3300
S. K. VUJJINI ET AL.
dichloromethane layer was washed twice with water (2 ꢂ 125 L) and once with brine
(125 L). The organic layer was separated and concentrated. The crude residue (con-
taining the hydrazone intermediate) was cyclized to form the indole moiety. Methanol
(50 L) and methanolic HCl (15.0%, 150 mL) were added to the residue. and the
solution was refluxed for 6 h. The reaction mass was then cooled to room temperature
(25 ꢀC) and the obtained solid was filtered, washed with methanol (25 L), and dried to
furnish the title compound 7. Yield 46.8 kg (78%); mp 215–220 ꢀC; 1H NMR:
(DMSO-d6, 200 MHz): d 11.55 (s, 1H), 7.78 (s, 4H), 7.4 (s, 1H), 7.35 (d, 1H,
J ¼ 8.4 Hz), 7.1 (d, 1H, J ¼ 8.4 Hz), 4.25 (q, 2H, J ¼ 7.2 Hz), 4.08 (m, 1H), 3.9–3.8
(m, 4H), 3.4–3.3 (m, 2H), 2.9–2.6 (m, 2H), 1.35 (t, 3H, J ¼ 7.2 Hz); 13C NMR:
(DMSO-d6, 50 MHz): d 14.2, 23.4, 38.4, 40.9, 51.5, 53.2, 60.4, 68.2, 112.7, 118.9,
119.1, 119.9, 122.9, 123.8, 124.1, 126.7, 127.6, 127.7, 131.6, 134.3, 135.3, 158.7,
161.7, 162.1, 167.7; IR tmax cmꢁ1(KBr): 3357 (br), 2940 (br), 1759 (br), 1707, 1544,
1466, 1440, 1396, 1248, 1026 cmꢁ1; MS: m=z 462 (100%, M þ 1; Et ester).
Preparation of (S)-Ethyl 3-(2-aminoethyl)-5-((2-oxooxazolidin-
4-yl)methyl)-1H-indole-2-carboxylate Hydrochloride 8
Hydrazine hydrate (10.52 L, 10.84 kg, 216.9 mol) was added dropwise to a
stirred solution of ethyl 3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-5-[(4S)-2-
oxo-oxazolidin-4-ylmethyl]-1H-indole-2-carboxylate 7 (25 kg, 54.2 mol) in methanol
(250 L) at room temperature (25–30 ꢀC) in about 20–30 min, and the reaction mixture
was maintained under stirring at 35–40 ꢀC for 2 h. After the completion of reaction
(monitored by TLC, using ethyl acetate as mobile phase), the reaction mass was
cooled to 10 ꢀC and 2 N HCl (237.5 L, 379.4 mol) was added to it in a dropwise
manner. Then the acidified reaction mixture was diluted with 137.5 L demineralized
(DM) water, the solvent was evaporated, and the misture was cooled to 10 ꢀC. The
solid residue was filtered off, and the filtrate was concentrated to 87.5–100 L volume
and stirred for 15 min at 10 ꢀC. The resulting solid was filtered and recrystallized from
a mixture of methanol (125 L) and acetone (500 L) to get the title compound 8. Yield
1
10.9 kg (61%); mp: 260–265 ꢀC. H NMR (DMSO-d6, 200 MHz): d 11.7 (s, 1H),
8.16–8.0 (br s, 2H), 7.83 (s, 1H), 7.64 (s, 1H), 7.39 (d, 1H, J ¼ 8.6 Hz), 7.18 (d, 1H,
J ¼ 8.8 Hz), 4.40–4.20 (m, 3H), 4.15–4.10 (m, 2H), 3.35 (m, 2H), 3.04–2.80 (m, 4H),
1.37 (t, 3H, J ¼ 7.0 Hz); 13C NMR (DMSO-d6, 50 MHz): d 14.4, 22.7, 40.9, 51.8,
52.9, 60.4, 68.3, 112.6, 117.6, 120.5, 124.2, 127.0, 127.4, 127.9, 135.3, 158.7, 161.6;
IR tmax cmꢁ1(KBr): 3344, 3222, 3151, 2973 (br), 2933, 1761, 1691, 1594, 1542, 1470,
1442, 1338, 1252, 1034 cmꢁ1; MS (Electronspray, þve mode): m=z 315.0 [(M þ 1)þ
for Me ester], 332.0 [(M þ 1)þ for Et ester, 100%), 663.3 [(2M þ 1)þ for Et ester].
MS (Electronspray, -ve mode): m=z 330.3 [(M ꢁ 1)ꢁ, Et ester], 366.0 [(M ꢁ 1 þ HCl)þ
for Et ester; 100%].
Preparation of 4-(S)-((3-(2-(Dimethylamino)ethyl)-1H-indol-5-yl)
methyl)-oxazolidin-2-one 1
To a stirred solution of (S)-ethyl-3-(2-aminoethyl)-5-((2-oxooxazolan-4-yl)
methyl]-1H-indole-2-carboxylate hydrochloride 8 (5.0 kg,13.6 mol) in methanol
(50 L) at room temperature, 20% sodium carbonate solution was added dropwise