+
acidified with 1 N HCl (aqueous) to produce a white solid
, which was collected by filtration and dried (6.74 g, 73%).
6 3 3
278 (M ), 277, 144. Anal. Calcd for C10H F NO S: C, 43.33;
7
H, 2.18; N, 5.05. Found: C, 43.40; H, 2.42; N, 4.88.
4-Bromoisoquinoline-N-oxide (13). 4-Bromoisoquinoline
(12) (7.2 kg, 34.6 mol) and Na
1
H NMR (DMSO-d
d, 2H), 7.76 (s, 1H), 7.82 (t, 1H), 8.01 (t, 1H), 8.61 (broad
s), 8.72 (d, 1H), 8.95 (d, 1H), 11.59 (s, 1H). MS 321.3 m/z
M + H).
4,7′]Bis-isoquinolinyl-1-yl-(4-tert-butyl-phenyl)-
6
): δ 1.36 (s, 9H), 7.50 (d, 2H), 7.62
(
2 4 2
WO ‚2 H O (360 g, 1.1 mol)
were charged into a reactor. AcOH (72 L) and 30% H
2
O
2
(
(8.64 L, 76 mol) were added. The reaction mixture was
heated to 80 °C (external temperature) and stirred for 3 h at
this temperature. The reaction was checked by HPLC
(product/starting material, 60:24). Further H
6.4 mol) was added. The mixture was stirred for another 2
h (62:22 ) product/starting material). Another portion H
[
amine (2). a) To a solution of (4- tert-butyl-aniline)-
isoquinolin-1-yl boronic acid (7) (8.9 g, 27.8 mmol),
isoquinolin-7-yl triflate (8) (7.0 g, 25.3 mmol), and dichloro-
bis(triphenylphosphine) palladium(II) (1.75 g, 2.5 mmol) in
2 2
O (720 mL,
2 2
O
DMF (500 mL) was slowly added a solution of 1 M K
(
[
2
CO
65 mL, 65 mmol) at room temperature with vigorous stirring
some yellowish solid precipitated from the solution]. After
3
(720 mL, 6.4 mol) was added, and the reaction mixture was
stirred at 80 °C (external temperature) for 15 h (63:19 )
product: starting material). Further Na
2
WO (120 g, 0.364
4
.
stirring at 100 °C for 2 h, the black solution was concentrated
mol) 2 H
2
O was added, followed by H O (720 mL, 6.4
2 2
to remove off most of DMF. The residue was diluted with
mol). After another 3 h the reaction was checked by HPLC
CH
then further purified by flash chromatography with CH
5% and EtOAc 5% to give a light yellow solid (6.52 g).
2
Cl
2
(50 mL) and filtered through a short silica gel plug,
again (64:19 ) product/starting material) and another portion
H O (720 mL, 6.4 mol) was added. After 3 h further heating
2 2
at 80 °C, the reaction was again checked by HPLC (67:20).
A part of HOAc (55.5 L) was distilled off. Then at 60 °C
2
Cl
2
9
The product was further purified by reverse phase HPLC to
yield pure product 2 (6.2 g, 60.9% yield) as free base.
H
2
O (47 L) was added, followed by 30% NaOH (aq) (35
L). The mixture was seeded and stirred at 10 °C for 20 h.
The suspension was filtered and washed with H O (24 L).
(
b) A suspension of 1-chloro-[4,7′]bis-isoquinolinyl (10)
5.0 g, 17.2 mmol), 4-tert-butylaniline (4) (4.0 mL, 1.5
equiv), and 4.0 M HCl/dioxane (6.45 mL/1.5 equiv) in EtOH
100 mL) was stirred for 20 h in a sealed tube at 80 °C. The
(
2
The crude product was crystallized from toluene (60 L) to
yield purified product 13 (4.45 kg; HPLC purity 98.5%).
From the mother liquor a further 652 g of product (98.5%
(
reaction mixture was cooled and concentrated to a yellow
oil. The oil was dissolved in EtOAc (100 mL) and neutralized
with 3 N NaOH. The organic phase was separated, dried
HPLC purity) could be isolated (total yield: 65.8%).
1
H NMR (d
6
-DMSO, 400 MHz): δ 7.75-7.85 (m, 2H),
+
4
(MgSO ), concentrated, and purified on silica gel chroma-
7.95-8.07 (m, 2H), 8.68 (s, 1H), 9.08 (s,1H). MS: 226 (M ),
224 (M ), 209, 207.
