Synthesis of Silodosin by Copper-Catalysed C–C Arylation
chromatography (toluene/EtOAc, 7:3) to give pure compound 9 as
a pale yellow oil. [α]3D2 = –32.46 (c = 1.050, MeOH). 1H NMR
(300 MHz, CDCl3): δ = 7.71 (d, J = 6 Hz, 2 H, 9 Hz, Bz), 7.54–
7.38 (m, 3 H, Bz), 7.30 (s, 1 H, CH), 7.25 (s, 1 H, CH), 7.05–6.88
(m, 4 H, Ph), 4.37 (q, J = 8.4 Hz, 2 H, CH2CF3), 4.20–3.91 (m, 5
H, CHN, CH2), 3.55–3.45 (m, 2 H, CH2), 3.21–2.94 (m, 1 H, CH2),
2.98 (t, J = 8.1 Hz, 2 H, CH2), 2.72 (J = 13.8, 6.6 Hz, 1 H, dd,
CH2), 1.46 (s, 9 H, Boc), 1.28 (d, J = 6.9 Hz, 3 H, CH3) ppm. 13C
NMR (CDCl3, 75 MHz; two Boc rotamers): δ = 168.7, 155.0,
154.5, 148.9, 146.8, 146.7, 146.4, 142.4, 136.3, 135.5, 134.4, 131.4,
131.3, 129.7, 128.6, 128.2 (2 C), 128.1 (2 C), 127.8, 124.9, 123.5,
123.3 (q, J = 276.9 Hz, 1 C), 121.0, 120.7, 116.5, 113.7, 113.3,
103.6, 84.7, 79.5, 67.6, 67.1 (q, J = 33.9 Hz, 1 C), 54.4, 52.8, 44.2,
40.1, 39.5, 28.9, 28.0 (3 C), 27.2, 26.9, 26.6, 18.6, 17.8 ppm. LC–MS
(ESI+): m/z = 624.15 [M + H]+, 646.18 [M + Na]+ (tR = 6.70 min).
C34H36F3N3O5 (623.67): calcd. C 65.48, H 5.82, N 6.74; found C
64.84, H 5.66, N 6.62.
CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.1, 128.3 (2 C),
127.5 (2 C), 73.1, 68.6, 60.9, 32.1 ppm.
Et3N (47.4 g, 0.469 mol) and DMAP [4-(dimethylamino)pyridine;
4.4 g, 0.036 mol] were added to a solution of the 1-benzyloxy-3-
propanol in toluene (420 mL). The mixture was cooled to 5 °C.
para-Toluenesulfonyl chloride (73.9 g, 0.387 mol) was then added
portionwise over 40 min, and stirring was continued overnight at
20 °C. The mixture was diluted with water (500 mL), the phases
were separated, and the aqueous phase was extracted with toluene
(2 ϫ 100 mL). The combined organic layers were dried with
Na2SO4, the solid was removed by filtration, and the filtrate was
concentrated to dryness to give a yellowish oil (120 g). This oil was
crystallised from isopropanol (120 mL) to give 3-benzyloxypropyl-
1-tosylate (11; 66.7 g, 0.208 mol, 47%) as a white solid, m.p. 33–
1
34 °C (ref. 33 °C). H NMR (300 MHz, CDCl3): δ = 7.78 (d, J =
8.4 Hz, 2 H, Ts), 7.35–7.22 (m, 7 H, Bn, Ts), 4.40 (s, 2 H, CH2),
4.17 (t, J = 6.3 Hz, 2 H, CH2), 3.50 (d, J = 6.3 Hz, 2 H, CH2), 2.42
(s, 3 H, CH3), 1.94 (p, J = 6.3 Hz, 2 H, CH2) ppm. 13C NMR
(75 MHz, CDCl3): δ = 144.7, 138.1, 133.1, 129.9, 128.4 (2 C), 127.9
(2 C), 127.6 (2 C), 127.5 (2 C), 73.1, 67.7, 65.7, 29.4, 21.6 ppm.
