PAPER
Enantioselective Synthesis of Safinamide
1755
13C NMR (50 MHz, CDCl3): δC = 165.4 (C), 160.5 (C), 158.0 (C),
139.6 (C), 133.5 (CH), 130.2 (CH), 128.7 (CH, 2 C), 122.7 (CH),
114.8 (CH, 2 C), 113.9 (CH), 69.1 (CH2), 64.9 (CH2).
the aqueous layer was acidified with 2 M HCl to pH 3–4. The or-
ganic layer was separated, washed successively with H2O (2 × 15
mL) and brine (2 × 10 mL), and concentrated under reduced pres-
sure to give a colorless semi-solid; yield: 1.1 g (85%); [α]D22 –20.4
(c 1.1, CHCl3).
MS: m/z = 255 [M + Na]+.
1-Fluoro-3-{[4-(iodomethyl)phenoxy]methyl}benzene (10)
I2 (3.27 g, 12.9 mmol) was added to a stirred solution of Ph3P (2.82
g, 10.8 mmol) and imidazole (0.73 g, 10.76 mmol) in anhyd CH2Cl2
(20 mL) at 0 °C, and the solution was stirred for 5 min. A solution
of alcohol 9 (2.5 g, 10.8 mmol) in CH2Cl2 (5 mL) was added drop-
wise over 10 min, and the mixture was then stirred for 1 h with ex-
clusion of light. When the reaction was complete (TLC), the
reaction was quenched with aq 1 M Na2S2O3 (15 mL), and the mix-
ture was extracted with CH2Cl2 (2 × 20 mL). The combined organic
layers were washed with brine (2 × 10), dried (Na2SO4), filtered,
and concentrated under reduced pressure. Purification of the crude
residue by column chromatography [silica gel, PE–EtOAc, (95:5)]
gave a colorless oil; yield: 3.4 g (93%).
IR (CHCl3): 3398, 3095, 1718, 1612, 1591, 1543, 1512, 1489, 1457,
1371, 1303, 1251, 1163, 1059, 900, 852, 831, 778, 684 cm–1.
1H NMR (200 MHz, CDCl3): δH = 1.44 (d, J = 7.3 Hz, 3 H), 4.23 (d,
J = 15.6 Hz, 1 H), 4.64 (d, J = 15.6 Hz, 1 H), 4.82–4.90 (q, J = 7.4
Hz, 1 H), 4.92 (s, 2 H), 6.68 (d, J = 8.6 Hz, 2 H), 6.89–7.01 (m, 2
H), 7.07–7.13 (m, 3 H), 7.18–7.33 (m, 2 H), 7.43–7.55 (m, 3 H),
8.81 (br s, 1 H).
13C NMR (50 MHz, CDCl3): δC = 176.5 (CO), 165.0 (C), 158.0 (C),
147.4 (C), 139.4 (C), 134.1 (C), 133.2 (CH), 131.4 (CH), 130.3
(CH), 129.9 (CH, 2 C), 128.4 (C), 124.1 (CH), 122.6 (CH), 115.0
(CH), 114.6 (CH, 2 C), 114.3 (CH), 113.8 (CH) 69.1 (CH2), 56.1
(CH), 49.0 (CH2), 16.8 (CH3).
MS: m/z = 511 [M + Na]+.
IR (CHCl3): 3503, 3033, 2925, 2089, 1607, 1509, 1488, 1381, 1301,
1250, 1155, 1079, 944, 869, 776, 684 cm–1.
1H NMR (200 MHz, CDCl3): δH = 4.47 (s, 2 H), 5.04 (s, 2 H), 6.85–
6.91 (m, 2 H), 6.96–7.02 (m, 1 H), 7.05–7.12 (m, 1 H), 7.16–7.20
(m, 1 H), 7.29–7.40 (m, 3 H).
13C NMR (50 MHz, CDCl3): δC = 165.4 (C), 160.5 (C), 158.1 (C),
131.9 (C), 130.2 (CH), 130.1 (CH, 2 C), 122.7 (CH), 115.1 (CH, 2
C), 114.7 (CH), 113.9 (CH), 69.2 (CH2), 6.33 (CH2).
