Stereoselective Synthesis of Palinavir
J . Org. Chem., Vol. 62, No. 11, 1997 3447
The resulting wet cake was placed in a 22 L flask, and cold
concd HCl (2 L) was added slowly. The mixture was kept at
∼15 °C by means of external cooling and stirred 3.5 h. After
complete deprotection (as shown by HPLC analysis), the
solution was further cooled to 5-10 °C and basified (pH 12)
with 10 N NaOH (2.7 L). The mixture was extracted with
EtOAc (4 × 1 L), and the combined extracts were washed with
brine. After drying over MgSO4-decolorizing charcoal, volatiles
were removed under reduced pressure, and the residue was
coevaporated twice with THF (1 L). The resulting oil was
slowly poured into vigorously stirred hexanes (4 L) and allowed
to crystallize. The solid was collected by filtration, washed
with 1:1 ether-hexanes and dried in vacuo. The desired
product 5 was obtained as a beige colored crystalline solid
(944.4 g, 54% yield): Rf 0.28 (9:1 CHCl3/MeOH). Mp 79-81
°C dec. [R]25D +8.7° (c 1, MeOH). IR (KBr) ν 3349, 3233, 2960,
stream of argon. After cooling to room temperature, the
suspension was filtered (3 L of THF for rinses) and the product
eluted from the alumina using 10% MeOH in EtOAc (20 L).
The filtrate and washings were combined and evaporated
under reduced pressure. The residue was dissolved in EtOAc
(4 L), and unreacted 5 was extracted into 1 M KH2PO4 (3 × 2
L). The aqueous phase was saved for recovery of 5 (see below).
The EtOAc layer was extracted with a solution of concd HCl
(400 mL) in water (2 L). The aqueous phase was separated
and washed with EtOAc (1 L), and concd HCl (1 L) was added.
After stirring the aqueous solution for 1 h, deprotection was
shown to be complete (TLC). The solution was cooled in an
ice-water bath and basified to pH 12 with 10 N NaOH (3 L),
maintaining the temperature <40 °C. The oily product was
extracted with EtOAc (3 × 1.5 L), washed with water (2 L)
and brine (2 L), and dried (MgSO4). Removal of volatiles under
reduced pressure and drying to constant weight in vacuo gave
crude 10 as a burgundy-colored glass (944 g, 63% yield): Rf
0.48 (7:3 CHCl3/MeOH). [R]23D -34.9° (c 1, MeOH). IR (KBr)
1667, 1514 cm-1 1H NMR (CDCl3) δ 8.55 (broad, d, J ) 4.5
.
Hz, 2H), 7.25 (broad d, J ) 5.5 Hz, 2H), 6.67 (broad s, 1H),
4.64 (d, J ) 13.4 Hz, 1H, part of AB), 4.54 (d, J ) 13.4 Hz,
1H, part of AB), 3.47 (m, 1H), 3.19 (dt, J ) 12.4, 3.8 Hz, 1H),
3.13 (dd, J ) 11.2, 3.0 Hz, 1H), 2.67 (dt, J ) 12.4, 2.9 Hz, 1H),
2.49 (m, 1H), 2.24 (broad s, 1H), 2.02 (m, 1H), 1.53-1.36 (m,
2H), 1.34 (s, 9H). 13C NMR (50 MHz, DMSO-d6) δ 171.8, 149.6,
148.5, 121.9, 75.8, 67.1, 58.6, 50.0, 43.1, 36.1, 32.4, 28.5. FAB-
MS m/z 292 (MH+). Anal. Calcd for C16H25N3O2: C, 65.95;
H, 8.65; N, 14.42. Found: C, 65.61; H, 8.68; N, 14.16. An
authentic sample of (2R,4S)-5 was prepared as described above
but starting from (2R,4S)-8 and used as analytical standard.
An aliquot of both samples was converted to the corresponding
N-trifluoroacetamide by heating for 10 min in TFAA and
analyzed by HPLC (Chiralcel OD, 15% EtOH in hexane,
isocratic, 0.5 mL/min flow rate): (2S,4R)-5, tR 27.9 min
(>99.5% isomeric purity), (2R,4S)-5, tR 25.0 min (<0.5%).
