Synthesis and molecular structure analysis of venlafaxine intermediate and its analog

Article abstract of DOI:10.1007/s10870-005-5249-y

1-(cyano-(4-methoxyphenyl) methyl cyclohexanol (2), C₂₄U ₃₂N₂O₂, a Venlafaxine intermediate is found to crystallize in both monoclinic (2a) and orthorhombic (2b) crystal systems. The form 2a crystallizes in the space group C2/c with the cell parameters a = 23.506(3), b = 5.550(3), c = 23.192(3), and β = 115.116(2)°. 2b crystallizes in space group P2₁2₁2₁ with cell parameters α = 5.7850(6), b = 11.2680(6), and c = 20.6730(19). The intermolecular hydrogen bonding in the case of the monoclinic polymorph leads to the formation of dimer. The synthesis, characterization, and crystal structure studies of Venlafaxine analog 1-[2-1-(4-dimethylamino-phenyl)-ethylideneamino]- 1-(4-methoxyphenyl)-ethyl]-cyclohexanol (4) is reported. 4 crystallizes in P1 space group with cell parameters a = 10.801(7), b = 12.078(7), c = 9.928(5), α = 96.12(5)°, β = 110.49(5)°, and γ = 112.42(6)°.

Full text of DOI:10.1007/s10870-005-5249-y

ꢀC
Journal of Chemical Crystallography, Vol. 35, No. 12, December 2005 ( 2005)
DOI: 10.1007/s10870-005-5249-y
Synthesis and molecular structure analysis of venlafaxine
intermediate and its analog
C.V. Kavitha,(1) S. Lakshmi,(2) Basappa,(1) K. Mantelingu,(1) M.A. Sridhar,(2)
J. Shashidhara Prasad,(2) and K.S. Rangappa(1)∗
Received December 1, 2004; accepted April 13, 2005
1-(cyano-(4-methoxyphenyl) methyl cyclohexanol (2), C24H32N2O2, a Venlafaxine inter-
mediate is found to crystallize in both monoclinic (2a) and orthorhombic (2b) crystal
systems. The form 2a crystallizes in the space group C2/c with the cell parameters
a = 23.506(3), b = 5.550(3), c = 23.192(3), and β = 115.116(2)◦. 2b crystallizes in space
group P212121 with cell parameters a = 5.7850(6), b = 11.2680(6), and c = 20.6730(19).
The intermolecular hydrogen bonding in the case of the monoclinic polymorph leads
to the formation of dimer. The synthesis, characterization, and crystal structure studies
of Venlafaxine analog 1-[2-1-(4-dimethylamino-phenyl)-ethylideneamino]-1-(4-methoxy-
¯
phenyl)-ethyl]-cyclohexanol (4) is reported. 4 crystallizes in P1 space group with cell
parameters a = 10.801(7), b = 12.078(7), c = 9.928(5), α = 96.12(5)◦, β = 110.49(5)◦,
and γ = 112.42(6)◦.
KEY WORDS: Venlafaxine intermediates; crystal structure; polymorph.
Introduction
Paroxetine (SSRI), Reboxetene (NARI), Nebiolol
(NEB), Respiridone (RP), and Venlafaxine (VNF)
In literature, we have seen the develop-
are reported to exhibit significant inhibitory effect
against depression. Among these, Venlafaxine3–5
(VNF) is found to be the potent antidepressant
agent and shows a faster onset of action and higher
efficiency. Venlafaxine was first synthesized by
J. P. Yarderly and coworkers.6–8 Previously, we
have reported a novel method for the synthesis of
Venlafaxine9 and risperidone intermediate.10
A second synthetic approach was under-
taken in an effort to provide additional options
in the target molecule length and concurrently
circumvent problems with the antidepressant
therapy. We report here the synthesis of
venlafaxine analog 1-[2-1-(4-dimethylamino-
phenyl)-ethylideneamino]-1-(4-methoxy-phenyl)-
ethyl]-cyclohexanol (4) through imine forming
reactions with aromatic aldehydes. The synthesis
ment of a number of nontricyclic antidepressants
with diminished cardiovascular anticholinergic
liability.1 However, the goal of rapid-onset antide-
pressants remain elusive. Indeed, the pharmaco-
logically observable increase in monoamine level
characteristic of most antidepressants has led to
an extensive reappraisal of the simple monoamine
hypothesis of depression.2 The most commonly
used antidepressants are (S)-Fluoxetine (SSRI),
Nisoxetine (NARI), Mirtazapine (NSSA), (R,S)-
(1) Department of Studies in Chemistry, University of Mysore,
Manasagangotri, Mysore 570 006, India.
(2) Department of Studies in Physics, University of Mysore,
Manasagangotri, Mysore 570 006, India.
∗To whom correspondence should be addressed; e-mail: ranga
ppaks@chemistry.uni-mysore.ac.in.
957
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C
1074-1542/05/1200-0957/0 2005 Springer Science+Business Media, Inc.