N2-{4-[(3-Fluorobenzyl)oxy]benzyl}-N2-[(2-nitrophenyl)sulfo-
nyl]-L-alaninamide [(S)-13]
EtO2CCl (0.21 mL, 2.2 mmol) was added to a solution of acid (S)-
12 (1 g, 2.04 mmol) and Et3N (0.34 mL, 2.4 mmol) in anhyd THF
(20 mL) at 0 °C under N2. After 1 h, 25% aq NH4OH (1.4 mL, 10.2
mmol) was added and the mixture was stirred at r.t. for 16 h. When
the reaction was complete, K2CO3 (0.29 g, 2.1 mmol) was added.
The mixture was filtered, then washed with EtOAc (2 × 15 mL), and
concentrated under reduced pressure. The resulting crude product
was purified by column chromatography [silica gel, PE–EtOAc
N-{4-[(3-Fluorobenzyl)oxy]benzyl}-N-[(1S)-2-hydroxy-1-meth-
ylethyl]-2-nitrobenzenesulfonamide [(S)-11]
A solution of the iodide compound 10 (1.84 g, 5.4 mmol) in MeCN
was added slowly to a stirred solution of sulfonamide (S)-6 (1 g, 3.8
mmol) and K2CO3 (2.65 g, 19.2 mmol) in anhyd MeCN (25 mL),
and the mixture was heated at 70 °C for 72 h. When the reaction was
complete (TLC), H2O (20 mL) was added and the mixture was ex-
tracted with EtOAc (3 × 15 mL). The organic layers were combined,
washed with brine (2 × 10), dried (Na2SO4), filtered, and concen-
trated under reduced pressure. Purification of the crude residue by
column chromatography [silica gel, PE–EtOAc (80:20)] gave a col-
orless oil; yield: 1.46 g (80%); [α]D22 +5.4 (c 1.5, CHCl3).
22
(50:50)] to give a colorless oil; yield: 0.9 g (91%); [α]D –32.1 (c
1.2, CHCl3).
IR (CHCl3): 3472, 1961, 1611, 1592, 1542, 1511, 1449, 1371, 1304,
1243, 1163, 1060, 1029, 895, 852, 684 cm–1.
1H NMR (200 MHz, CDCl3): δH = 1.43 (d, J = 7.1 Hz, 3 H), 4.44 (d,
J = 15.4 Hz, 1 H), 4.59 (d, J = 15.5 Hz, 1 H), 4.60–4.71 (q, J = 7.0
Hz, 1 H), 5.01 (s, 2 H), 5.50 (br s, 1 H), 6.31 (br s, 1 H), 6.78 (d, J =
8.71 Hz, 2 H), 6.98–7.11 (m, 2 H), 7.15–7.22 (m, 3 H), 7.31–7.45
(m, 2 H), 7.59–7.64 (m, 3 H).
13C NMR (50 MHz, CDCl3): δC = 172.3 (CO), 165.5 (C), 158.2 (C),
147.5 (C), 139.6 (C), 139.4 (C), 133.6 (CH), 131.7 (CH), 130.5
(CH, 2 C), 130.3 (CH), 128.1 (C), 124.2 (CH), 122.7 (CH), 115.1
(CH), 114.7 (CH, 2 C), 114.4 (CH), 113.9 (CH), 69.0 (CH2), 55.7
(CH), 48.3 (CH2), 14.9 (CH3).
IR (CHCl3): 3445, 3020, 2928, 2400, 1613, 1544, 1512, 1453, 1371,
1216, 1162, 1029, 852, 668 cm–1.
1H NMR (200 MHz, CDCl3): δH = 1.07 (d, J = 6.9 Hz, 3 H), 1.91 (t,
J = 5.2 Hz, 1 H), 3.41–3.53 (m, 2 H), 4.05–4.22 (m, 1 H), 4.37–4.57
(m, 2 H), 5.02 (m, 2 H), 6.87 (d, J = 8.53 Hz, 2 H), 6.97–7.12 (m, 2
H), 7.20 (d, J = 7.2 Hz, 2 H), 7.32 (d, J = 8.7 Hz, 2 H), 7.47–7.67
(m, 3 H), 7.89 (d, J = 8.09 Hz, 1 H).
