acetate (1000 mL and 400 mL). The combined organic layers
were evaporated to dryness in vacuo.
6.76 (app d, J ) 7.6 Hz, 1H), 4.94 (br s, 1H), 4.29 (app d,
J ) 10.8 Hz, 1H), 4.07-4.21 (m, 1H), 3.96 (app d, J )
13.2 Hz, 2H), 3.61 (dt, J ) 2.4, 8.0 Hz, 1H), 3.39 (d, J )
13.6 Hz, 2H), 3.01-3.15(m, 4H), 2.93-2.99 (m, 1H), 2.60-
2.82 (m, 5H), 2.15-2.24 (m, 1H), 1.67-175 (m, 1H), 1.53-
1.66 (app ddt, 2H), 1.51 (sept, J ) 7.6 Hz, 1H), 0.87 (app
d, J ) 5.6 Hz, 3H), 0.84 (app d, J ) 5.6 Hz, 3H). 13C NMR
(100 MHz): δ 170.4, 156.7, 140.5, 139.3, 138.6, 129.4,
129.3, 129.1, 128.6, 128.5, 128.2, 127.2, 126.2, 126.0, 69.1
(CH), 64.0 (CH), 63.0 (br, CH), 54.1 (CH2), 49.3 (CH), 41.1
(CH2), 40.8 (br, CH2), 40.2 (CH2), 39.8 (CH2), 31.7 (CH2),
25.3 (CH), 21.6 (CH2), 19.6 (CH3), 18.7 (CH3). MS (DCI/
NH3) 647 (M + H).+ Anal. Calcd for C41H50N4O5: C, 76.12;
H, 7.79; N 8.66. Found: C, 75.92; H, 7.84; N 8.63.
[1S-[1R*(R*),3R*,4R*]]-N-[4-amino-3-hydroxy-5-phen-
yl-1-(phenylmethyl)pentyl]tetrahydro-R-(1-methylethyl)-
2-oxo-1(2H)-pyrimidineacetamide (13). A 1-L, three-
necked, round-bottomed flask equipped with a mechanical
stirrer, reflux condenser with nitrogen inlet adapter, and a
thermometer was charged with 55.7 g of crude 12 (0.086
mol, 1.0 equiv), 15.1 g of ammonium formate (0.239 mol,
2.78 equiv), 10.4 g of 5% w/w palladium on carbon (50%
wet), and 260 mL of methanol. The reaction mixture was
heated to 50 °C overnight at which time HPLC analysis
revealed complete consumption of the starting material. The
reaction mixture was filtered through a pad of diatomaceous
earth which was washed once with 250 mL of methanol.
The combined filtrates were reduced to dryness affording
41.9 g of a yellow syrup (104%).
The residual solid was dissolved in 600 mL of anhydrous
3A ethanol at reflux, carbon-treated to remove color, filtered,
and reduced to dryness in vacuo. The residue was dissolved
in 600 mL of hot ethyl acetate. Approximately one-third of
the total volume was removed by atmospheric distillation
and the suspension cooled to below 10 °C for 1 h. The
product was isolated by filtration and dried in vacuo at less
than 45 °C, affording 64.6 g of an off-white solid (77%) in
>99% ee.21
IR: 3300, 2960, 2500 (br, weak), 1930 (br, weak), 1720,
1
1618, 1535, 1320, 1290 cm-1. H NMR (400 MHz, d6-
DMSO): δ 12.40 (br s, 1H), 6.18 (br s, 1H), 4.41 (d, J )
10 Hz, 1H), 3.25 (m, 1H), 3.14 (m, 1H), 3.08 (app dt, 2H),
2.08 (m, 1H), 1.87 (app p, 2H), 0.92 (d, J-7 Hz, 3H), 0.84
(d, J ) 7 Hz, 3H). 13C NMR (100 MHz, d6-DMSO): δ 173.1,
155.8, 61.8, 41.7, 39.5, 26.6, 21.8, 19.8, 19.0.). MS (DCI/
NH3): 201 (M + H)+, 218 (M + NH4)+. Anal. Calcd for
C9H16N2O3: C, 53.99; H, 8.05; N 13.99. Found: C, 54.00;
H, 7.96; N 14.11.
[1S-[1R*(R*),3R*,4R*]]-N-[4-[bis(phenylmethyl)amino]-
3-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]tetrahydro-
R-(1-methylethyl)-2-oxo-1(2H)-pyrimidineacetamide (12).
