Synthesis of (S)-2-(2-tert-Butoxycarbonylamino-2-
methyl-propionylamino)-3-(1H-indol-3-yl)propionic Acid
Methyl Ester (9). A 72-L flask equipped with a heating
mantle, a digital thermocouple, a mechanical stirrer, a gas
inlet, and a reflux condenser was charged with 6 (1.5 kg,
7.38 mol) and 11‚HCl (1.88 kg, 7.38 mol). Dichloromethane
(15 L) and triethylamine (821 g, 8.12 mol) were added to
the flask. The resulting white suspension was heated to 38
°C under nitrogen, and then a solution of DHOBt (301 g,
1.845 mol), EDCI‚HCl (1.56 kg, 8.12 mol), and triethylamine
(821 g, 8.12 mol) in dichloromethane (15 L) was added over
a period of 30 min. Approximately 15 min after the end of
the addition, the mixture became a homogeneous orange
solution, which was stirred at 38 ( 2 °C for 3 h. (Conversion
was monitored by HPLC.) The heating was discontinued,
and ice-cold water (15 L) was added to the warm solution;
the biphasic mixture was transferred to a 100-L separatory
vessel. An additional portion of cold water (15 L) was added
to the vessel, and the mixture was stirred rapidly for 15 min.
The layers were separated, and the organic layer was
concentrated in vacuo to give 4.05 kg of an orange oil, which
was redissolved in MTBE (9 L). The solution was washed
successively with a 10% aqueous solution of NaHSO4 (9
L), then with a saturated aqueous solution of NaHCO3 (9
L), and finally with a 1:1 mixture of water and saturated
brine (4 L). The resulting orange MTBE solution was used
in the next step without further purification.
PPACA-Mediated Synthesis of (R,R)-{1-[2-[3-Benzyl-
3-(N,N′,N′-trimethyl-hydrazinocarbonyl)piperidin-1-yl]-
1-(1H-indol-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1-methyl-
ethyl}carbamic Acid tert-Butyl Ester (7). Dipeptide 8 (171
g, 0.439 mol) and hydrazide 3 (192 g, 0.551 mol) were
charged into a jacketed 5-L three-necked round-bottom flask
equipped with an N2 inlet, a digital thermocouple, and a
mechanical stirrer. The flask was flushed with nitrogen for
10 min; then dichloromethane (1.71 L) was added and the
jacket temperature set to -10 °C. The first portion of Et3N
(153 mL) was added when the jacket temperature fell below
15 °C, and a second portion of Et3N (307 mL) was added
when the jacket temperature reached -10 °C. Meanwhile a
50 wt % solution of n-propylphosphonic acid cyclic anhy-
dride in EtOAc (0.44 L, 0.746 mol) was mixed with CH2Cl2
(0.44 L) in a 1-L round-bottom flask. Immediately after the
second portion of Et3N was added, the n-propylphosphonic
acid cyclic anhydride solution was added to the reaction
mixture (subsurface) at a rate of approximately 3 mL/min.
The temperature of the jacket was kept at -10 to -15 °C
during the addition (total addition time was 4.5 h). One hour
after completed addition, the reaction was quenched with
water (50 mL), and after a further 15 min the jacket
temperature was then set to 20 °C. An additional portion of
water (1.7 L) was added once the reaction reached 20 °C.
The organic phase was separated and the solvent removed
to afford an amorphous solid. (Note: For the workup, the
crude materials from two 0.439 mol scale reactions were
combined.) The solid was dissolved in EtOAc (8 L) and
washed twice with a solution of NaHSO4 (170 g) in water
(1.7 L). The organic phase was washed twice with a solution
of NaOH (68 g) in water (1.7 L), then washed with water
(3.4 L), and dried over Na2SO4; the solvent was removed
on a rotary evaporator to afford 7 as a colorless amorphous
foam (610 g, 91.3% AUC by HPLC).