Qu in olin e-2-ca r boxylic Acid L-Va lyl Am id e, F r a gm en t
9. A 20 L reaction vessel was charged with Na2CO3 (916 g,
8.64 mol), water (8 L), and L-valine (503 g, 4.30 mol). After
dissolution and cooling to 0 °C, quinoline-2-carboxylic acid
chloride (20)22 (747 g, 3.90 mol) was added followed by TBME
(4.3 L). After 1 h, the organic layer was separated and
extracted with water (2 L). The aqueous phases were com-
bined, acidified with 6 N HCl (3.2 L), and extracted with EtOAc
(4 L). The organic extract was washed with brine and dried
over MgSO4. Volatiles were removed under reduced pressure
and the solid residue crystallized from EtOAc-hexanes to give
9 as a tan-colored crystalline solid in two crops (931 g, 88%
ν 3600-2500, 1663, 1601, 1530 cm-1 1H NMR (CDCl3) δ 8.57
.
(dd, J ) 4.4, 1.6 Hz, 2H), 7.36-7.18 (m, 7H), 6.50 (s, 1H), 4.62
(d, J ) 13.4 Hz, 1H, part of AB), 4.53 (d, J ) 13.4 Hz, 1H,
part of AB), 3.78 (m, 1H), 3.46 (tt, J ) 9.9, 4.3 Hz, 1H), 3.40
(dt, J ) 12.7, 3.8 Hz, 1H), 3.10 (dt, J ) 10.5, 3.8 Hz, 1H), 2.94-
2.85 (m, 2H), 2.79 (dd, J ) 13.4, 3.5 Hz, 1H), 2.55 (dd, J )
13.4, 10.5 Hz, 1H), 2.45 (dd, J ) 13.0, 8.0 Hz, 1H), 2.36 (dd, J
) 12.3, 1.9 Hz, 1H), 2.31 (dm, J ) 10.2 Hz, 1H), 2.01-1.93
(m, 1H), 1.72-1.58 (m, 2H), 1.36 (s, 9H). 13C NMR (CDCl3) δ
172.1, 150.0, 148.0, 138.7, 129.4, 129.0, 126.9, 122.0, 75.3, 72.3,
68.4, 67.1, 56.6, 56.7, 51.2, 50.5, 38.1, 33.8, 31.5, 30.0, 28.9.
FAB-MS m/z 455 (MH+). RP-HPLC (Supelcosil LC-ABZ; 0 f
20% 0.1% TFA-CH3CN/0.1% TFA in 35 min, then 20 f 100%
0.1% TFA-CH3CN/0.1% TFA in 10 min; 1.0 mL/min flow
rate): 10 tR 24.0 min (96.4%).
Recovery of unreacted 5: The KH2PO4 extract from above
(6 L) was basified to pH 10 with solid NaOH (300 g, 7.5 mol).
NaCl (500 g) was added and the solution extracted with EtOAc
(3 × 750 mL). The extracts were combined, dried (Na2SO4),
and concentrated to an oil that was coevaporated with THF
(2 × 250 mL). The residue was dissolved in THF (200 mL)
and the solution added dropwise (over 3 h) to hexanes (2.5 L)
under vigorous stirring. The crystallized solid was filtered,
washed with 10% THF in hexanes (2 × 500 mL), and dried in
vacuo to give 5 (200 g) of sufficient purity for recycling: mp
89-92 °C. [R]25 +11.7° (c 1, CHCl3).
D
yield): mp 135-136 °C. [R]25 +61.2° (c 1.22, MeOH). IR
Cr u d e P a lin a vir (1). Fragment 9 (980 g, 3.603 mol) and
N-methylmorpholine (792 mL, 7.2 mol) were dissolved in THF
(6 L), and the solution was cooled to -30 °C under a nitrogen
atmosphere. Freshly distilled isoobutyl chloroformate (467
mL, 3.6 mol) was added dropwise over 15 min, maintaining
an internal temperature <-20 °C. The reaction mixture was
stirred for 0.5 h after completion of the addition. Crude amine
10 (1489 g, 3.275 mol) was dissolved in THF (5 L + 1 L rinse)
and added as rapidly as possible (1 h), keeping the reaction
temperature below -20 °C. The reaction mixture was then
stirred 3 h, allowing the temperature to rise to 10 °C after
which point it was quenched by addition of water (2 L). THF
was removed under reduced pressure and the residue dissolved
in EtOAc (3 L). The organic phase was separated and washed
successively with water (2 L), 3 N NaOH (2 × 2 L), and water
(2 L). Crude 1 was then extracted into a solution of concd HCl
(1.6 L) in water (1.5 L). The EtOAc layer was extracted once
more with concd HCl (200 mL) in water (500 mL), and the
combined aqueous phases were washed with EtOAc (2 × 2 L).
