phenoxypropanolamine (14) 1.85 kg (11.1 mol) and dichloro-
methane (40 L) at 10-20 °C. To the mixture was added
dropwise the solution of acid chloride at 23 °C. After the
reaction mixture was stirred for 0.5 h, the organic layer was
separated and washed with 1.2 M HClaq (10 L), 5% NaHCO3aq
(10 L), and 20% NaClaq (10 L). The organic layer was
concentrated under reduced pressure to give an oily residue.
To change the solvent, i-PrOH was added to the residue and
concentrated (30 L + 20 L). To the residue was then added
i-Pr2O (80 L) and the solution was stirred at 20 °C for 19 h for
crystallization. The slurry was centrifuged and washed with
i-Pr2O (10 L) to give wet crystals (6.68 kg). Drying at 40 °C
under reduced pressure gave (S)-N-(2-hydroxy-3-phenoxyprop-
yl)-2-(4-nitrophenyl)acetamide (15): 2712 g (8.21 mol, 74.2%
yield) as a white solid. 1H NMR (DMSO-d6, 400 MHz): ¤ 3.13-
3.19 (1H, m), 3.26-3.33 (1H, m), 3.63 (2H, s) 3.78-3.89 (3H,
m), 5.24 (1H, d, J = 4.4 Hz), 6.85-6.94 (3H, m), 7.24-7.29
(2H, m), 7.54 (2H, d, J = 8.8 Hz), 8.13-8.17 (2H, m), 8.29 (1H,
t, J = 6.0 Hz). 13C NMR (DMSO-d6, 100 MHz): ¤ 42.42, 42.73,
68.28, 70.46, 114.94, 121.06, 123.82, 129.96, 130.86, 145.17,
146.72, 159.04, 169.80. MS (m/z) = 331 (M+ + 1) Anal.
Calcd for C17H18N2O5¢0.1 H2O: C, 61.48; H, 5.52; N, 8.43%.
(S)-1-{[2-(4-Aminophenyl)ethyl]amino}-3-phenoxypro-
pan-2-ol Monohydrochloride (2). An autoclave was purged
with nitrogen gas and charged with (S)-1-{[2-(4-nitrophenyl)-
ethyl]amino}-3-phenoxypropan-2-ol monohydrochloride (7a)
1.45 kg (4.11 mol), EtOH (14 L), water (0.70 L), and 10% Pd-
C (54.2% wet) (0.32 kg). The reactor was purged with hydro-
gen (1.0 MPa) and the suspension was stirred under 0.1-1.0
MPa of hydrogen pressure at 17-42 °C until reaction comple-
tion. The reaction mixture was filtered and washed with 95%
EtOHaq (5.0 L), and the filtrate was concentrated under reduced
pressure. The residue was dissolved in i-PrOH (22 L) and the
solution was concentrated under reduced pressure (2 times).
The residue was then dissolved in i-PrOH (22 L) at 45 °C and
cooled to 25 °C. The resulting mixture was charged with i-Pr2O
(22 L) to crystallize. The slurry was cooled to 20 °C and stirred
for 18 h. After filtration, the crystals were washed with i-Pr2O
(20 L). The crystals were dried under reduced pressure at 40 °C
to give (S)-1-{[2-(4-aminophenyl)ethyl]amino}-3-phenoxypro-
pan-2-ol monohydrochloride (2): 1.24 kg (3.84 mol, 93.2%
yield) as white crystals. 1H NMR (DMSO-d6, 400 MHz): ¤
2.78-2.87 (2H, m), 2.98-3.09 (3H, m), 3.18 (1H, d, J =
11.6 Hz), 3.93-4.01 (2H, m), 4.21-4.26 (1H, m), 5.09 (2H, brs),
5.93 (1H, d, J = 4.2 Hz), 6.53 (2H, d, J = 8.0 Hz), 6.90 (2H, d,
J = 8.8 Hz), 6.94-6.97 (3H, m), 7.28-7.33 (2H, m), 8.87 (1H,
brs), 9.11 (1H, brs). 13C NMR (DMSO-d6, 100 MHz): ¤ 31.17,
49.28, 50.01, 65.41, 70.15, 114.69, 115.02, 121.37, 124.45,
129.56, 130.06, 147.71, 158.75. MS (m/z) = 287 (M+ + 1),
Anal. Calcd for C17H22N2O2¢HCl: C, 63.25; H, 7.18; N,
8.68; Cl, 10.98%. Found: C, 62.87; H, 7.12; N, 8.68; Cl,
20
Found: C, 61.31; H, 5.42; N, 8.40%. Mp: 105-106 °C, ½ꢀꢀD
3.92 (c 0.101, MeOH), HPLC (YMC-Pack ODS-A, 150 © 4.6
mm I.D. S-5 ¯m, 12 nm, 0.05 M KH2PO4aq/MeCN = 75/25,
flow rate 1.0 mL min¹1, 254 nm): tR = 37 min. 98.1%.
