PAPER
Synthesis of (S,R,R,R)-Nebivolol
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3.01–2.94 (m, 2 H, FC6H3CH2), 2.32–2.27 (m, 1 H,
FC6H3CH2CHH), 2.03–2.01 (m, 1 H, FC6H3CH2CHH).
13C NMR (100 Hz, CDCl3): d = 23.0 (FC6H3CH2CH2), 24.5
(FC6H3CH2CH2), 63.3 (CH2OH), 73.5 (CHOH), 76.5 (OCHCH),
113.9 (C6H3F), 115.5 (C6H3F), 117.5 (C6H3F), 123.1 (C6H3F), 150.1
(C6H3F), 158.1 (C6H3F).
The bottle was sealed and then heated to 80 °C. The reaction was
cooled, then the solvent was evaporated at reduced pressure. (S,R)-
2a (0.7 g, 80%) was obtained.
Mp 97–100 °C; [a]D20 +33.1 (c 0.1, MeOH).
IR (KBr): 3364, 3287, 2904, 2857, 1493, 1436, 1216 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.79–6.69 (m, 3 H, C6H3F), 3.90–
3.86 (m, 1 H, CHOH), 3.65–3.64 (m, 1 H, CHOC6H3F), 3.00–2.77
(m, 4 H, FC6H3CH2, CH2NH2), 2.16–1.15 (m, 4 H, FC6H3CH2CH2,
NH2, OH), 1.85–1.80 (m, 1 H, FC6H3CH2CH2).
MS (EI): m/z = 212, 150.
Anal. Calcd for C11H13FO3: C, 62.26; H, 6.17. Found: C, 61.97; H,
6.12.
13C NMR (100 Hz, CDCl3): d = 23.1(CH2CH2C6H3F), 24.5
(CH2CH2C6H3F), 43.1 (CH2NH2), 72.7 (CHOH), 77.1 (CHO),
113.8 (C6H3F), 115.2 (C6H3F), 150.5 (C6H3F), 155.6 (C6H3F), 157.9
(C6H3F).
(R)-1-[(R)-6-Fluoro-3,4-dihydro-2H-chromen-2-yl]ethane-1,2-
diol [(R,R)-3]
Yield: 2 g (62%); mp 92–94 °C; [a]D20 +63.08 (c 0.1, MeOH).
IR (KBr): 3406, 3281, 2960, 2924, 2885, 1496, 1217, 1081, 1052
MS (EI): m/z = 212, 176, 57.
cm–1.
Anal. Calcd for C11H14FNO2: C, 62.55; H, 6.68. Found: C, 62.43; H,
6.72.
1H NMR (400 MHz, CDCl3): d = 6.82–6.73 (m, 3 H, C6H3F), 4.07–
4.04 (m, 1 H, FC6H3OCH), 3.84–3.78 (m, 3 H, CHOH, CH2OH),
2.88–2.78 (m, 2 H, FC6H3CH2), 2.40 (s, 2 H, OH), 2.00–1.93 (m,
2 H, FC6H3CH2CH2).
13C NMR (100 Hz, CDCl3): d = 23.5 (FC6H3CH2CH2), 24.6
(FC6H3CH2CH2), 63.6 (CH2OH), 73.6 (CHOH), 76.7 (OCHCH),
113.9 (C6H3F), 115.3 (C6H3F), 117.6 (C6H3F), 123.1 (C6H3F), 150.1
(C6H3F), 158.1 (C6H3F).
(S,R,R,R)-a,a¢-[Iminobis(methylene)]bis(6-fluoro-3H,4H-dihy-
dro-2H-1-benzopyran-2-methanol) (1)
A mixture of (R,R)-2 (0.19 g, 0.52 mmol), (S,R)-2a (0.11 g, 0.52
mmol), and MeOH (15 mL) was stirred at ambient temperature.
When the reaction was complete, the solvent was removed. The res-
idue was dissolved in CH2Cl2, washed, and then dried over K2CO3.
After evaporation of the solvent, 1 (0.13 g, 65%) was obtained.
MS (EI): m/z = 212, 151, 57.
Mp 128–130 °C; [a]D20 +0.11 (c 0.1, MeOH).
IR (KBr): 3378, 2924, 2853, 1493, 1434, 1258, 1217 cm–1.
Anal. Calcd for C11H13FO3: C, 62.26; H, 6.17. Found: C, 62.13; H,
6.08.
1H NMR (400 MHz, CDCl3): d = 6.79–6.67 (m, 6 H, FC6H3), 3.95–
3.89 (m, 4 H, CHOH, CHO), 3.15–2.73 (m, 8 H, FC6H3CH2,
CH2NH), 2.17–2.14 (m, 2 H, FC6H3CH2CH2), 1.83–1.81 (m, 2 H,
FC6H3CH2CH2), 1.25 (s, 1 H, NH).
