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Upon completion of reaction, the mixture was quenched with aqueous citric
acid (metal chelator), which precipitated Pd black and by-products from the
ligand. Following phase separation and water washes, the product-rich or-
ganic layer was treated with charcoal (type not specified; 10 wt% per 35)at
20-30 1C to remove further Pd residues and color. After filtration through
Celite, concentration to remove water via azeotropic distillation and further
dilution with toluene, 4.97 kg of 38 were isolated as a 2:1 diastereomeric
mixture in a toluene solution that was used in the next step without further
purification (96% purity by GC-MS). Both diastereomers could be employed
in subsequent chemistry without the need to separate them at this stage. It
was also mentioned that charcoal performed better than other metal scav-
enger treatments such as Silicycle's Si-Diamine to remove colored impur-
ities. The combined yield for this step and the subsequent ester reduction to
the corresponding alcohol with LiAlH
4
was 84%. No information was pro-
vided about the level of residual Pd in 38.
Researchers at AMRI described the preparation of the triple reuptake in-
hibitor ALB 109780 (43), a candidate for the treatment of depressive dis-
orders (Scheme 15.8).
74f
a-Arylation of lactam 40 was implemented in the
presence Pd(OAc)
2
(5 mol%), (
)-BINAP (5 mol%) and NaOt-Bu as base in
dioxane at 80 1C. Even though dioxane is carcinogenic and therefore gen-
erally avoided by process chemists, this solvent was chosen for further de-
velopment since it provided better conversion and product purity than
toluene. With the goal of taking this chemistry into the plant, calorimetric
studies revealed that the addition of NaOt-Bu was exothermic but that heat
evolution could be managed via slow dosing of the base. A second exotherm
occurred when the reaction temperature reached 60 1C, which generated
enough heat potentially to give rise to a runaway reaction if appropriate
cooling was not applied. This second exotherm could also be controlled by
slow addition of the aryl bromide at high temperature, but this approach led
to the formation of more impurities. Based on these results, it was decided
to carry out multiple small-scale reactions in which heat evolution could be
more easily managed than in a larger vessel. In the laboratory, to a mixture
of 40, 41, Pd(OAc)
2
and (
)-BINAP in 1,4-dioxane was added NaOt-Bu por-
tionwise over 30 min. The resulting mixture was then heated to 60 1C (at this
point the reaction became self-heating and external heating was stopped)
O
i. Pd(OAc)
2
(5 mol%)
(
±
)-BINAP (5 mol%)
NaO
t
-Bu, dioxane,
60 ºC; then 80 ºC, 1.5 h
ii. aqueous workup
iii.
i
-PrOAc slurry, 60 ºC, 15 min
iv. silica gel plug
66%
S
S
N
N
Me
O
CO
2
H
40
(+)
+
O
CO
2
H
N
N
N
Me
N
Me
Br
S
O
O
42
(480 g)
43
(ALB 109780)
5 ppm Pd
41
(1.05 equiv)
Scheme 15.8 Pd-mediated a-arylation en route to ALB 109780.
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