filtered, and the filter cake was rinsed with EtOAc (700 mL).
The volume was reduced to 2200 mL (30% of original
volume) and methylcyclohexane (5000 mL) was added to
the residue over 45 min at 60 °C. The solution was cooled
to 0 °C to induce crystallization and was stirred for 4 h. The
product was filtered, and the filter cake was rinsed with
methylcyclohexane/EtOAc (6/1, 800 mL) to give 4c as a
white solid (536 g, 71% from 2b): mp 129 °C; 1H NMR δ
7.33 (br s, 5 H), 7.05-6.99 (m, 3 H), 6.88-6.65 (m, 2 H),
5.30 (s, 1 H), 5.07 (s, 2 H), 4.77 (br s, 1 H), 4.24-4.02 (m,
2 H), 3.72 (s, 3 H), 3.03 (br s, 3 H), 2.23-1.70 (m, 8 H),
at 0 °C for 1 h and filtered, and the filter cake was washed
with cold TBME (30 mL) to give 6b as a white solid (32.7
g, 68%): mp 118 °C (dec); H NMR δ 9.49 (br s, 2 H),
1
4.05 (d, 1 H, J ) 6.8), 3.28 (septet, 2 H, J ) 6.5), 2.17 (m,
1 H), 1.28 (d, 12 H, J ) 6.5), 0.99 (d, 3 H, J ) 6.6), 0.98
(d, 3 H, J ) 6.5); IR 3036, 2850, 1625, 1583 cm-1; [R]25
D
) +4.51° (H2O). Anal. Calcd for C11H24BrNO2: C, 46.81;
H, 8.57; N, 4.96; Br, 28.31. Found: C, 46.89; H, 8.66; N,
5.01; Br, 28.22.
N-[[1-[((2-R)-Bromo-3-methyl-1-oxobutyl)amino]-1-cy-
clopentyl]carbonyl]-O-methyl-L-tyrosine Ethyl Ester (7).
Method A. N-Methylmorpholine (31.1 g, 0.34 mol) was
added over 3 min to a solution of 6b (79.52 g, 0.28 mol)
and CDMT (47.22 g, 0.27 mol) in THF (600 mL) at -10
°C. The mixture was stirred for 2 h and then a solution of
5 (95.0 g, 0.26 mol) in THF (350 mL) was added over 15
min. This mixture was stirred for 2.5 h at -10 °C, then
warmed to 23 °C, and stirred for 16 h. Water (1110 mL)
was added over 1 h and then the mixture was cooled to 0
°C and held for 1 h. The suspension was filtered, and the
filter cake was rinsed with H2O/THF (3/1, 800 mL) to give
crude 7 (95.6 g). Purification by recrystallization (930 mL
of EtOH/400 mL H2O) gave pure 7 as a white solid (94.4 g,
74% based on 5).
Method B. A suspension of 6b (101.4 g, 0.359 mol) in
toluene (600 mL) was washed with 1 N HCl (2 × 250 mL).
The resulting 6b free acid was dried by azeotropic distillation.
More toluene (200 mL) was added, and the solution was
treated with DMF (1.4 mL, 0.018 mol) and SOCl2 (25 mL,
0.343 mol). This mixture was heated to 55 °C and stirred
for 3 h. The volume was reduced to 194 mL (85% of
original volume) under vacuum to remove HCl and SO2. The
solution of (R)-2-bromo-3-methylbutanoyl chloride (6c) in
toluene was added to a suspension of 5 (74.96 g, 0.202 mol)
in toluene (675 mL) at -5 °C. Neat N-methylmorpholine
(60 mL, 0.546 mol) was added to the mixture over 9 min
while the temperature was maintained below 7 °C. After
addition was complete, the mixture was stirred for 2 h at 7
°C. Water (187 mL) was added, and the mixture was heated
to 80 °C to dissolve the solids. The separated top organic
layer was washed with 1 N HCl (2 × 180 mL) and H2O
(180 mL) at 75 °C. The still hot solution was filtered, and
the filtrate was cooled to 0 °C over 3 h. The product was
filtered, and the filter cake was rinsed with TBME (300 mL)
to give crude 7 (81.6 g). Purification by recrystallization
(720 mL of EtOH/325 mL H2O) gave pure 7 as a white solid
(75.0 g, 75% based on 5): mp 156 °C; 1H NMR δ 7.06 (m,
2 H), 6.99 (br d, 1 H, J ) 8.7), 6.81 (m, 2 H), 6.68 (br s, 1
H), 4.74 (m, 1 H), 4.18 (d, 1 H, J ) 6.4), 4.16 (q, 2 H, J )
7.2), 3.80 (s, 3 H), 3.06 (m, 2 H), 2.29 (m, 3 H), 1.97 (m, 2
H), 1.75 (m, 4 H), 1.25 (t, 3 H, J ) 7.2), 1.04 (d, 3 H, J )
7.0), 0.96 (d, 3 H, J ) 7.0); IR 3382, 3259, 1730, 1681 cm-1;
[R]25D ) +30.7°. Anal. Calcd for C23H33BrN2O5: C, 55.54;
H, 6.69; N, 5.63; Br, 16.06. Found: C, 55.44; H, 6.71; N,
5.85; Br, 16.01.