(R)-2-[(S)-6-Fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydroxy-
ethyl-4-methylbenzenesulfonate [(S,R)-2]
To a solution of the enediol (S,R)-3 (1.0 g, 4.7 mmol) in dry pyridine
(20 mL), tosyl chloride (1.0 g, 4.8 mmol) in dry pyridine (15 mL)
was added. After stirring for 24 h, ice-water was added and the mix-
ture was extracted with Et2O (3 × 20 mL). The combined organic
layer was washed with HCl (2 M, 3 × 20 mL), sat. NaHCO3 (3 × 25
mL), brine (3 × 30 mL) and dried over MgSO4. The solvent was re-
moved to give crude product, which was recrystallized from EtOAc.
MS (EI): m/z = 405, 224, 44.
Acknowledgment
We thank the National Natural Science Foundation of China (Nos.
20472090 and 10576034) for financial support.
20
Yield: 1.46 g (85%); mp 103–105 °C; [a]D +28.96 (c 0.164,
CHCl3).
IR (KBr): 3518, 3095, 3063, 2925, 2847, 1596, 1493, 1345, 1260,
1220, 1175, 948 cm–1.
References
(1) (a) Pauwells, P. J.; Gommeren, W.; Van Lommen, G.;
Janssen, P. A. J.; Leysen, J. E. Mol. Pharm. 1988, 34, 843.
(b) Van Lommen, G.; De Bruyn, M.; Schroven, M. J.
Pharm. Belg. 1990, 45, 355. (c) Peeters, O. M.; Blaton, N.
M.; De Ranter, C. J. Acta Crystallogr., Sect. C 1993, 49,
2154. (d) Zhang, H.-C.; Costanzo, M. J.; Maryanoff, B. E.
Tetrahedron Lett. 1994, 35, 4891.
(2) (a) De Cree, J.; Geukens, H.; Leempoels, J.; Verhaegen, H.
Drug Dev. Res. 1986, 8, 109. (b) De Cree, J.; Geukens, H.;
Cobo, C.; Verhaegen, H. Angiology 1987, 38, 440. (c) Van
de Water, A.; Janssens, W.; Van Nueten, J.; Xhonneux, R.;
De Cree, J.; Verhaegen, H.; Reneman, R. S.; Janssen, P. A.
J. J. Cardiovasc. Pharmacol. 1988, 11, 552.
1H NMR (400 MHz, CDCl3): d = 7.97 (d, J = 8.2 Hz, 2 H,
C6H4CH3), 7.49 (d, J = 8.2 Hz, 2 H, C6H4CH3), 6.90 (m, 2 H,
C6H3F), 6.77–6.74 (m, 1 H, C6H3F), 4.53 (dd, J = 10.0, 2.0 Hz, 1 H,
CH2OTs), 4.37 (dd, J = 10.0, 2.0 Hz, 1 H, CH2OTs), 4.06–4.05 (m,
2 H, OCH, CHOH), 2.95–2.89 (m, 2 H, CH2C6H3F), 2.60 (s, 3 H,
CH3C6H4), 2.35–2.32 (m, 1 H, CH2CHO), 1.92–1.91 (m, 1 H,
CH2CHO).
13C NMR (100 Hz, CDCl3): d = 21.7 (CH3), 23.0 (FC6H3CH2CH2),
24.2 (FC6H3CH2CH2), 70.5 (CHOH), 71.1 (OCHCH), 75.1 (CH2O),
113.8 (C6H3F), 114.1 (C6H3F), 117.3 (C6H3F), 123.0 (C6H4CH3),
128.0 (C6H4CH3), 130.0 (C6H4CH3), 145.2 (C6H4CH3), 150.1
(C6H3F), 156.1 (C6H3F), 158.1 (C6H3F).
(3) (a) Midol-Monet, M.; Davy, M.; Heimburger, M.; Beslot, F.;
Cohen, Y. J. Pharm. Pharmacol. 1991, 43, 504. (b) Van de
Water, A.; Xhonneux, R. S.; Janssen, P. A. J. Eur. J. Pharm.
1988, 156, 95. (c) Xhonneux, R. S.; Wouters, L.; Renman,
R. S.; Janssen, P. A. J. Eur. J. Pharm. 1990, 181, 261.
(d) Bowden, C. R.; Marchione, C. S. J. Pharmacol. Exp.
Ther. 1989, 251, 599.
MS (EI): m/z = 366, 151, 91.
Anal. Calcd for C18H19FO5S: C, 59.00; H, 5.23. Found: C, 59.21; H,
5.32.
(R)-2-Amino-1-[(S)-6-fluoro-3,4-dihydro-2H-chromen-2-
yl]ethanol [(S,R)-2a]
A Parr bottle was charged with (S,R)-2 (1.5 g, 4.1 mmol) and dry
MeOH (25 mL), and the bottle was then tared. NH3 was then bub-
bled through the solution until NH3 (0.14 g, 8.2 mmol) dissolved.
(4) Howe, R.; McLoughlin, B. J.; Rao, B. S.; Smith, L. H.;
Chodnekar, M. S. J. Med. Chem. 1969, 12, 452.
Synthesis 2007, No. 8, 1154–1158 © Thieme Stuttgart · New York