Pergamon
AbstractAn efficient and practical total synthesis of cis-(1)-Sertraline is developed involving intramolecular FriedelCrafts cyclization
of an appropriately tailored d-phenylglycine. q 2000 Elsevier Science Ltd. All rights reserved.
compounds8 has prompted us to investigate the total synthesis of Sertraline. Described herein is an altogether different
approach starting from cheap and readily accessible
d-phenylglycine for the first time (Scheme 1).9
Scheme 1.
00404020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-402 0(99)01067-4
1112
Scheme 2.
atmosphere. The total reaction was taken into water (25 mL)
and to this was added dilute acetic acid and stirred vigorously to get a clear solution. The acidic solution was treated
with NH4OH solution to adjust pH to 8.5 and extracted with
ether (50 mL). The total extracts were washed with water
(25 mL) saturated NaHCO3 solution (20 mL) and dried over
Na2SO4. The solvent was removed under vacuum to get the
crude oily compound and was purified by column chromatography (ethyl acetate/hexane 5:95) to afford the pure ester
6 (1.6 g, 83%) as a yellow viscous oil. [Anal. Calcd for
C25H27NO2: C, 80.40; H, 7.29; N, 3.75. Found: C, 80.52;
H, 7.40; N, 3.92]; Rf (20% ethyl acetate/hexane) 0.6; [a ]25
D
241.4 (c 1, CHCl3); IR (neat): 2990, 1740, 1600,
1350 cm21; 1H NMR (200 MHz, CDCl3); d 7.457.15
(15H, m, 3Ph), 3.85 (2H, d AB system, J13.8 Hz,
NCH2Ph), 3.70 (1H, t, J7.5 Hz, CHNBn2), 3.62 (3H,
s, OMe), 3.12 (2H, d AB system, J13.8 Hz, NCH2Ph),
2.452.30 (2H, m, CH2), 2.152.0 (2H, m, CH2 CHN); EI
MS m/z: 373 [M]1.
(4S)-N,N-(Dibenzyl)-4-amino-4-phenyl-1-butanol (7). A
solution of ester 6 (1.5 g, 4 mmol) in THF (20 mL) was
added to a suspension of LiAlH4 (0.25 g, 6.1 mmol) in dry
THF (50 mL) at 08C and stirred for 30 min at the same
temperature and at room temperature for overnight. The
reaction mixture was cooled to 08C and excess reagent
was quenched by careful addition of 15% aqueous NaOH
solution (0.5 mL) and (water 1 mL). After stirring for
30 min the solution was filtered through a pad of silica
and Na2SO4 and filtrate was concentrated under vacuum.
The crude product was purified by column chromatography
(ethyl acetate/hexane 2:8) to afford the pure alcohol 7
(1.05 g, 76%) as a semisolid. [Anal. Calcd for C24H27NO:
C, 83.44; H, 7.88; N, 4.05. Found: C, 83.53; H, 7.90; N,
4.07]; Rf (30% ethyl acetate/hexane) 0.35; [a ]25
D 249.20 (c
1, CHCl3); IR (neat): 3500, 3030, 2990, 1600, 1350 cm21;
1
H NMR (200 MHz, CDCl3); d 7.407.40 (15H, m, 3Ph),
3.8 (2H, d AB system, J13.8 Hz, NCH2Ph), 3.7 (1H, t,
J5.9 Hz, CHNBn2), 3.55 (2H, t, J5.9 Hz, CH2 OH),
3.15 (2H, d AB system, J13.8 Hz, NCH2 Ph), 1.951.5
(4H, m, CH2 CH2); HRMS (FAB) Calcd for C24H27NO
346.2129; Found 346.2126.
(1S,R4S)-N,N-(Dibenzyl)-4-amino-1-(3,4-dicholrophenyl)4-phenyl-1-butanol (2). To a stirred solution of 7 (1.0 g,
2.8 mmol) in dichloromethane (25 mL) was added pyridinium dichromate (2.1 g, 5.7 mmol) in portions with
stirring at room temperature, after 5 h the reaction mixture
was diluted with ether (50 mL) and filtered through a short
silica gel column. The column was washed with ether
(50 mL) and the filtrates were concentrated at low temperature to afford the aldehyde (0.85 g, 2.4 mmol). The aldehyde
was added to a solution of 3,4 dichloro phenylmagnesium
bromide {The solution of 3,4-dichloro phenylmagnesium
bromide was prepared from 3,4-dichlorobromo benzene
(1.1 g, 4.9 mmol and magnesium (0.209 g, 8.7 mmol) in
THF (20 mL)}. The reaction mixture was stirred for 5 h,
quenched with saturated ammonium chloride solution
(15 mL), and compound was extracted with ether (50 mL).
The combined extracts were washed with water (25 mL)
brine (25 mL) and dried over Na2SO4. The solvent was
removed under vacuum to get the residue, which was
purified by column chromatography (ethyl acetate/hexane
1113
1114