(S)-1-{[2-(4-Nitrophenyl)ethyl]amino}-3-phenoxypropan-
2-ol Monohydrochloride (7a). Under nitrogen atmosphere, a
mixture of (S)-N-(2-hydroxy-3-phenoxypropyl)-2-(4-nitrophen-
yl)acetamide (15) 1.80 kg (5.45 mol) and THF (36 L) was
cooled to ¹15 °C. 1 M BH3-THF 12.0 L (2.20 mol) was added
to this mixture in a dropwise fashion over 1 h at ¹12 °C. The
mixture was then warmed to 65 °C and stirred for 2 h. After
monitoring the reaction, the mixture was cooled again to
¹8 °C. Then keeping under 20 °C, MeOH (4 L) and 3 M HClaq
24 L (13.2 mol) were added to the reaction mixtures that were
warmed and stirred for 2 h at 65 °C. After cooling to 25 °C, 4 M
KOHaq 18 L (13.2 mol) and EtOAc (50 L) was added to the
mixture. The organic layer was separated and washed with
water (25 L) and 2% NaClaq (25 L © 2) and then concentrated
under reduced pressure. The residue in i-PrOH (18 L) was
warmed to 45 °C, and then i-Pr2O (18 L) was added to the clear
solution. The mixture was cooled to 30 °C, and concentrated
HCl (0.48 L) was added. The resulting slurry was filtered and
washed with i-Pr2O (5 L). Drying at 50 °C in vacuo gave (S)-1-
{[2-(4-nitrophenyl)ethyl]amino}-3-phenoxypropan-2-ol mono-
hydrochloride (7a): 1.49 kg (4.22 mol, 77.6% yield) as white
crystals. 1H NMR (DMSO-d6, 400 MHz): ¤ 3.00-3.31 (6H, m),
3.94-4.02 (2H, m), 4.25 (1H, brs), 5.96 (1H, s), 6.94-6.97 (3H,
m), 7.28-7.33 (2H, m), 7.58 (2H, d, J = 8.4 Hz), 8.22 (2H, d,
J = 8.8 Hz), 9.02 (1H, brs), 9.32 (1H, brs). 13C NMR (DMSO-
d6, 100 MHz): ¤ 31.65, 47.88, 50.10, 65.39, 70.13, 115.01,
121.39, 124.34, 130.06, 130.64, 146.09, 146.99, 158.74. MS
(m/z) = 317 (M+ + 1) Anal. Calcd for C17H20N2O4¢HCl: C,
57.87; H, 6.00; N, 7.94; Cl, 10.05%. Found: C, 57.70; H, 5.99;
20
11.18%. Mp: 129-131 °C. ½ꢀꢀD ¹20.4 (c 0.108, MeOH),
HPLC (YMC-Pack ODS-A, 150 © 4.6 mm I.D. S-5 ¯m, 12 nm,
0.05 M KH2PO4aq/MeCN 75/25, flow rate 1.0 mL min¹1, 254
nm): tR = 4.1 min. 99.3%.
(S)-2-(2-Phenylamino-1,3-thiazol-4-yl)-4¤-{2-[(2-hydroxy-
3-phenoxypropyl)amino]ethyl}acetanilide (1). A mixture of
2-phenylamino-1,3-thiazol-4-acetic acid (3) 0.87 kg (3.71 mol),
(S)-1-{[2-(4-aminophenyl)ethyl]amino}-3-phenoxypropan-2-ol
monohydrochloride (2) 1.20 kg (3.71 mol), DMF (18 L), water
(12 L), and EDCI¢HCl 0.72 kg (3.76 mol) was stirred for 22 h
at 23-25 °C. After the mixture was diluted with water (20 L),
85% (w/w) phosphoric acid 3.43 kg (29.8 mol) was added to
the solution at 25-27 °C. The mixture was diluted with water
(18 L) and washed with EtOAc (36 L © 2). To the aqueous layer
was added EtOAc (54 L), and pH value was adjusted to 8.1 with
4 M KOHaq (approximately 15 L, 60 mol). The mixture was
separated and extracted with EtOAc (24 L) from the aqueous
layer. The collected organic layers were washed with water
(36 L) and concentrated under reduced pressure. The residue
was dissolved in EtOH (32.8 L) and water (9 L) under heating.
The solution was filtered and washed with 50% EtOHaq (3.0 L)
and then cooled to 15 °C for crystallization and stirred for 18 h.
The resulting slurry was filtered and washed with 77% EtOHaq
(6.5 L © 2), and the crystals were dried under reduced pressure
at 40 °C to provide (S)-2-(2-phenylamino-1,3-thiazol-4-yl)-4¤-
{2-[(2-hydroxy-3-phenoxypropyl)amino]ethyl}acetanilide (1):
1.46 kg (2.90 mol, 78.1% yield). 1H NMR (DMSO-d6, 400
MHz): ¤ 1.73 (1H, brs), 2.57-2.75 (6H, m), 3.62 (2H, s), 3.81-
3.95 (3H, m), 4.97 (1H, s), 6.64 (1H, s), 6.89-6.93 (4H, m), 7.15
(2H, d, J = 8.4 Hz), 7.24-7.28 (4H, m), 7.52 (2H, d, J = 8.4
20
N, 7.84; Cl, 10.08%. Mp: 126-129 °C. ½ꢀꢀD ¹20.7 (c 0.101,
MeOH), HPLC (YMC-Pack ODS-A, 150 © 4.6 mm I.D. S-
5 ¯m, 12 nm, 0.05 M KH2PO4aq/MeCN = 75/25, flow rate
1.0 mL min¹1, 254 nm): tR = 14 min. 98.7%.
© 2014 The Chemical Society of Japan