958
Kavitha et al.
of title compound 4 involves the conversion of
4-methoxyphenyl acetonitrile into 1-[(cyano-
(4-methoxyphenyl)methyl cylcohexanol 2 by
Experimental
TLC accomplished reaction monitoring and
determination of the products. The melting points
were determined on SELACO-650 hot stage ap-
paratus and are uncorrected. The IR (nujol) spec-
tra were measured on Shimadzu 8300 IR spec-
trophotometer. Spectra 1H NMR were recorded on
Shimadzu AMX 400 MHz spectrometer by using
CDCl3 as solvent and TMS as an internal standard
(chemical shift in δ ppm). Elemental analysis were
done on a Vario-EL instrument. The products are
known compounds and were identified by com-
parison of their spectra and physical data with
those of authentic samples.
using 4-methoxyphenyl acetonitrile
1 and
cyclohexanone in the presence of sodium
methoxide at 25–30◦C in methanolic media. The
pure compound 2 obtained was recrystallized by
using water and methanol as solvents and the
crystals of 2a and 2b were obtained by slow
evaporation method, respectively. The reason for
using two different solvents to crystallize 2 was
just the fact that we were trying to crystallize 2
and in the process we ended having crystals from
both the solutions.
The condensed product 2 was subjected
to catalytic transfer hydrogenation method by
using Raney-nickel/hydrogen at 10-atmosphere
pressure in the presence of anhydrous ammonia in
methanol to obtain the compound 1-[2-amino-1-
(4-methoxy-phenyl)-ethyl]-cyclohexanol mono-
acetate (3). The venlafaxine analog, 1-[2-1-(4-
dimethylamino-phenyl) -ethylideneamino] -1- (4-
Synthesis of 1-(cyano-(4-methoxyphenyl)
methyl cyclohexanol 2
Sodium methoxide (20 g, 0.5 mol) was added
to a mixture of tetra butyl ammonium bromide
(5 g) and a solution of 4-methoxyphenyl acetoni-
trile (50 g, 0.340 mol) in cyclohexanol (49.9 g,
0.515 mol). The reaction mass was stirred for
15 h at room temperature (25–30◦C) and fil-
tered, the residue was thoroughly washed with
methoxy-phenyl)-ethyl]-cyclohexanol
4
was
obtained by stirring 3 overnight with N,N-
dimethyl benzaldehyde followed by the base
potassium carbonate (Scheme 1).
Scheme 1. Reagents and conditions: i) cyclohexanone, NaOMe, Bu4NBr, MeOH,
rt, 15 h, 96%; ii) Raney-Ni, H2 (10 atm), MeOH, 35–400◦C, 3 h; iii) N,N-dimethyl
benzaldehyde and sodium carbonate.