+
tography (9:1 hexane/EtOAc and then 4:1 hexane/EtOAc).
The product 2 was isolated as a yellow solid (4.5 g; 65%);
4-Bromo-1-chloroisoquinoline (9). The suspension of 13
(5.1 kg, 22.8 mol) in toluene (38 L) and DMF (13 L) was
cooled to 5 °C. Phosphorus oxychloride (5.095 kg, 33.2 mol)
was added within 1 h. After the addition was complete, the
temperature was raised to 20 °C. After 1 h the reaction
mp 217-219 °C.
1
H NMR (DMSO-d ) δ 1.31 (s, 9H), 7.37 (d, 2H), 7.73
6
(m, 2H), 7.80 (m, 2H), 7.92 (m, 2H), 8.04 (s, 1H), 8.09 (d,
1
9
H), 8.24 (s, 1H), 8.57 (d, 1H), 8.67 (d, 1H), 9.31 (s, 1H),
.40 (s, 1H). MS 404.21 m/z (M + H).
2
mixture was added to H O (55 L) at 45 °C. Then NaOH
Trifluoromethanesulfonic Acid Isoquinolin-7-yl ester
(30%, 13 L) was added, and the reaction mixture (pH ) 7)
(8). To a suspension of 7-hydroxyisoquinoline (11) (11.7 kg,
was filtered and the filter residue washed with toluene (10
80.6 mol) in EtOAc (157 L) and pyridine (31.9 kg, 403 mol)
2
L). The layers were separated, and the H O phase was
at 0 °C was added trifluormethansulfonic acid anhydride (25
kg, 88.6 mol) within 95 min, at such a rate that the
temperature was maintained between 0 and 5 °C. The
temperature was raised to 22 °C within 40 min and the batch
extracted with toluene (30 L). The combined organic layers
were washed with brine (2 × 30 L), and the aqueous phase
was reextracted with toluene (30 L). The toluene layer was
4
dried over MgSO , filtered, and evaporated to dryness.
stirred for 19 h. To the reaction mixture was added NaHCO
8% (aq), 100 L), and the phases were separated. The organic
phase was washed with NaHCO (8% (aq), 100 L), and H
100 L). The aqueous layers were re-extracted with EtOAc
100 L). The combined organic layers were dried over
(11 kg), filtered, and evaporated to dryness to yield
crude product (27.3 kg). This crude product was distilled as
a solution in 25 kg of Triton X over a thin film evaporator
at <1mbar (120 °C), to yield 8 as an almost colorless oil
3
Methanol (18 L) was added to the residue and then
evaporated again to dryness. Then methanol (26 L) was
added and the mixture heated to reflux. The mixture was
cooled to 0 °C within 4-6 h, stirred over the weekend at 0
°C, filtered, and washed with methanol (2 L). This product
was dried at 45 °C to yield 9 (2.846 kg; 51.5%; 98.5% HPLC
purity).
(
3
2
O
(
(
MgSO
4
1H NMR (CDCl
7.84-7.88 (m, 1H), 8.16-8.18 (m, 1H), 8.32-8.34 (m, 1H),
3
, 400 MHz): δ 7.72-7.75 (m, 1H),
1
3
(
10.8 kg; 48.2% yield; HPLC > 98 area %).
8.46 (s, 1H). C NMR (CDCl
3
, 500 MHz): δ 118.6; 126.2;
1
3
H NMR (CDCl , 400 MHz): δ 7.57 (dd, J ) 2.5; 8.9;
126.5; 127.4; 129.0; 132.0; 135.8; 142.4; 150.6. MS: 246
+
+
+
1
9
H), 7.70 (d, J ) 5.9; 1H), 7.88 (d, J ) 2.4; 1H), 7.92 (d,
9 5
(M ), 244 (M ), 242 (M ). Anal. Calcd for C H NClBr: C,
1
3
.0; 1H), 8.60 (d, J ) 5.9; 1H), 9.29 (s, 1H). C NMR
, 500 MHz): δ (114.9; 117.4; 120.0; 122.5); 119.1;
20.1; 124.3; 128.4; 129.6; 134.7; 144.4; 147.4; 152.4. MS:
44.58; H, 2.08; N, 5.78. Found: C, 44.74; H, 2.41; N, 5.71.
1-Chloro-[4,7′]bis-isoquinolinyl (10). A solution of 9
(7.05 kg, 29 mol) in THF (80.8 L) was cooled to - 70 °C.
(CDCl
3
1
Vol. 10, No. 1, 2006 / Organic Process Research & Development
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