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Basappa et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3279–3281
which can be conveniently applied for industrial scale
synthesis.
product venlafexine hydrochloride is highly soluble in
water (hygroscopic). The base 1-[2-dimethylamino-1-(4-
methoxy-phenyl)-ethyl]-cyclohexanol, thus obtained is
converted to hydrochloride salt 4 using isopropyl alco-
hol (IPA) hydrochloride, which is a pure white crystal-
line compound with purity 99.7% (by HPLC).
In the first step 4-methoxyphenyl acetonitrile 1 was
converted to 1-(cyano-(4-methoxyphenyl) methyl) cyclo-
hexanol 2 by reacting with cyclohexanone in presence of
sodium hydroxide at 25–30 °C in aqueous methanolic
media. The condensed product was subjected to cata-
lytic transfer hydrogenation method by using Raney-
nickel/hydrogen at 10-atm pressure in presence of
anhydrous ammonia and a methanol as a solvent. After
reduction was completed, 5 equiv of 37–40% formalde-
hyde solution was added and the reaction mixture was
stirred for 3 h. After completion of the reaction, the
catalyst was filtered, methanol was distilled, precipitate
was washed with water (200 mL) and hexane (100 mL)
to get 80% of 3 (Scheme 1).
In summary, we report an inexpensive, simple, two step,
easy to operate, nonhazordous, effluent free, which can
be conveniently applied to the large-scale synthesis.
3. Typical procedure
3.1. Synthesis of 1-(cyano-(4-methoxyphenyl)methyl)-
cyclohexanol 2
The oxazine 3 thus obtained is suitable as an interme-
diate for conversion to venlafaxine and extensive puri-
fication is avoided at this stage. More over, the oxazine
being solid, handling is easier and preferred in industry
in large scale. Further more, the oxazine 3 is found to be
stable for long periods of time from heat, air, and light.
The dissolved sodium hydroxide (20 g, 0.5 mol) and tetra
butyl ammonium bromide (5 g) in methanolic water
(500 mL each) were slowly added to a stirred solution of
4-methoxyphenyl acetonitrile (50 g, 0.340 mol) in cyclo-
hexanol (49.9 g, 0.515 mol). The reaction mass was stir-
red for 15 h at room temperature (25–30 °C) and filtered,
the residue was thoroughly washed with water (500 mL)
and hexane (200 mL) to obtain a compound 2 (80 g,
96%). Mp: 122–124 °C (Ref. 7).
The isolated oxazine 3, which is treated with 10 equiv of
formic acid, 5 equiv of 37–40% formaldehyde solution in
presence of water. After completion of the reaction,
basify the reaction mass with 30% NaOH solution
1
H NMR (300 MHz, CDCl ): d 7.30 (d, 2H, Ar–H); 6.91
3
(
pH ¼ 12) and extract the venlafaxine by heptane. The
(d, 2H, Ar–H), 3.81 (s, 3H, OCH
1.55 (m, 10H, cyclohexyl).
3
); 3.75 (s, 1H, OH);
basic solution is extracted to remove venlafaxine using
solvents like toluene, xylene, heptane, ethylene dichlo-
ride, and methylenedichoride, etc., the preferred solvents
being heptane. This solvent is of special importance as
they can be distilled off azeotropically to remove water.
Removal of water is atmost in this case as the final
13
C NMR (100 MHz, CDCl
114.1, 72.9, 55.56, 49.5, 34.9, 25.3, 21.6.
3
): d 159.8, 130.8, 123.8, 120,
3.2. 5-(4-Methoxyphenyl)-3-aza-1-oxaspiro[5,5]
undecane 3
NC
OH
CN
i)
The nitrile 2 (50 g, 0.204 mol) was dissolved in 1000 mL
methanol containing 20 g of ammonia and 20 g of Raney
nickel. An autoclave equipped with hydrogen inlet and
gas induction stirring system was charged with two
solutions. The reactor was inhertilzed with nitrogen. The
reactor was pressurized with hydrogen so as to reach
hydrogen pressure 10 kg. The hydrogenation was con-
tinued at 35–40 °C for 3 h until no more of hydrogen gas
consumption was found. After the completion of the
reaction, 250 mL of 37–40% formaldehyde solution was
added and stirred for 3 h. The catalyst was filtered.
Distilled the methanol upto three volumes and the pre-
cipitate was filtered at cooled condition (10–15 °C) and
washed with chilled hexane to obtain 3 (45 g, 83.3%) mp:
121–123 °C.
O
O
2
1
ii)
HCl.
N
H
N
OH
iii)
O
O
O
1
H NMR (300 MHz, CDCl
Ar–H); 6.81 (d, 2H, J ¼ 7:4 Hz, Ar–H), 4.52 (q, 2H, O–
3
): d 7.08 (d, 2H, J ¼ 7:9,
4
3
CH –NH), 3.78 (s, 3H, OCH ); 3.41 (t, 1H, CH–CH );
3
2
2
Scheme 1. Reagents and conditions: (i) cyclohexanone, NaOH,
Bu NBr, water–MeOH, rt, 15 h, 96%; (ii) Raney-Ni, H (10 atm),
anhydrous NH
, MeOH, 35–40 °C, 3 h, then aqueous formaldehyde
2
(
.91 (d, 2H, CH
m, 10H, cyclohexyl).
2
–NH), 2.34 (d, 2H, CH
2
–NH) 0.9–1.55
4
2
3
solution, 25–30 °C, 3 h, 83%; (iii) formic acid, aqueous formaldehyde
solution, reflux (100 °C), 25–30 h, then HCl in i-PrOH (pH ¼ 2), 85%
1
3
C NMR (100 MHz, CDCl ): d 159.8, 130.8, 123.8, 120,
3
(
99.7% purity by HPLC).
114.1, 72.9, 55.56, 49.5, 34.9, 25.3, 21.6.
Basappa
