1-(4-Isopropyl-1H-pyrrolo[3,2-c]pyridin-2-yl)-butan-1-
one (5).12 Keto-ester 16 (5.1 kg, 18.7 mol), toluene (187 mL)
and methanol (187 mL) were added to 1 M HCl (28 L, 28.0
mol) and the mixture heated to 95 °C for 3 h. Approximately
1 L of distillate was collected and the mixture cooled to 50 °C.
K3PO4 (5.96 kg, 28.0 mol) in water (9.4 L) was added over
1 h and the resultant slurry cooled to 5-20 °C for 1 h. The
yellow crystalline solid was filtered and washed with cold water
(15-20 L). The solid was dried overnight in the filter pot and
then in a vacuum oven at 45 °C to afford ketone 5 as yellow
crystalline needles (3.7 kg, 91 wt %, 84% yield): mp 129-132
°C; 1H NMR (CDCl3, 400 MHz): δ 8.39 (d, J ) 5.9 Hz, 1H),
7.17 (dd, J ) 6.0, 0.7 Hz, 1H), 7.14 (d, J ) 0.8 Hz, 1H), 4.45
(t, J ) 6.4 Hz, 2H), 3.34 (sept, J ) 6.9 Hz, 1H), 3.23 (t, J )
6.4 Hz, 2H), 1.41 (d, J ) 6.9, 6H), 13C NMR (CDCl3, 100.6
MHz): 192.5, 165.4, 142.1, 138.1, 135.3, 126.5, 103.3, 98.1,
40.1, 39.3, 33.7, 21.7; HRMS C13H14N2O [M + H] calcd,
215.1184; found, 215.1184 (0 error).
Calcd for C16H18N2O2: C, 71.09; H, 6.71; N, 10.36. Found: C,
71.03; H, 6.70; N, 10.31.
(R)-3-(4-Isopropyl-1H-pyrrolo[3,2-c]pyridin-2-yl)hexanoic
Acid Methyl Ester (7). A 5-gal autoclave was charged with
ene ester 6 (2.2 kg, 8.0 mol) and toluene (8.5 L). The orange
slurry was stirring and was degassed using vacuum/nitrogen
purges.
[Catalyst preparation: In an inert atmosphere glovebox,
degassed 1,2-dichloroethane (166 mL) was charged to a vessel
containing Ir(COD)2BF4 (10.7 g, 21.6 mmol) and SLW005-2
(24.96 g, 23.8 mmol). The solution was stirred for 1.5 h at room
temperature after which time the resulting deep-red homoge-
neous solution was charged into a stainless steel bomb to enable
direct, inert charging to the hydrogenation vessel].
Confirmation of the activity/selectivity of the catalyst solution
was obtained by use test and vessel conditioning runs.
The iridium catalyst solution [(SLW005-2) Ir(COD)BF4]
previously prepared was charged to the autoclave.
Safety Warning: introduction of hydrogen produces an
exotherm which must be carefully controlled to aWoid tem-
perature run away.
HPLC (method C) retention times: pyrrole ketone methyl
ester 6.9 min; desired indole methyl ester 4.1 min; methyl keto-
ester 4.3 min; tricyclic ketone 3.2 min; dimeric byproducts
(unsaturated ketone isomers) 4.4 and 4.5 min.
The solution was hydrogenated under hydrogen gas (90 psig)
at 15 °C for 1 h then at 22 °C for 23 h.
(E)-3-(4-Isopropyl-1H-pyrrolo[3,2-c]pyridin-2-yl)-hex-2-
enoic Acid Methyl Ester (6). To a solution of trimethyl
phosphonoacetate (3.9 kg, 21.4 mol) in THF (30 L) was added
sodium amylate (1.8 kg, 16.1 mol) in one portion (exotherm
from 17 to 32 °C). The thick, white slurry was aged for 2 h.
The mixture was cooled to -2 °C and ketone 5 (2.3 kg, 10.7
mol) added in 2 equal portions. The mixture was aged for 23 h
under nitrogen between -3 and 2 °C and reaction progress
monitored by HPLC assay until <3% ketone remained. 85%
H3PO4 (1.1 L, 16.2 mol) in water (9.3 L) was added to the
reaction mixture (exothermic; yellow solid precipitates). An
aqueous solution of p-TSA monohydrate (2.1 kg, 10.9 mol) in
H2O (1.2 L) was added in one portion. The mixture was aged
for 1 h and concentrated under reduced pressure to ap-
proximately 27 L. Water (23 L) was added and the slurry aged
at 20 °C for 2 h. The fine, pale-yellow crystals were filtered
and washed with water (15 L). The product was dried in Vacuo
for 48 h to afford unsaturated ester 6 as yellow needles (3.7
kg, 77%).