Basification to pH 11 with 10 N NaOH (4.5 L), extraction with
EtOAc (2 × 1 L), drying (MgSO4-decolorizing charcoal), and
evaporation of the solvent under reduced pressure gave crude
palinavir (1) as a thick brown oil (yield not determined). HPLC
analysis (Supelcosil LZ-ABZ, 10-50% 1% TFA in MeCN/1%
TFA in 25 min, 1 mL/min flow rate): 1, tR 17.80 min (84.1%);
24, tR 18.47 min (2.0%); 25, tR 19.97 min (1.45%).
D
(KBr) ν 3500-2500, 3365, 1730, 1650, 1535, 1420 cm-1
.
1H
NMR (CDCl3) δ 8.76 (d, J ) 8.9 Hz, 1H), 8.31 (m, 2H), 8.17 (d,
J ) 8.3 Hz, 1H), 7.89 (dd, J ) 8.0, 0.6 Hz, 1H), 7.78 (ddd, J )
7.0, 6.9, 1.9 Hz, 1H), 7.63 (ddd, J ) 8.2, 7.0, 1.0 Hz, 1H), 4.83
(dd, J ) 9.1, 5.0 Hz, 1H), 2.47 (m, 1H), 1.13 (d, J ) 6.7 Hz,
3H), 1.12 (d, J ) 6.7 Hz, 3H). 13C NMR (CDCl3) δ 175.9, 164.9,
148.9, 146.5, 137.6, 130.1, 129.9, 129.4, 128.1, 127.6, 57.5, 31.4,
19.2, 17.9. CI-MS (isobutane) m/z 273 (MH+). Anal. Calcd
for C15H16N2O3: C, 66.16; H, 5.92; N, 10.29. Found: C, 66.17;
H, 5.95; N, 10.22. The enantiomeric purity of an aliquot of
the product was assessed by HPLC on a chiral support
(Chiralcel OD, 5% EtOH in hexane, isocratic, 1 mL/min flow
rate) after conversion to the methyl ester (CH2N2): tR 8.28 min,
>99.5% (>99.5% ee).
Quinoline-2-carboxylic acid D-valyl amide was prepared from
D-valine in an analogous fashion and used as analytical
standard: mp 134-136.5 °C. [R]25 -59.7° (c 1.08, MeOH).
D
IR, 1H NMR, 13C NMR, and MS data identical to that of
L-enantiomer. Anal. Calcd for C15H16N2O3: C, 66.16; H, 5.92;
N, 10.29. Found: C, 66.08; H, 6.00; N, 10.30. HPLC of methyl
ester (Chiralcel OD, 5% EtOH in hexane, isocratic, 1 mL/min
flow rate): tR 10.02 min.
Am in e 10. Pipecolic derivative 5 (958 g, 3.29 mol) and
epoxide 316a (1022 g, 3.88 mol, 1.18 equiv) were charged in a
22 L flask equipped with a reflux condenser and mechanical
stirrer. THF (12 L) was added and the solution degassed by
bubbling Ar through the solution for 1 h. The solution was
then heated to 45-50 °C, and basic alumina (5 kg, deactivated
by shaking with 2.5% w/w water for 18 h) was added. The
resulting slurry was stirred 23 h at 45-50 °C under a slow
P a lin a vir Dih yd r och lor id e. Crude palinavir, derived as
above from amine 10 (1971 g, 4.355 mol), was dissolved in
MeOH (4 L) and the solution stirred vigorously as 4 N HCl in
dioxane (2.25 L, 9.0 mol) was added. To the resulting hot
solution of palinavir dihydrochloride was added 2-propanol (8