tert-Butyl [(2R)-1-(7-Cyanoindolin-5-yl)propan-2-yl]-{2-[2-(2,2,2-tri-
fluoroethoxy)phenoxy]ethyl}carbamate (10): Crude tert-butyl [(2R)-
1-(1-benzoyl-7-cyanoindolin-5-yl)propan-2-yl]-{2-[2-(2,2,2-tri-
fluoroethoxy)phenoxy]ethyl}carbamate 9 (40.0 g) was dissolved in
methanol (160 mL), and sodium methoxide (3.5 g, 0.065 mol) was
added. The mixture was stirred for 6 h at room temperature, then
water (20 mL) was added, and the mixture was stirred for 3 h at
40 °C. The mixture was then cooled to room temp., and H2O was
added. The acetonitrile was removed under reduced pressure, and
the aqueous phase was extracted with EtOAc (3ϫ 100 mL). The
combined organic layers were dried with Na2SO4, the solid was
removed by filtration, and the filtrate was concentrated to dryness
to give tert-butyl [(2R)-1-(7-cyanoindolin-5-yl)propan-2-yl]-{2-[2-
(2,2,2-trifluoroethoxy)phenoxy]ethyl}carbamate (10; 37.98 g) as a
brown oil. A sample (0.5 g) was purified by flash chromatography
(CH2Cl2/MeOH, 9:1) to give pure compound 10 as a pale yellow
tert-Butyl {(2R)-1-[1-(3-Benzyloxypropyl)-7-cyanoindolin-5-yl]-
propan-2-yl}{2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}carbamate
(12): A solution of tert-butyl [(2R)-1-(7-cyanoindolin-5-yl)propan-
2-yl]-{2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}carbamate
(37.98 g) in DMF (240 mL) was transferred by cannula to a stirred
suspension of NaH (2.4 g, 0.097 mol) in DMF (60 mL). The re-
sulting mixture was stirred for 60 min at 0 °C. 3-Benzyloxy-propyl-
1-tosylate (22.9 g, 0.071 mol) was then added portionwise, and the
resulting mixture was stirred for 3 h at room temp. The mixture
was then cooled to 0 °C, and quenched with H2O (20 mL), diluted
with H2O (500 mL), and extracted with methyl tert-butyl ether
(MTBE; 3 ϫ 200 mL). The combined organic layers were dried
with Na2SO4, the solid was removed by filtration, and the filtrate
was concentrated to dryness to give tert-butyl {(2R)-1-[1-(3-benzyl-
oxypropyl)-7-cyanoindolin-5-yl]propan-2-yl}{2-[2-(2,2,2-trifluoro-
ethoxy)phenoxy]ethyl}carbamate (12; 48 g) as an oil. 1H NMR
(300 MHz, CDCl3): δ = 7.39–7.25 (m, 5 H, Bn), 7.10–6.87 (m, 6
H, Ph, CH), 4.54 (s, 2 H, CH2), 4.38 (q, J = 8.3 Hz, 2 H, CH2CF3),
4.25–3.84 (m, 3 H, CHN, CH2), 3.76–3.59 (m, 4 H, CH2), 3.58–
3.35 (m, 4 H, CH2), 2.90 (t, J = 8.6 Hz, 2 H, CH2), 2.86–2.66 (m,
1 H, CH2), 2.55 (dd, J = 13.8, 6.6 Hz, 1 H, CH2), 1.99 (p, J =
6.5 Hz, 2 H, CH2), 1.45 (s, 9 H, Boc), 1.26 (d, J = 6.9 Hz, 3 H,
CH3) ppm. 13C NMR (CDCl3, 75 MHz; two Boc rotamers): δ =
155.6, 155.1, 151.8, 149.5, 147.4, 147.2, 138.5, 132.7, 131.4, 129.5,
128.6, 128.4 (2 C), 127.8, 127.7 (2 C), 127.6, 124.1, 123.6 (q, J =
277.2 Hz, 1 C), 121.5, 121.1, 119.6, 117.3, 114.3, 113.8, 87.6, 79.9,
73.2, 67.6, 67.7 (q, J = 24.7 Hz, 1 C), 55.0, 54.3, 53.3, 45.3, 43.9,
40.3, 39.8, 28.5 (3 C), 28.0, 27.4, 19.1, 18.3 ppm. LC–MS (ESI+):
m/z 668.20 [M + H]+ , 690.24 [M + Na]+ (tR = 25.61).
