In summary, we have successfully developed and dem-
onstrated a cost-effective, scalable synthetic process to
manufacture both anti-HIV compounds 1 and 2. Two
chemical steps were eliminated from the original synthesis,
and the process now employs reagents much more suitable
for use on an industrial scale. The process does not require
any specialized equipment, and we expect it to be scalable
to produce even larger batch sizes of 1 and 2.
approximately 150 L with a final batch temperature of 115
°C. The resulting solution was slowly cooled to 60-65 °C
to give a slurry, which was further cooled to 0-5 °C. The
slurry was filtered, and the filter cake was washed with
toluene (200 L) and dried in a vacuum oven at 50-60 °C to
give 4 (46.3 kg, 83%) as a tan-colored solid: mp 158.6-
6
159.3 °C (lit. mp 155-157 °C); IR (1% KBr disk) 1757,
-
1
1720, 1585, 1556, 1448, 1437, 1211, 1196, 877 cm .
[
S-(R*,R*)]-2-{[2-[[2-[(1-Carboxy-2-methylbutyl)car-
Experimental Section
bamoyl]phenyl]dithio]benzoyl]amino}-3-methylpenta-
noic Acid (2). 2,2′-Dithiobis(benzoyl chloride) (46.2 kg,
35 mol), L-isoleucine (38.8 kg, 296 mol), sodium bicarbon-
ate (34.2 kg, 407 mol), and THF (462 L) were charged to a
reactor. With agitation, the mixture was heated to 60-65
C and held at that temperature for 2 h. The reaction slurry
was then added slowly to a rapidly stirred mixture of
hydrochloric acid (37%, 37.6 kg), water (353 L), and MTBE
496 L) such that excessive foaming was avoided. The
reactor was rinsed with THF (94 L), MTBE (95 L), and water
94 L), and the rinses were added to the quenched solution.
The biphasic mixture was agitated rapidly for 15 min and
allowed to settle. The lower aqueous phase was separated,
and the upper organic layer was washed with water (235 L)
followed by dilute hydrochloric acid (0.06%, 235 L, then
General Methods. All reagents, solvents, and processing
aids are commercial products and were used as received.
Pilot-scale reactions used glass-lined reactors having variable
rate agitation, a -10 to 140 °C jacket temperature range,
and a 60-mmHg vacuum to a 30-psig pressure rating. All
equipment was inspected visually for cleanliness and integrity
before use. Nitrogen was routinely used to break vacuums
and to blanket reactions for safety reasons. Standard
equipment-cleaning procedures were followed. An airline
respirator, a rubber rain suit, rubber gloves, and rubber boots
were worn by personnel during the charging of bromine and
thionyl chloride, and local exhaust ventilation was used at
the drum openings.
1
°
(
(
Melting points were measured on a Mettler FP80 ap-
paratus and are uncorrected. Proton NMR spectra were
1
18 L). Hexane (663 L) was added to the MTBE/THF
13
recorded at 300.13 MHz and C NMR spectra were recorded
at 75.47 MHz on a Bruker AM300 spectrometer using
tetramethylsilane as an internal standard. IR spectra were
measured on Analect Diamond-20 and Bruker IFS 66
spectrometers, and the IR absorption bands reported have
either strong or very strong intensities. Elemental analyses
were performed on a CEC 440 elemental analyser. The
following conditions were used for high-performance liquid
chromatography (HPLC) analysis of 2: Phenomenex Ul-
tramex CN, 250 × 4.6 mm, 3-µm normal-phase column; 20%
tetrahydrofuran in hexane with 0.1% trifluoroacetic acid
mobile phase; 1.5 mL/min flow rate; 20-µL injection volume;
detection at 251 nm. The following conditions were used
for HPLC analysis of 1: Alltech Hypersil BDS C18, 150 ×
solution, and the resulting slurry was stirred at ambient
temperature for 3 h and filtered. The filter cake was washed
with hexane (120 L) and dried in a vacuum oven at 60-65
°C to give crude 2 (59.7 kg) as an off-white solid. The crude
product and THF (1015 L) were charged to a reactor, and
the mixture was heated to 60 °C to dissolve the solids. The
solution was heated under reflux, and THF (730 L) was
distilled out of the mixture. The solution was cooled to
ambient temperature and filtered. The filtration equipment
was rinsed with THF (25 L), and with rapid agitation, hexane
(537 L) was added to the combined filtrates. The resulting
slurry was stirred at ambient temperature for 17 h and
filtered. The filter cake was washed with hexane (200 L),
dried in a vacuum oven at 60-65 °C, and milled to give 2
4.6 mm, 5-µm reverse-phase column; 680 mL of 0.5%
(
[
53.6 kg, 75%) as a white powder: mp 210.3-212.3 °C;
aqueous triethylamine to pH 2.8 with phosphoric acid/320
mL of tetrahydrofuran; 1.2 mL/min flow rate; 20-µL injection
volume; detection at 230 nm.
