Practical synthesis of (±)-venlafaxine

Article abstract of DOI:10.1080/00397910701572266

A practical total synthesis of antidepressant (±)-venlafaxine is disclosed. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701572266

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Practical Synthesis of (±)‐Venlafaxine
a
a
a
Subhash P. Chavan , Dushant A. Khobragade , Mahesh Thakkar & Uttam
a
R. Kalkote
a
Division of Organic Chemistry—Technology, National Chemical Laboratory,
Pune, India
Published online: 19 Nov 2007.
To cite this article: Subhash P. Chavan , Dushant A. Khobragade , Mahesh Thakkar & Uttam R. Kalkote
(2007): Practical Synthesis of (±)‐Venlafaxine, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:22, 3901-3906
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Synthetic Communications , 37: 3901–3906, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701572266
Practical Synthesis of (+)-Venlafaxine
Subhash P. Chavan, Dushant A. Khobragade,
Mahesh Thakkar, and Uttam R. Kalkote
Division of Organic Chemistry—Technology, National Chemical
Laboratory, Pune, India
Abstract: A practical total synthesis of antidepressant (+)-venlafaxine is disclosed.
Keywords: antidepressant, Grignard reaction, Michael addition
INTRODUCTION
In connection with an ongoing program on the synthesis of antidepressants
paroxetine 1 and venlafaxine 2 (Fig. 1), a technically and economically
[
viable protocol for the synthesis of antidepressant drug venlafaxine 2 was
1]
developed (Fig. 1, Scheme 1), which was followed by a similar synthesis by
2]
[
Rangappa et al.
Venlafaxine 2 is a new generation, cost-effective antidepression
[3,4]
drug,
quite different from other antidepressants because it has an
unique structure and morphological effects. It offers potential pharmaco-
logical benefits including early onset of action, dose flexibility, broad
range of activity, improved tolerance, and improved efficacy. An earlier
response can be particularly beneficial in more severely depressed
[
5]
patients.
Address correspondence to Subhash P. Chavan, Division of Organic Chemistry—
Technology, National Chemical Laboratory, Pune 411 008, India. E-mail:
sp.chavan@ncl.res.in
3
901

3
902
S. P. Chavan et al.
Figure 1. Two of the most important antidepressants, paroxetine 1 and venlafaxine 2.
Scheme 1. Reagents and conditions: (a) 10% aqueous NaOH, TBAHSO
4
, 0–158C,
3
cycloalkanol 5 is recovered).
0 min–1 h, quantitative yield; (b) H , 280 psi, formalin, MeOH, 1008C, 30% (60%
2
RESULTS AND DISCUSSION
[
6–14]
Reported methods
for the synthesis of venlafaxine 2 involve the use of
expensive reagents, strong and hazardous bases such as BuLi and LDA, for
coupling p-methoxyphenylacetonitrile 3 with cyclohexanone 4 under
cryogenic conditions and anhydrous organic solvents to give 1-[cyano
(4-methoxyphenyl)methyl]cycloalkanol 5. The yields are low, and the
conditions are not suitable for industrial synthesis.
In this communication, we disclose the synthesis of venlafaxine 2 by a
modified procedure employing the aminoester 6. Retrosynthetic analysis
(
Scheme 2) reveals that target molecule 2 could be obtained from aminoester
and 1,5-dibromopentane 7. Grignard reaction of 1,5-dibromopentane 7 with
6
Scheme 2. Retrosynthetic analysis.

Practical Synthesis of (+ )-Venlafaxine
3903
aminoester 6 gives the target molecule 2. Aminoester 6 in turn could be
derived from ester 8.
[
The literature procedure for the preparation of aminoester 6 from ester
15]
8
involves use of a strong base such as LDA or BuLi under cryogenic con-
ditions and anhydrous organic solvents followed by reduction of the
resultant N,N-dimethylamino acrylate derivative with various reagents
such as Pd/C, LiAlH , and NaBH . These conditions are not suitable for a
4
4
large-scale synthesis.
Accordingly, a solution of ester 8 in toluene was heated with commer-
cially available anhydrous paraformaldehyde, in the presence of K CO and
2
3
tetrabutylammonium iodide (TBAI) to furnish a,b-unsaturated ester 9,
which upon treatment with a THF solution of Me NH at 08C in the
2
presence of a catalytic amount of FeCl rendered aminoester 6 in 79% yield
3
[
16]
(in two steps).
Grignard reaction of aminoester 6 with 1,5-dibromopentane
in THF afforded venlafaxine 2 as a colorless solid in 50% yield (Scheme 3).
Thus, a very short and practical synthesis of the commercially important
antidepressant (+)-venlafaxine has been accomplished employing Michael
addition followed by the Grignard reaction.
EXPERIMENTAL
All solvents were freshly distilled before use. IR spectra were recorded on a
Perkin-Elmer infrared spectrophotometer model 68B or on a Perkin-Elmer
1
615 FT infrared spectrophotometer. H NMR spectra were recorded on a
1
1
3
Bruker AC-200 (200 MHz). C spectra were recorded on a Bruker AC-200
50 MHz). The carbon spectra were assigned using dimensionless enhance-
(
ment by polarization transfer (DEPT) experiments. Coupling constants (J )
were recorded in hertz. Mass spectra were recorded at an ionization energy
of 70 eV on a Finnigan MAT-1020 and on an API Q Starpulsar using
electron spray ionization (ESI). Microanalytical data were obtained using a
Carlo-Erba CHNS-O EA 1108 elemental analyzer. Progress of the reactions
were monitered by thin-layer chromatography (TLC) using Merck silica-gel
Scheme 3. Reagents and conditions: (a) (HCHO)
.5 h; (b) Me NH, FeCl (cat.), rt, 45 min, 79% (two steps); (c) BrMg(CH
THF, 08C then reflux, 3.5 h, 50%.
n
, K
2
CO
3
, TBAI, PhMe, 808C,
3
2
3
2 5
)
MgBr,