1.25-1.20 (m, 3 H); IR 3450, 1745, 1686, 1521 cm-1; [R]25
D
) +24.0° (CHCl3). Anal. Calcd for C26H32N2O6: C, 66.65;
H, 6.88; N, 5.98. Found: C, 66.29; H, 6.61; N, 5.90.
N-[(1-Amino-1-cyclopentyl)carbonyl]-O-methyl-L-ty-
rosine Ethyl Ester Monohydrochloride (5). From 4.
Gaseous HCl (80.1 g, 2.19 mol) was passed into a cooled
solution of 4 (60.0 g, 0.14 mol) in absolute EtOH (360 mL)
at 23 °C over 20 min (caution: exothermic). After stirring
for 1 h, the mixture was reduced to 104 mL (23% of the
original volume). EtOAc (800 mL) was added to the
concentrate over 5 min, and seeds of authentic 5 were added.
The suspension was cooled to 0 °C and stirred for 1 h. The
product was collected on a filter, and the filter cake was
rinsed with EtOAc (40 mL) to give 5 as a hygroscopic white
solid (42.8 g, 84%).
From 4c. A solution of HCO2H (7.14 g, 0.155 mol) in
EtOAc (54 mL) was added to a suspension of 4c (66.12 g,
+
-
0.141 mol), 10% Pd/C (3.0 g, 0.003 mol), and NH4 HCO2
(4.45 g, 0.071 mol) in EtOAc (535 mL) at 23 °C over 1.5 h.
After addition was complete, the mixture was stirred for 1.5
h. Catalyst was filtered off, and the filter cake was rinsed
with EtOAc (55 mL). Concentrated HCl (13.90 g, 0.141
mol) was added to the filtrate, and the solvent was removed
under vacuum. EtOAc (300 mL) was added to the residue,
and seeds of authentic 5 were added. The suspension was
cooled to 0 °C, stirred for 1 h, and filtered, and the filter
cake was rinsed with EtOAc (55 mL) to give 5 as a
hygroscopic white solid (47.3 g, 90%): mp 129 °C; 1H NMR
(DMSO-d6) δ 8.68 (d, 1 H, J ) 5.7), 8.26 (s, 3 H), 7.20 (d,
2 H, J ) 8.5), 6.83 (d, 2 H, J ) 8.5), 4.54-4.39 (m, 1 H),
4.09 (q, 2 H, J ) 7.1), 3.71 (s, 3 H), 3.12-2.90 (m, 2 H),
2.20-1.70 (m, 8 H), 1.16 (t, 3 H, J ) 7.1); IR 3298, 3225,
1721, 1675 cm-1; [R]25 ) -13.7°. Anal. Calcd for
D
C18H27ClN2O4: C, 58.29; H, 7.34; N, 7.55; Cl, 9.56.
Found: C, 57.97; H, 7.14; N, 7.38; Cl, 9.52.
(R)-2-Bromo-3-methylbutanoic Acid (1:1) N-(1-Meth-
ylethyl)-2-propanamine (6b). A solution of NaNO2 (16.0
g, 0.225 mol) in H2O (29 mL) was added over 2.5 h to a
solution of 6a (20.0 g, 0.171 mol), 48% HBr (60 mL, 0.53
mol), and H2O (39 mL) at -5 °C. The mixture was stirred
at 0 °C for 1 h, then warmed to 23 °C, and extracted with
TBME (3 × 50 mL). The combined organic extracts were
washed sequentially with 10% Na2S2O3 (40 mL), H2O (40
mL), and brine (40 mL). After the organic portion was
filtered and cooled to -4 °C, diisopropylamine (23.8 mL,
0.17 mol) was added over 12 min, with the temperature
maintained below 5 °C. The resulting suspension was stirred
N-[[1-[[(S)-2-(Acetylthio)-3-methyl-1-oxobutyl]amino]-
1-cyclopentyl]carbonyl]-O-methyl-L-tyrosine Ethyl Ester
(1). Thioacetic acid (80.7 g, 1.06 mol) was added over 15
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