2
5
R]
D
-31.4° (c ) 1.00, MeOH); HPLC (w/w vs reference
1
standard) 98.7%; H NMR (DMSO-d
8
7
6
) δ 12.7 (br s, 2H),
.71 (d, J ) 8.3 Hz, 2H), 7.67 (dd, J ) 8.1, 1.1 Hz, 2H),
.66 (dd, J ) 7.4, 1.5 Hz, 2 H), 7.45 (ddd, J ) 8.1, 7.4, 1.5
2,2′-Dithiobis(benzoyl chloride) (4). 2,2′-Dithiobis-
(benzoic acid) (50 kg, 163 mol), toluene (250 L), and N,N′-
Hz, 2H), 7.31 (ddd, J ) 7.4, 7.4, 1.1 Hz, 2H), 4.36 (dd, J )
dimethylformamide (0.1 kg, 1.4 mol) were charged to a
reactor. To the agitated mixture was added thionyl chloride
8
1
.3, 6.8 Hz, 2H), 1.96 (dddq, J ) 8.7, 6.8, 6.8, 4.2 Hz, 2H),
.53 (ddq, J ) 13.6, 7.4, 4.2 Hz, 2H), 1.32 (ddq, J ) 13.6,
(53.5 kg, 450 mol) followed by toluene (25 L) while the
temperature was maintained below 35 °C. The mixture was
heated at 70-75 °C for 16 h and filtered to remove
suspended solids. The solids were washed with toluene (50
L), and the combined filtrates were heated to reflux. Thionyl
chloride and toluene were distilled out of the mixture until
a final batch volume of approximately 150 L remained in
the reactor. Additional toluene (250 L) was added, and
thionyl chloride and toluene were distilled out of the mixture
under atmospheric conditions until a final batch volume of
approximately 150 L remained. A further charge of toluene
8.7, 7.4 Hz, 2H), 0.97 (d, J ) 6.8 Hz, 6H), 0.89 (t, J ) 7.4
13
6
Hz, 6H); C NMR (DMSO-d ) δ 172.8, 167.2, 136.6, 133.8,
131.0, 128.4, 125.8, 125.8, 57.1, 35.8, 25.0, 15.6, 11.1; IR
-
1
(Nujol) 3297, 2969, 2876, 1718, 1633, 1530 cm . Anal.
Calcd for C26 : C, 58.63; H, 6.06; N, 5.26.
32 2 6 2
H N O S
Found: C, 58.49; H, 6.06; N, 5.19.
[S-(R*,R*)]-3-Methyl-2-(3-oxo-3H-benzo[d]isothiazol-
2-yl)pentanoic Acid (1). A reactor was charged with 2 (50.0
kg, 94 mol) and acetic acid (332 kg). Bromine (16.5 kg,
103 mol) was added to the agitated mixture while the batch
temperature was maintained at 22-30 °C, and the resulting
(250 L) was made and the batch volume reduced to
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