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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4.4.17. Methyl 2-[2-(3,5-dimethylphenyl)-3-((1S)-2-{[(2,4-
dinitrophenyl) sulfonyl]amino}-1-methylethyl)-1H-indol-
5-yl]-2-methylpropanoate 6. The general procedure A
was used with indole 4 (4.92 mmol) and aziridine 2f
(3.28 mmol) to afford the title compound 6 (1.69 g,
85%) was obtained as an orange solid, mp=211–213°C
1
(toluene). H NMR (d-DMSO) l 10.98 (s, 1H), 8.70 (d,
J=2.2, 1H), 8.54 (br.s, 1H), 8.29 (dd, J=2.2, 8.7, 1H),
7.85 (d, J=8.7, 1H), 7.45 (d, J=0.9, 1H), 7.17 (d,
J=8.5, 1H), 7.09 (s, 2H), 6.98 (m, 2H), 3.60 (s, 3H),
3.44 (m, 2H), 3.31 (m, 1H), 2.34 (s, 6H), 1.56 (s, 3H),
1.56 (s, 3H), 1.32 (d, J=7.0, 3H). 13C NMR (d-DMSO)
l 177.5, 149.4, 147.4, 138.6, 138.0, 136.4, 135.4, 135.2,
133.1, 131.0, 129.5, 127.2, 126.8, 126.7, 120.1 119.5,
116.3, 113.0, 111.7, 52.3, 48.9, 46.4, 32.1, 27.3, 27.2,
21.4, 18.8. Anal. calcd for C30H32N4O8S: C, 59.20; H,
5.30; N, 9.20. Found: C, 59.26; H, 5.20; N, 8.99.
8. Ujjainwalla, F.; Walsh, T. F. Tetrahedron Lett. 2001, 42,
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