To a suitable flask equipped with mechanical stirring was
charged acid 5 (35.2 g, 0.176 mol, 1.02 equiv) and 480 mL
of THF. The resulting suspension was cooled to 4 °C, and
thionyl chloride (28.6 g, 0.240 mol, 1.37 equiv) was added
dropwise over 10 min. The resulting thick slurry was warmed
to room temperature and stirred for 5.5 h, at which time
HPLC revealed complete consumption of the acid.22 The
reaction mixture was reduced to dryness in vacuo. Heptane
(250 mL) was added to the residue and the slurry again
reduced to dryness in vacuo. The residual solid acyl chloride
11 was then partially dissolved in 170 mL of dry DMF.
Ethyl acetate (50 mL) and 80.0 g (0.172 mol, 1.0 equiv)
of 4 (combined HPLC purity of the 4 diastereomers is >93%
with the desired isomer present in 87%) were charged to a
mechanically stirred reaction vessel. The solution was cooled
to 2 °C, and 36.0 g (0.529 mol, 3.07 equiv) imidazole was
added. To this reaction mixture was rapidly added the slurry
of 11 prepared above. The reaction mixture was stirred at 4
°C for 1 h and subsequently warmed to 30 °C overnight.
The reaction mixture was then quenched with a solution of
32.5 g of concentrated aqueous HCl in 200 mL of water,
which, after mixing, made the lower aqueous layer pH ) 3.
After the solution was mixed for 30 min, the organic layer
was separated and washed three times with 250 mL of
saturated NaCl solution. The organic layer was then evapo-
rated to dryness in vacuo, producing 96.4 g of 12 as a foamy
off-white solid (87% yield). Crude 12 assays as >94% pure
by HPLC (combined total of 4 diastereomers).
IR 3315, 3060, 3027, 2961, 2869, 1643 (st), 1509, 1452,
1
1307, 701 cm-1. H NMR (400 MHz): δ 7.14-7.31 (m,
10H), 5.21 (br s, 1H), 4.11-4.35 (m, 2H), 3.54-3.58 (app
sextet, J ) 4 Hz, 1H), 3.15-3.25 (br m, 2H), 3.05-3.14
(m, 1H), 2.91-3.01 (m, 2H), 2.61-2.90 (m, 4H), 2.53 (dd,
J ) 9.6, 13.6 Hz, 1H), 2.15-2.24 (m, 2H), 1.71-1.85 (M,
3H), 1.53-1.64 (M, 1H), 1.40-1.51 (m, 1H), 1.31 (d, J )
16.8 Hz, 1H), 0.91 (d, J ) 6.4 Hz, 3H), 0.84 (d, J ) 6.4 Hz,
3H). 13C NMR (100 MHz): δ 170.5, 156.8, 139.2, 138.6,
129.5, 129.4, 129.1, 128.7, 128.6, 128.4, 128.3, 126.4, 126.1,
71.5 (CH), 64.6 (CH), 56.3 (CH), 48.6 (CH), 41.5 (CH2),
40.8 (CH2), 40.0 (CH2), 39.5 (CH2), 38.9 (CH2), 25.3 (CH),
21.6 (CH2), 19.6 (CH3), 18.5 (CH3). MS (ESI+) 467 (M +
H)+, 489 (M + Na)+. MS (ESI-) 465 (M - H)-. Anal. Calcd
for C27H38N4O3: C, 69.50; H, 8.21; N 12.01. Found: C,
69.58; H, 8.12; N 11.65.
[1S-[1R*(R*),3R*,4R*]]-N-[4-amino-3-hydroxy-5-phen-
yl-1-(phenylmethyl)pentyl]tetrahydro-R-(1-methylethyl)-
2-oxo-1(2H)-pyrimidineacetamide, 5-Oxo-L-proline salt
(15). Crude 13 (37.3 g, 0.080 mol, 1 equiv) was slurried in
150 mL of 1,4-dioxane at room temperature. The dioxane is
subsequently removed in vacuo, and 370 mL of dioxane was
charged to the flask.23 Solid L-pyroglutamic acid (14) (10.3
g, 0.080 mol, 1 equiv) was added and the suspension heated
to 50 °C, which resulted in the formation of a clear, yellow-
colored solution. After 1 h at 50 °C, no solid was present,
and the solution was slowly cooled to room temperature
IR: 3381 (br), 3060, 3026, 2950, 2932, 2869, 1948 (w),
1874 (w), 1797 (w), 1643 (st), 1509, 1496, 1452, 1307, 748,
1
699 cm-1. H NMR (400 MHz): δ 7.08-7.37 (m, 20H),
(21) Enantiomeric excess is determined by HPLC (Chiracel OD column, elution
with hexane: ethanol: trifluoroacetic acid (930: 70: 1). The desired L-isomer
has a retention time of approximately 14 min; the D-isomer, 11.5 min.
(22) Analysis was performed on crude reaction aliquots quenched into methanol.
(23) Karl Fischer titration at this point: 0.07% water. Anhydrous conditions
facilitate the crystallization.
268
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Vol. 4, No. 4, 2000 / Organic Process Research & Development