170.1, 147.6, 142.8, 130.6, 124.3, 43.6, 27.0; MS m/z 184.1
[M + H]+; HPLC >99%.
(s, 2 H), 3.58 (s, 2 H), 3.12 (s, 3 H); 13C NMR (75 MHz, CDCl3)
δ 169.5, 163.4, 160.2, 132.8, 132.7, 129.5, 129.3, 127.9, 127.8,
115.2, 115.2, 112.4, 112.1, 53.0, 36.2, 34.7; MS m/z 180.1 [M
+ H]+; HPLC 86.2%.
Large-Scale Preparation of 5a. To a stirred suspension of
4-bromophenylacetic acid (4a) (3.31 kg, 15.39 mol) in toluene
(6.6 L) was added DMF (0.11 kg, 1.54 mol). The suspension
was heated to 38 °C, at which point SOCl2 (2.2 kg, 18.47 mol)
was added over 1.5 h while maintaining the temperature at
35-40 °C. The reaction was stirred at 40 °C for 30 min, at
which point HPLC analysis indicated that the reaction was
complete.20 The reaction was cooled to ambient temperature
and added to a solution of methylamine (40 wt %, 5.98 kg,
76.96 mol) in water (6.6 kg) over 3 h at 0-25 °C. The reaction
was stirred at ambient temperature for 16 h, and the resulting
suspension was filtered. The filter cake was rinsed with water
(2 × 6.0 L) and dried under vacuum at 40 °C for 64 h to afford
3.31 kg of the desired product as a white solid [94% yield, >99%
purity (tR ) 8.1 min)].
General Procedure for the Preparation of 6 Analogues.
N-Methyl phenylacetamide (10 mmol) in Eaton’s reagent (10
mL) was treated with paraformaldehyde (12 mmol, 1.2 equiv)
and heated at 80 °C for 1 h. The solution was allowed to cool
to room temperature, diluted with water (10 mL), and basified
with 50% NaOH solution (8 mL) to pH ) 8. The resulting
solution was extracted with EtOAc (2 × 20 mL), and the
organic layer was dried over Na2SO4, filtered, and concentrated
to give the desired product as a yellow solid.
7-Bromo-2-methyl-1,4-dihydro-2 H-isoquinolin-3-one
(6a):21 yellow solid; yield: 95%; 1H NMR (300 MHz, CDCl3)
δ 7.38 (dd, 1 H, J1 ) 1.7 Hz, J2 ) 8.1 Hz), 7.33 (s, 1 H), 7.05
(d, 1 H, J ) 8.2 Hz), 4.46 (s, 2 H), 3.55 (s, 2 H), 3.10 (s, 3 H);
13C NMR (75 MHz, CDCl3) δ 168.6, 133.4, 131.7, 131.0, 129.4,
128.5, 120.6, 52.7, 36.8, 34.8; MS m/z 241.9 [M + H]+; HPLC
93.1%.
7-Chloro-2-methyl-1,4-dihydro-2 H-isoquinolin-3-one
(6b):21 yellow solid; yield: 98%; 1H NMR (300 MHz, CDCl3)
δ 7.22 (d, 1 H, J ) 8.1 Hz), 7.15 (s, 1 H), 7.07 (d, 1 H, J ) 8.1
Hz), 4.47 (s, 2 H), 3.56 (s, 2 H), 3.08 (s, 3 H); 13C NMR (75
MHz, CDCl3) δ 168.6, 133.0, 132.6, 131.1, 129.1, 128.1, 125.6,
52.8, 36.7, 34.7; MS m/z 196.0 [M + H]+; HPLC 95.2%.
7-Fluoro-2-methyl-1,4-dihydro-2 H-isoquinolin-3-one (6c):
yellow solid; yield: 89%; 1H NMR (300 MHz, CDCl3) δ 7.12
(dd, 1 H, J1 ) 5.4 Hz, J2 ) 8.5 Hz), 6.98 (dt, 1 H, J1 ) 2.7 Hz,
J2 ) 8.7 Hz), 6.87 (dd, 1 H, J1 ) 2.4 Hz, J2 ) 8.8 Hz), 4.48
2-Methyl-1,4-dihydro-2 H-isoquinolin-3-one (6d):22 yellow
solid; yield: 96%; HPLC 85.0%. Spectral data were consistent
with those reported in the literature.
7-Nitro-2-methyl-1,4-dihydro-2 H-isoquinolin-3-one (6e):
yellow solid; yield: 98%; 1H NMR (300 MHz, CDCl3) δ 8.15
(d, 1 H, J ) 8.5 Hz), 8.07 (s, 1 H), 7.35 (d, 1 H, J ) 8.5 Hz),
4.58 (s, 2 H), 3.75 (s, 2 H), 3.15 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 167.6, 147.2, 140.2, 132.9, 128.8, 123.2, 120.9, 52.8,
37.5, 34.9; MS m/z 207.0 [M + H]+; HPLC >99%.
Large-Scale Preparation of 6a. To a stirred solution of
Eaton’s reagent (11.5 L) was added N-methyl-4-bromopheny-
lacetamide (5a) (2.30 kg, 10.08 mol) portionwise, causing a
mild exotherm from 19 to 31 °C. Paraformaldehyde (0.36 kg,
12.1 mol) was added, and the resulting reaction mixture was
heated to 80 °C over 30 min and stirred at 80 °C for 75 min,
at which point HPLC analysis indicated that the reaction was
complete. The reaction was cooled to 60 °C and quenched into
water (11.5 L) over 2 h at <50 °C. IPAc (9.2 L) was added,
followed by 50 wt % NaOH to adjust the pH to 8.0-8.5. The
layers were heated to 30-40 °C and separated, and the aqueous
layer was extracted with IPAc (9.2 L). The combined organic
layers were washed with brine (9.2 L), concentrated to a thick
suspension, and filtered. The solid was dried at 25 °C under
vacuum to afford 2.54 kg of the desired product as a yellow
solid [100% yield, 94.1% purity (tR ) 8.7 min)].
Acknowledgment
We are grateful to our colleagues, Dr. Bruce Sargent and
Dr. David Manning, for their support during this program. We
thank our colleagues in the analytical group for their invaluable
support in the method development and to the kilo lab team
members for assisting in the initial scale-up of this compound.
Note Added after ASAP: This paper was published on
the Web on November 17, 2009, with errors in the descrip-
tion of Eaton’s reagent and in the title of Scheme 1. The
corrected version was reposted on December 31, 2009.
Received for review September 28, 2009.
OP9002533
(19) Misra, V. S.; Husain, M. I. J. Indian Chem. Soc. 1959, 36, 270.
(20) IPC sample was prepared by quenching a sample of the reaction
mixture into aqueous methylamine solution.
(21) Molino, B. F.; Liu, S.; Guzzo, P. R.; Beck, J. P. U.S. Patent 7,541,357,
2009.
(22) Tamura, Y.; Uenishi, J.; Maeda, H.; Choi, H.; Ishibashi, H. Synthesis
1981, 7, 534.
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