°C was treated with
mercaptoacetic acid (1.95 L, 28.0 mol) in one portion.
The mixture was warmed to 40°C for 2 h. and cooled to
20°C. Ethyl acetate (25.0 L) and 5% aqueous NaHCO3
(22.0 L) were added. The phases were mixed, the
organic layer was separated and washed with 5%
aqueous NaHCO3 (22.0 L). Water (15 L) was added to
the organic layer and the pH adjusted to 1.5–2.0 using
2N HCl. The aqueous layer was separated and washed
with ethyl acetate (15.0 L). The aqueous layer was
adjusted to pH 10 with 5 M NaOH and extracted with
ethyl acetate (15.0 L). Concentration of the solution
under reduced pressure and addition of MEK (10 L)
provided a slurry that was aged at 0°C for 30 h. The
slurry was filtered and the cake washed with cold
(0–5°C) MEK (1 L) and dried in vacuo to afford the
title compound GnRH 1 as a white crystalline solid
(2.45 kg, 78%). All spectral data were identical to those
obtained above.
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1
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