Synthesis of (S)-2-(2-tert-Butoxycarbonylamino-2-
methyl-propionylamino)-3-(1H-indol-3-yl)propionic Acid
(8). The orange solution of 9 (approx 7.83 mol) in MTBE
(9 L) was combined with a 5% aqueous solution of NaOH
(9 L), and the resulting biphasic mixture was stirred
vigorously overnight at ambient temperature. HPLC analysis
of both layers showed that no more starting material remained
and that the product was in the aqueous layer. The layers
were separated, and the aqueous layer was transferred into
a 100-L separatory vessel and fresh MTBE (9 L) added. The
biphasic mixture was acidified with 2 M HCl to pH 2. After
the mixture was stirred rapidly for 15 min, the layers were
separated, and the aqueous layer was extracted with another
portion (6 L) of MTBE. The combined organic layers were
washed with saturated brine (4 L), dried over Na2SO4, and
concentrated on a rotary evaporator to give an orange foam.
The foam was diluted with dichloromethane (1.5 L) and the
mixture concentrated again. The resulting orange foam was
dissolved with stirring in warm (35-40 °C) dichloromethane
(9 L) and then slowly allowed to cool to room temperature
during which time a white precipitate formed. The solid was
isolated by filtration, washed with dichloromethane (1.5 L),
and dried in a vacuum oven to give 8 as a white powder
(2.48 kg, 86% over two steps, >99% AUC by HPLC).
HRMS (ESI) calcd for C20H27N3NaO5 [M + Na]+ 412.1848,
found 412.1868. 1H NMR (DMSO-d6) δ 12.67 (s, 1H), 10.83
(s, 1H), 7.51 (d, J ) 7.5 Hz, 1H), 7.34 (m, 1H), 7.32 (d, J
) 8 Hz, 1H), 7.09 (d, J ) 2.5 Hz, 1H), 7.05 (t, J ) 7.5 Hz,
1H), 6.97 (t, J ) 7.5 Hz, 1H), 6.88 (bs, 1H), 4.49 (dd, J )
DHOBt-Promoted Synthesis of (R,R)-{1-[2-[3-Benzyl-
3-(N,N′,N′-trimethyl-hydrazinocarbonyl)-piperidin-1-yl]-
1-(1H-indol-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1-methyl-
ethyl}carbamic Acid tert-Butyl Ester (7). Dipeptide 8
(460.0 g, 1.181 mol) and hydrazide 3 (411.4 g, 1.181 mol)
were mixed in methylene chloride (4.6 L) in a 22-L round-
bottom flask equipped with a mechanical stirrer, a digital
thermocouple, a gas (N2) inlet, and a reflux condenser.
Triethyl-
amine (251 g) was added, resulting in the formation of a
homogeneous, dark-brown solution. A solution of DHOBt
(212 g, 1.30 mol), EDCI hydrochloride (249.1 g, 1.299 mol),
and triethylamine (131.5 g) in methylene chloride (4.6 L)
was then added to the flask over a period of 5 min. The
dark-orange solution was then stirred at 25 °C for 20 h at
which point HPLC analysis of the reaction mixture showed
a conversion from 8 to 7 of >95% (AUC). The solution was
transferred into a separatory vessel and washed with water
(9.6 L). The organic layer was concentrated on a rotary
evaporator to afford an oily, orange residue, which was
redissolved in ethyl acetate (9.5 L). The organic layer was
washed sequentially with a 10% aqueous solution of NaHSO4
(9.5 L), then a 1 M solution of NaOH (9.5 L), and finally
with saturated brine (4 L). To the resulting solution were
added anhydrous sodium sulfate (500 g) and activated carbon
7.0, 13.5 Hz, 1H), 3.1-3.4 (m, 2H), 1.2-1.4 (m, 15 H). 13
C
NMR (DMSO-d6) δ 174.3, 173.2, 154.3, 136.1, 127.4, 123.7,
120.9, 118.34, 118.29, 111.3, 109.5, 78.2, 55.8, 52.8, 28.2,
27.3, 25.3, 24.9.
344
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Vol. 10, No. 2, 2006 / Organic Process Research & Development