3
904
S. P. Chavan et al.
60 F254 precoated plates, and compounds were visualized by fluorescence
quenching or using iodine or by charring after treatment with the mixture of
p-anisaldehyde þ AcOH þ H SO in ethanol. Column chromatography was
2
4
performed using flash silica gel (230–400 mesh).
Ethyl 3-(Dimethylamino)-2-(4-Methoxyphenyl) Propanoate (6)
A mixture of ethyl p-methoxyphenylacetate 8 (4 g, 20.62 mmol), paraform-
aldehyde (1.05 g, 35.0 mmol), and TBAI (0.381 g, 1.03 mmol) was heated
in PhMe (16 mL) at 80–858C for 3.5 h. The reaction mixture was allowed
to cool. Then, a solution of Me NH in THF was added to the reaction
mixture at 08C in the presence of catalytic FeCl (0.160 g, 0.001 mol) and
2
3
stirred for 45 min. After completion of the reaction, 100 mL of water was
added to the reaction mixture, and the aqueous layer was acidified with
conc. HCl (pH ¼ 2). The aqueous layer was washed with DCM
(
3 ꢀ 50 mL), made alkaline (pH ¼ 8) using 5% NaOH solution, extracted
with DCM (3 ꢀ 50 mL), washed with water and brine, dried over
anhydrous Na SO , filtered, and concentrated under reduced pressure.
2
4
Column chromatographic purification over silca gel (0.5% MeOH in
CHCl ) furnished aminoester 6 as a thick colorless oil (3.08 g, 79%). IR
3
(
CHCl ): 3498, 3356, 3018, 2978, 1727, 1611, 1513, 1249, 1216, 1178,
3
2
1 1
7
58 cm . H NMR (200 MHz, CDCl ): d 7.23 (d, J ¼ 8.8 Hz, 2H), 6.83
3
(
d, J ¼ 8.8 Hz, 2H), 4.14 (m, 2H), 3.78 (s, 3H), 3.73 (dd, J ¼ 9.8 Hz and
1
2.2 Hz, 1H); C NMR (50 MHz, CDCl ): d 172.4, 158.6, 129.4, 128.5,
3
1
3
þ
1
13.7, 62.7, 59.8, 54.5, 49.3, 45.2, 13.8; MS (ESI) m/z: 251 (M ), 206,
162, 148, 133, 119, 101, 91, 77, 65, 58. Analysis calculated for C H NO :
C, 64.50; H, 7.58; N, 5.01. Found: C, 64.75, H, 7.38; N, 5.17.
1
5
21
4
Venlafaxine (2)
To a suspension of Mg (0.114 g, 4.75 mmol) in THF (2 mL), a solution of
dibromopentane 7 (0.536 g, 2.33 mmol) in THF (2 mL) was added dropwise
at 0–58C. After addition, the reaction mixture was allowed to warm to
room temperature and stirred for 1.5 h. Again, the reaction mixture was
cooled to 0–58C, and a solution of amino ester 6 (0.45 g, 1.79 mmol) in
THF (5 mL) was added to it dropwise. After the addition, the reaction
mixture was first allowed to come to room temperature within 0.5 h and
then refluxed for 3.5 h. The reaction mixture was allowed to cool, and 50%
aq. NaOH solution was added to the reaction mixture (pH ¼ 12). It was
extracted with ethyl acetate (2 ꢀ 50 mL), washed with water and brine,
dried over anhydrous Na SO , filtered, and concentrated in vacuo. The
2
4
residue was purified by flash column chromatography (20 g of silica gel,
% MeOH in CHCl as eluent) to furnish venlafaxine 2 as a colorless solid
5
3

Practical Synthesis of (+ )-Venlafaxine
3905
(
0.25 g, 50%). Mp 74–768C. IR (CHCl ): 3164, 2982, 2938, 2860, 2832,
3
2
1
2
1
782, 1610, 1512, 1465, 1445, 1277, 1246, 1217, 1180, 1039, 755 cm
;
H NMR (200 MHz, CDCl ): d 7.03 (d, J ¼ 8.79 Hz, 2H), 6.79
3
(
d, J ¼ 8.8 Hz, 2H), 3.79 (s, 3H), 3.28 (t, J ¼ 12.2 Hz, 1H), 2.93 (dd,
J ¼ 2.9 Hz and 12.2 Hz, 1H), 2.33 (s, 6H), 2.28 (dd, J ¼ 3.4 Hz and
1
3
1
2.7 Hz, 1H), 1.23–1.27 (m, 8H), 0.83–1.00 (m, 2H); C NMR (100 MHz,
CDCl ): d 157.7 (C), 132.0 (C), 129.4 (CH), 112.7 (CH), 73.4 (C), 60.7
3
(
CH ), 54.3 (CH ), 51.2 (CH), 44.8 (CH ), 37.5 (CH ), 30.7 (CH ), 25.5
2 3 3 2 2
þ
CH ), 21.0 (CH ), 20.7 (CH ); MS (ESI) m/z: 277 (M ), 258, 219, 179,
2 2 2
(
1
5
62, 134, 119, 99, 91, 81. Analysis calculated for C, 73.61; H, 9.81; N,
.05. Found: C, 73.49; H, 9.55; N, 4.82.
ACKNOWLEDGMENT
D. A. K. and M. T. thank Council for Scientific and Industrial Research
(CSIR), New Delhi, India, for providing fellowships.
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