Organic Process Research & Development
Article
has the possibility of overheating). Heating was then reapplied,
and the reaction was stirred at 80 °C for 1.5 h, at which point
HPLC analysis indicated that the reaction was complete (<1% of 10).
The reaction mixture was allowed to cool to ambient
temperature, quenched into water (6.0 L), and extracted with
DCM (3.0 L, 1.5 L). The combined organic extracts were
washed with brine (3.0 L), and the organic layer was
concentrated to afford crude product as a brown residue. It
was combined with the crude product from a 170-g scale
reaction for purification as follows.
analysis indicated that it was complete (<5% of 15). The reaction
was cooled to ambient temperature and filtered. The filter cake
was rinsed with acetone (2 × 10 mL), and the combined filtrates
were concentrated to dryness. The residue was purified by a silica
gel plug using 5% MeOH/EtOAc as eluent to give the desired
product 10 as a light-yellow solid (2.62 g, 75% yield). Spectro-
scopic analysis was in agreement with that obtained via the coup-
ling of 4 and 8.
(+)-4-(4-(Benzothiophen-5-yl)-2-methyl-1,2,3,4-tetra-
hydroisoquinolin-7-yl)morpholine DTTA Salt (17). A
solution of 9 (650 g, 1.78 mo1) and acetone (10.2 L) was
heated to 50 °C, and a solution of di-p-toluoyl-D-tartaric acid
(690 g, 1.78 mol) in acetone (1.5 L) was added over 10 min.
The solution was stirred at reflux for 10 min; at this point a
white precipitate formed. The suspension was cooled to am-
bient temperature over 2 h and further to −5 °C over 1 h. The
resulting slurry was stirred at −5 °C for 1 h and filtered. The
filter cake was rinsed with acetone (2 × 1.3 L) and dried under
vacuum at ambient temperature for 16 h to afford a white solid
(1.12 kg, 84%). HPLC 97.2%.
The combined crude product was suspended in IPAc (700 mL)
at 60 °C for 15 min, cooled to 5 °C, and filtered. The filter cake
was dissolved in DCM (1.5 L) and passed through a silica gel plug
using EtOAc as eluent. The product containing fractions was
concentrated to dryness to afford the desired product as a brown
1
solid [480 g, 66% yield (average for two reactions)]. H NMR
(
300 MHz, CDCl ) 7.77 (d, 1 H, J = 8.4 Hz), 7.50 (s, 1 H),
3
7
8
.39 (d, 1 H, J = 5.4 Hz), 7.26−7.18 (m, 2 H), 7.49 (d, 1 H, J =
.4 Hz), 6.87 (dd, 1 H, J = 2.4 Hz, J = 8.4 Hz), 6.77 (d, 1 H,
1
2
J = 2.4 Hz), 4.91 (s, 1 H), 4.64 (d, 1 H, J = 15.9 Hz), 4.28 (d,
H, J = 15.9 Hz), 3.88 (t, 4 H, J = 4.8 Hz), 3.19 (t, 4 H, J = 4.8 Hz),
1
The solid obtained above was suspended in 1:9 EtOH/THF
(20.0 L) and heated at 65 °C for 1 h; then heptane (10.0 L)
was added. The resulting slurry was heated at 65 °C for 1 h and
allowed to cool to ambient temperature over 1 h, then further
cooled to −5 °C over 1.5 h and stirred at −5 °C for 1 h. The
suspension was filtered, and the filter cake was rinsed with hep-
tane (2 × 1.1 L) and dried under vacuum at ambient tempera-
+
3.08 (s, 3 H); MS m/z 379.12 [M + H] ; HPLC 99.1%.
4
-(4-(Benzothiophen-5-yl)-2-methyl-1,2,3,4-tetrahy-
droisoquinolin-7-yl)morpholine (9) via Reduction of 11.
A solution of 11 (565 g, 1.49 mol) and THF (11.4 L) was
stirred for 10 min, and the reaction temperature was adjusted to
35 °C. BMS (300 mL, 3.16 mol) was added over 25 min while
maintaining the internal temperature at <40 °C. The reaction
was stirred at 40 °C for 4 h, at which point HPLC analysis
indicated that the reaction was complete (<1% of 11). It was
combined with 2 N HCl (2.24 L) over 25 min, and the
resulting mixture was stirred at 40 °C for 1 h. The mixture was
cooled to ambient temperature and basified using 2 N NaOH
ture for 72 h to afford 17 as a white solid (523 g, 47%). Mp
1
(DSC): 166 °C; H NMR (500 MHz, CD OD) 8.00 (d, 4 H,
3
J = 8.0 Hz), 7.87 (d, 1 H, J = 8.5 Hz), 7.70 (d, 1 H, J = 1.5 Hz),
7.60 (d, 1 H, J = 5.5 Hz), 7.33 (d, 1 H, J = 5.5 Hz), 7.27 (d,
4 H, J = 8.0 Hz), 7.13 (dd, 1 H, J = 1.5 Hz, J = 8.5 Hz), 6.83
1
2
(dd, 1 H, J = 2.5 Hz, J = 9.0 Hz), 6.77 (d, 1 H, J = 2.5 Hz),
1
2
(
2.5 L) to pH 13. The layers were separated, and the aqueous
6.71 (d, 1 H, J = 9.0 Hz), 5.86 (s, 1 H), 4.59 (dd, 1 H, J = 6.0 Hz,
1
layer was extracted with EtOAc (2 × 3.0 L). The combined
organic layers were concentrated, and the residue was passed
through a silica gel plug using 10% MeOH/EtOAc as eluent.