C37H44F3N3O5 (667.77): calcd. C 66.55, H 6.64, N 6.29; found C
65.88, H 6.49, N 6.14.
1
oil. [α]3D0 –55.74 (c = 0.04, MeOH). H NMR (300 MHz, CDCl3):
δ = 7.11–6.97 (m, 6 H, Ph, CH), 4.37 (q, J = 8.4 Hz, 2 H, CH2CF3),
4.19–3.98 (br. m, 3 H, CHN, CH2), 3.66 (t, J = 8.4 Hz, 2 H, CH2),
3.53–3.33 (br. m, 2 H, CH2), 3.01 (t, J = 8.5 Hz, 2 H, CH2), 2.81
(m, 1 H, CH2), 2.57 (dd, J = 13.8, 6.6 Hz, 1 H, CH2), 1.43 (s, 9 H,
Boc), 1.25 (d, J = 6.9 Hz, 3 H, CH3) ppm. 13C NMR (CDCl3,
75 MHz; two Boc rotamers): δ = 155.6, 155.1, 153.7, 149.5, 147.5,
147.2, 130.7, 130.0, 129.3, 124.1, 123.6 (q, J = 276.9 Hz, 1 C),
121.6, 121.2, 117.9, 117.2, 114.3, 113.8, 90.0, 68.0, 67.9 (q, J =
35.0 Hz, 1 C), 55.2, 54.5, 47.2, 44.1, 40.6, 40.0, 29.8, 29.2, 28.8,
28.5 (3 C), 19.1, 18.3 ppm. LC–MS (ESI+): m/z = 519.90 [M +
H]+ (tR = 13.37 min). C27H32F3N3O4 (519.56): calcd. C 62.42, H
6.21, N 8.09; found C 61.76, H 6.06, N 7.88.
3-Benzyloxypropyl-1-tosylate (11): A suspension of sodium hydride
(60%; 17.5 g, 0.438 mol) in THF (700 mL) was cooled to 15 °C,
and 1,3-propanediol (120 g, 1.57 mol) was added dropwise over
40 min. Stirring was continued for 60 min at 30 °C, then benzyl
bromide (75 g, 0.438 mol) was added dropwise over 30 min, and
the mixture was left overnight at 20 °C. Water (150 mL) was then
added, and the mixture was concentrated under reduced pressure
to remove the THF. The aqueous solution was extracted with
EtOAc (3ϫ 200 mL). The combined organic layers were dried with
Na2SO4, the solid was removed by filtration, and the filtrate was
concentrated to dryness to give a yellowish oil (120 g), which was
purified by fractional distillation under reduced pressure (170 °C,
18 Torr). 3-Benzyloxypropanol (60 g, 93% GC–MS purity) was ob-
tert-Butyl {(2R)-1-[1-(3-Benzyloxypropyl)-7-carbamoyl-indolin-5--
yl]propan-2-yl}{2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}carbamate
(13): NaOH (8.2 g, 0.206 mol) and H2O2 (50% aq.; 28 g, 0.412 mol)
were added to a solution of tert-butyl {(2R)-1-[1-(3-benzyloxypro-
pyl)-7-cyanoindolin-5-yl]propan-2-yl}{2-[2-(2,2,2-trifluoroethoxy)-
phenoxy]ethyl}carbamate (55.0 g, 0.0825 mol) in DMSO (360 mL),
and the mixture was stirred overnight at room temp. The mixture
was diluted with water (700 mL), and extracted with MTBE (3ϫ
100 mL). The combined organic layers were dried with Na2SO4, the
1
tained as a colourless oil. H NMR (300 MHz, CDCl3): δ = 7.33–
7.25 (m, 5 H, Bn), 4.52 (s, 2 H, CH2), 3.78 (t, J = 5.7 Hz, 2 H, solid was removed by filtration, and the filtrate was concentrated
CH2), 3.66 (d, J = 5.7 Hz, 2 H, CH2), 1.86 (p, J = 5.7 Hz, 2 H, to dryness to give tert-butyl {(2R)-1-[1-(3-benzyloxypropyl)-7-
Eur. J. Org. Chem. 2015, 6011–6016
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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