7222
A. D. Pechulis et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7219–7222
4. Hunt, P.; Hannengiesser, M. H.; Raynaud, J. P. J. Pharm. Pharmacol. 1974, 26, 370.
5. (a) Habibi, B.; Cartron, J. P.; Bretagne, M.; Rouger, P.; Salmon, C. Vox Sang. 1981,
40, 79.
chloride (3 ꢁ 100 ml). The combined organic extracts were washed with brine
and dried over anhydrous sodium sulfate, followed by filtration and
concentration in vacuo. Purification by column chromatography on silica gel
eluting with hexanes/ethyl acetate (3/1) provided the amino alcohol (4.3 g) as
a yellow oil; 1H NMR (300 MHz, CDCl3) d 7.08 7.30 (m, 7H), 4.73 (t, J = 6.0 Hz,
1H), 3.60 (ABq, JAB = 14.0 Hz, 2H), 2.55 (d, J = 8.0 Hz, 2H), 2.36 (s, 3H), 2.31 (s,
3H); CI MS m/z = 274 [C17H20NFO+H]+.
6. Harrison, J. H., Jr.; Jollow, D. J. J. Pharm. Exp. Ther. 1986, 238, 1045.
7. (a) Yu, J.; Brown, D. G.; Burdette, D. Drug Metab. Dispos. 2010, 38, 1767; (b) Yu,
J.; Mathisen, D. E.; Burdette, D.; Brown, D. G.; Becker, C.; Aharony, D. Drug
Metab. Dispos. 2010, 38, 46; (c) Obach, R. S.; Dalvie, D. K. Drug Metab. Dispos.
2006, 34, 1310; (d) Stephan, A. F.; Walker, D. P.; Bauman, J.; Price, D. A.; Baillie,
T. A.; Kalgutkar, A. S.; Aleo, M. D. Chem. Res. Toxicol. 2011, 24, 1345.
8. (a) Wigal, S. B. CNS Drugs 2009, 23, 21; (b) Findling, R. L. Clin. Ther. 2008, 30,
942.
9. Beck, J. P.; Curry, M. A.; Smith, M. A. U.S.7,163,949. The binding assay is
described in this patent.
10. Bymaster, F. P.; Dreshfield-Ahmad, L. J.; Threlkeld, P. G. Neuropsychopharmacology
2001, 25, 871. and references therein.
Step B: The product from Step A (1.0 g, 4.0 mmol) was stirred in methylene
chloride (100 ml) and treated dropwise with concentrated sulfuric acid (98%,
7.0 ml) over 3 min. After stirring for 1 h, the reaction mixture was diluted with
ice chips and made basic with 25% aqueous ammonium hydroxide. The
reactions mixture was extracted with methylene chloride (3 ꢁ 100 ml) and the
organic extracts combined, dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. Purification by column chromatography, eluting with
hexanes/ethyl acetate (3/1), afforded the desired tetrahydroisoquinoline as a
11. Molino, B.F.; Liu, S.; Guzzo, P. R.; Beck, J.P. U.S.7,541,375 B2.
12. The synthesis of these THIQ analogues is exemplified by the preparation of 43
as described below:
yellow oil: 1H NMR (300 MHz, CDCl3)
d 6.89 7.00 (m, 5H), 6.75 (d,
J = 8.0 Hz,1H), 4.21 (t, J = 7.0 Hz, 1H), 3.64 (ABq, JAB = 15.0 Hz, 2H), 3.02 (m,
1H), 2.56 (m, 1H), 2.41 (s, 3H), 2.29 (s, 3H); CI MS m/z = 256 [C17H18NF+H]+.
Step C: The product from Step B was subjected to chiral HPLC separation
employing a Chiral Technologies.
Step A: m-Tolualdehyde (1.66 g, 14.0 mmol) was treated with methylamine
(40% aqueous, 1.39 ml, 18.0 mmol) in methanol (20 ml) at room temperature.
The reaction was stirred for 20 min and treated with sodium borohydride
(0.26 g, 7.0 mmol) portionwise. The reaction was stirred for 1 h and treated
with 30-fluoro-2-bromoacetophenone (3.0 g, 14.0 mmol) followed by stirring
for 45 min at room temperature. The reaction was finally treated with sodium
borohydride (0.52 g, 14.0 mmol) portionwise, and stirring continued overnight.
The reaction was diluted with water (100 ml) and extracted with methylene
Chiracel™ AD column (5 ꢁ 50 cm) eluting with hexanes/isopropanol (9/1) to
afford the (R), ½a D25
ꢂ
ꢀ16.3 (c = 0.498, MEOH) and (S), ½a D25
ꢂ
+16.3 (c = 0.476, MeOH)
enantiomers in order of elution. The (S)-(+) enantiomer was treated with maleic
acid (1.0 equiv) and the resultant maleate salt filtered and dried to constant
weight. (S)-(+)-2,7-dimethyl-4-(3-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline,
maleate salt: mp 172–173.5 °C.