MS: m/z = 510 [M + Na]+.
N2-{4-[(3-Fluorobenzyl)oxy]benzyl}-L-alaninamide [(S)-14]
PhSH (0.2 mL, 1.9 mmol) was added to a solution of sulfonamide
(S)-13 (0.8 g, 1.64 mmol) and K2CO3 (0.56 g, 4.9 mmol) in anhyd
DMF (10 mL), and the mixture was vigorously stirred for 6 h. When
the reaction was complete (TLC), H2O (10 mL) was added and the
mixture was extracted with EtOAc (2 × 20 mL). The organic layers
were combined, washed with brine (2 × 10), dried (Na2SO4), fil-
tered, and concentrated under reduced pressure. The crude residue
was purified by column chromatography [silica gel, PE–EtOAc
(60:40)] to give a colorless solid; yield: 0.43 g (86%); mp 207–
09 °C; [α]D22 +3.89 (c 1.55, CHCl3).
13C NMR (50 MHz, CDCl3): δC = 165.5 (C), 160.6 (C), 158.4 (C),
147.7 (C), 139.6 (C), 134.1 (C), 133.4 (CH), 131.6 (CH), 131.4
(CH), 130.3 (CH), 129.7 (CH, 2 C), 124.1 (CH), 122.8 (CH), 115.1
(CH), 114. 9 (CH, 2 C), 114.0 (CH), 69.2 (CH2), 64.3 (CH2), 56.2
(CH), 46.9 (CH2), 15.4 (CH3).
MS: m/z = 497 [M + Na]+.
N-{4-[(3-Fluorobenzyl)oxy]benzyl}-N-[(2-nitrophenyl)sulfo-
nyl]-L-alanine [(S)-12]
A mixture of sulfonamide (S)-11 (1.25 g, 2.6 mmol), TEMPO
(0.028 g, 0.18 mmol), MeCN (20 mL), and sodium phosphate buffer
(16 mL, 0.67 M, pH 6.7) was heated to 35 °C. A solution of NaClO3
(0.47 g) in H2O (2 mL) and 4–6% bleach (0.09 mL) diluted in H2O
(1 mL) were added simultaneously over 1 h. The mixture was stirred
at 35 °C until the reaction was complete (3 h, TLC), then cooled to
r.t. H2O (30 mL) was added, and the pH was adjusted to 8 with 2 M
aq NaOH. The reaction was quenched by pouring the mixture into
ice-cold 1 M aq Na2SO3 maintained at <20 °C. The mixture was
then stirred for 30 min at r.t., EtOAc (20 mL) was added, and stir-
ring was continued for an additional 15 min. The organic layer was
separated and discarded. Additional EtOAc (20 mL) was added and
IR (CHCl3): 3341, 2970, 2927, 2853, 1648, 1592, 1512, 1489, 1445,
1406, 1384, 1254, 1176, 1137, 1030, 953, 928, 829, 680 cm–1.
1H NMR (200 MHz, CDCl3): δH = 1.34 (d, J = 6.9 Hz, 3 H), 2.49 (br
s, 2 H), 3.19–3.30 (q, J = 6.8 Hz, 1 H), 3.71 (dd, J = 19.4, 3.9 Hz, 2
H), 5.05 (s, 2 H), 5.85 (br s, 1 H), 6.95 (d, J = 8.7 Hz, 2 H), 7.00–
7.06 (m, 1 H), 7.13–7.24 (m, 4 H), 7.29–7.40 (m, 1 H).
13C NMR (50 MHz, CDCl3): δC = 178.3 (CO), 165.4 (C), 157.7 (C),
139.6 (C), 132.1 (C), 130.2 (CH), 129.3 (CH, 2 C), 122.7 (CH),
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1751–1756