After the resulting orange homogeneous solution aged
overnight (∼24 h), the pressure vessel was vented to atmo-
spheric pressure (assay yield 7, 99%, 98.0% ee). This solution
of 7 was used without further purification or processing in the
next step. A small amount of the solution was evaporated to
dryness for analytical data: 1H NMR (CDCl3, 400 MHz): δ 8.22
(d, J ) 5.5 Hz, 1H), 6.98 (d, J ) 5.5 Hz, 1H), 6.28 (s, 1H),
4.12 (ddd, J ) 10.2, 8.6, 4.2 Hz, 1H), 4.01 (app. ddd, J ) 10.2
Hz, 1H), 3.79 - 3.74 (m, 1H), 3.76 (s, 3H), 3.44 (app. p, J )
6.9, 1H), 2.88 (ddd submerged, J ) 12.3, 7.8, 4.2, 1H), 2.85
(dd, J ) 16.2, 6.5 Hz, 1H), 2.63 (dd, J ) 16.2, 8.3 Hz, 1H),
2.34 - 2.29 (m, 1H), 1.42 (d, J ) 2.1 Hz, 3H), 1.40 (d, J )
2.1 Hz, 3H); 13C NMR (CDCl3, 100.6 MHz) δ 172.23, 160.31,
146.43, 139.78, 136.19, 129.17, 127.04, 103.13, 91.8, 52.0, 43.1,
38.9, 34.9, 33.8, 22.0, 21.9. HRMS C16H20N2O2 [M + H] calcd,
273.1603, found 273.1602 (-0.4 error).
HPLC (method D) retention times: chiral ester 3.7 min; ene
ester (E isomer) 4.0 min; ene ester (Z isomer) 4.2 min; toluene
7.5 min.
To a solution of triethylamine (1.5 L, 10.8 mol) in MeOH
(8 L) was added tosylate ester 6 (3.66 kg, 8.26 mol) in one
portion and stirred to obtain complete dissolution. Water (0.8
L) was added, and the solution was seeded with product (1 g)
and aged for 30 min. Water (22.2 L) was added over 20 min,
maintaining the temperature between 20 and 26 °C. The slurry
was filtered and washed with water (20 L). The product was
dried in Vacuo to afford unsaturated ester 6 as a fine, yellow
crystalline solid (2.19 kg, >99 wt %, 98% yield): mp 137-140
°C; 1H NMR (CDCl3, 400 MHz): δ 8.29 (d, J ) 5.9 Hz, 1H),
7.08 (d, J ) 5.7 Hz, 1H), 6.86 (br s, 1H), 6.42 (t, J ) 2.6 Hz,
1H), 4.27 (t, J ) 6.5 Hz, 2H), 3.84 (dt, J ) 6.9 Hz, 2.6, 2H),
3.81 (s, 3 H), 3.52 (sept, J ) 6.9 Hz, 1H), 1.44 (d, J ) 6.9 Hz,
6H),; 13C NMR (CDCl3, 100.6 MHz): 167.2, 162.4, 148.2,
141.5, 140.8, 137.2, 126.9, 110.0, 103.2, 93.6, 51.3, 42.7, 34.1,
33.6, 21.7. HRMS C16H18N2O2 [M + Na] calcd, found. Anal.
Chiral HPLC (method E) retention times: toluene 2.0 min;
ene ester (Z isomer) 7.4 min; chiral ester (desired enantiomer)
8.2 min; ene ester (E isomer) 9.1 min; chiral ester (undesired
enantiomer) 11.2 min.
2-(3,4-Dichlorophenylsulfanyl)isoindole-1,3-dione (24).23
3,4-Dichlorothiophenol (4.46 kg, 24.9 mol), phthalimide (4.03
kg, 27.4 mol), and pyridine (10.9 kg, 79.1 mol) were added to
acetonitrile (35.2 L). The slurry was stirred, and bromine (725
mL, 2.34 kg, 14.6 mol) was added over 30 min. The temperature
was allowed to reach 40 °C before adding product seed (330
g, 1.02 mol) and additional bromine (100 mL, 311.9 g, 1.95
mol) over 15 min. The temperature was held at 38 °C and the
remainder of the bromine added dropwise over 25 min. After
45 min, the reaction was treated with 10% water in methanol
(34.5 L), cooled to 25 °C and filtered (typical mother liquor
loss 1.5%). The filter cake was washed with MeOH (20 L) and
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