The fractions containing product were combined and solvent-
swapped to acetonitrile (11.5 L). The resulting solution was
treated with activated charcoal (95 g) and heated at reflux for
J2 = 11.0 Hz), 4.46 (s, 2 H), 3.81 (t, 4 H, J = 5.0 Hz), 3.74 (dd,
1 H, J = 6.0 Hz, J = 12.0 Hz), 3.43 (t, 1 H, J = 12.0 Hz), 3.12
(t, 4 H, J = 5.0 Hz), 2.98 (s, 3 H), 2.39 (s, 6 H); C NMR (125
1
2
13
MHz, CD OD) 171.6, 167.4, 152.1, 145.5, 141.7, 140.5, 138.4,
3
131.2, 131.1, 130.5, 130.2, 128.6, 123.4, 126.9, 126.1, 125.4, 124.8,
124.0, 117.5, 113.4, 74.8, 67.9, 59.6, 56.8, 50.3, 43.5, 43.4, 21.7;
HRMS calculated for C H N OS (free base + H): 365.1688,
4
0 min. The suspension was cooled to 40 °C and filtered
through a Celite pad. The Celite pad was rinsed with acetonitrile
2 × 500 mL), and the combined filtrates were concentrated to
22
25
2
found: 365.1695; HPLC 95.3%; 93.3% ee.
(
(+)-4-(4-(Benzothiophen-5-yl)-2-methyl-1,2,3,4-tetra-
hydroisoquinolin-7-yl)morpholine (18). A mixture of 17
(825 g, 1.10 mol), acetone (8.25 L), and water (10.3 L) was
stirred for 10 min, and a solution of Na CO (700 g, 6.60 mol)
afford the desired product 9 as a yellow solid (360 g, 66% yield).
HPLC 95.4%. Spectroscopic analysis was in agreement with that
obtained via the coupling of 7 and 8.
2
3
7
-Amino-2-methyl-1,2-dihydroisoquinolin-3(4H)-one
15). A 500-mL Parr bottle was charged with 14 (7.4 g,
6 mmol), Pd/C (10%, 740 mg), EtOAc (74 mL), and EtOH
74 mL) under nitrogen. The mixture was purged with nitrogen
in water (4.0 L) was added. The resulting suspension was stirred at
ambient temperature for 75 min and filtered. The filter cake was
rinsed with water (2 × 2 L) and dried under vacuum (>30 in Hg)
(
3
(
to afford the desired product 18 as a white solid (394 g, 102%
1
and hydrogen sequentially and agitated under 20 psi of hydro-
gen for 2 h. The reaction was cooled to ambient temperature
and filtered through a Celite pad. The filtrate was concentrated
theory). Mp (DSC): 145 °C; H NMR (500 MHz, CDCl )
3
7.82 (d, 1 H, J = 8.0 Hz), 7.68 (d, 1 H, J = 2.0 Hz), 7.44 (d,
1 H, J = 5.5 Hz), 7.29 (d, 1 H, J = 5.5 Hz), 7.21 (dd, 1 H, J =
1
to afford the desired product 15 as a white solid (5.6 g, 89%
1.5 Hz, J = 8.5 Hz), 6.82 (d, 1 H, J = 8.5 Hz), 6.70 (dd, 1 H,
2
1
yield). H NMR (300 MHz, CDCl ) 6.93 (d, 1 H, J = 8.1 Hz),
J = 2.5 Hz, J = 8.5 Hz), 6.66 (d, 1 H, J = 2.5 Hz), 4.37 (dd,
3
1
2
6
.59 (dd, 1 H, J = 2.4 Hz, J = 8.1 Hz), 6.48 (d, 1 H, J = 2.4 Hz),
1 H, J = 6.0 Hz, J = 8.0 Hz), 3.88 (t, 4 H, J = 5.0 Hz), 3.77
1
2
1 2
13
4.39 (s, 2 H), 3.66 (bs, 1 H), 3.51 (s, 2 H), 3.09 (s, 3 H); C
(d, 1 H, J = 14.5 Hz), 3.67 (d, 1 H, J = 14.5 Hz), 3.16 (t, 4 H,
J = 5.0 Hz), 3.09 (dd, 1 H, J = 5.5 Hz, J = 11.5 Hz), 2.64 (dd,
NMR (75 MHz, CDCl ) 169.8, 145.4, 132.1, 128.6, 122.4, 115.1,
3
1
2
+
13
1
11.6, 53.4, 36.4, 34.8; MS m/z 177.10 [M + H] .
-Methyl-7-morpholino-1,2-dihydroisoquinolin-
(4H)-one (10) from 15. A mixture of 15 (2.50 g, 14.2 mmol),
1 H, J = 8.5 Hz, J = 11.5 Hz), 2.47 (s, 3 H); C NMR (125
1 2
2
MHz, CDCl ) 149.5, 141.2, 139.8, 137.9, 135.9, 130.2, 129.0,
3
3
126.5, 125.7, 123.9, 123.8, 122.3, 114.6, 112.7, 66.9, 62.3, 58.8,
49.5, 46.0, 45.1; HRMS calculated for C H N OS (M + H):
1
6 (6.48 g, 15.6 mmol), K CO (4.70 g, 34.1 mmol), and acetone
2 3
22 25
2
(50 mL) was heated at reflux for 7 h, at which point HPLC
365.1688, found: 365.1697; HPLC 97.1%; 94.3% ee.
5
05
dx.doi.org/10.1021/op3000064 | Org. Process Res. Dev. 2012, 16, 499−506