Synthesis and molecular structure
959
water (500 mL) and hexane (200 mL) to obtain
a compound 2 (80 g, 96%). We have grown the
compound 2 in two different solvents, water and
methanol to obtain the forms 2a and 2b, respec-
tively by slow evaporation method.
at 35–40◦C for 3 h until no more of hydrogen gas
consumption was found. After the completion of
the reaction, the catalyst was filtered. Distilled
the methanol upto three volumes and 10 mL of
glacial acetic acid is added to the reaction mass
and stirred for another one and half hour at 10–
15◦C. The precipitate was filtered at cooled con-
dition and washed with chilled hexane to obtain
3 mp: 102–105◦C.
Synthesis of 1-[2-amino-1-(4-methoxy-phenyl)-
ethyl]-cyclohexanol monoacetate 3
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 sys-
tem was charged with two solutions. The reactor
was inhertilized with nitrogen. The reactor was
pressurized with hydrogen so as to reach hydrogen
pressure 10 kg. The hydrogenation was continued
Synthesis of 1-[2-1-(4-dimethylamino-phenyl)-
ethylideneamino]-1-(4-methoxy-phenyl)-
ethyl]-cyclohexanol 4
The compound 3 (25 g, 0.07836 mol),N,N-
dimethyl benzaldehyde (11.67 g) and potassium
carbonate (54.15 g) were added to the 750 mL
of methanol solvent and stirred for 20 h at room
Table 1. Crystal Structure and Refinement Data of 2a, 2b and 4
2a 2b
254108
4
CCDC Ref. No.
Empirical formula
Melting point (◦C)
Formula weight
Z
254107
15H19NO2
254109
C24H32N2O2
125–127
380.52
2
C
C15H19NO2
245.31
8
245.31
4
˚
Wavelength (A)
0.71073
Monoclinic
C2/c
0.71073
Orthorhombic
P 212121
0.71060
Triclinic
P 1
Crystal system
Space group
Cell dimensions
˚
a (A)
23.506(3)
5.5500(3)
23.192(3)
90
115.12(1)
90
2739.5(5)
1.190
3.79–32.52
6136
Full-matrix least-squares on F2
5.7850(6)
11.2680(6)
20.6730(19)
90
90
90
1347.6(2)
1.209
2.06–32.49
6620
10.801(7)
12.078(7)
9.928(5)
96.12(5)
110.49(5)
112.42(6)
1077.5(11)
1.173
˚
b (A)
˚
c (A)
α (◦)
β (◦)
γ (◦)
3
˚
Volume (A )
Dc (Mgm−3
θ range (◦)
Reflections
)
2.20–32.49
8173
Refinement method
Independent reflections/R(int)
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2σ(I)]
wR2
3523/0.0196
3523/0/165
1.060
0.0541
0.1459
3545/0.0238
3545/0/165
1.082
0.0526
0.1431
0.209
−0.231
7801/0.1033
7801/0/256
1.043
0.0821
0.2700
0.428
−0.295
−3
˚
ꢀρmax (e·A
)
0.166
−3
˚
ꢀρmin (e·A
Measurement
Program system
)
−0.156
DIPLabo Kappa DIPLabo Kappa AFC7S
Denzo11−13
Denzo
teXsan14

960
Kavitha et al.
Fig 2. Packing of 2a showing hydrogen bonds resulting in
Fig 1. ORTEP of 2a at 50% probability.
the formation of dimer.
---
J = 14 Hz, Ar CH N)1.28–1.7 (m, 10H, cy-
---
temperature. The reaction completion was mon-
itored by TLC (mobile phase: chloroform:
methanol: 9:1). After completion of the TLC, the
solvent was distilled off and demineralized wa-
ter was added to the residue. The crude com-
pound 4 was extracted with ethyl acetate and
dried (Na2SO4), filtered and solvents were evap-
orated to dryness. The crude was dissolved in
four volumes of n-hexane and filtered at cold
condition. The pure compound 4 was recrystal-
lized from the solvent methanol by slow evap-
oration method. mp: 125–127◦C; IR (Nujol):
---
clohexyl); 2.87–3.0 (s, 6H, N CH3)2); 1–1.6
---
---
(d, 1H, ); 3.65–3.76 (s, 3H, O CH3); 6.6–6.72
---
(d, 2H, Ar H); 6.72–6.84 (d, 2H, J = 13.5 Hz,
---
Ar H); 7.1–7.2 (d, 2H, J15 Hz, ArvH); 7.36–
---
7.46 (do, 2H, J = 16 Hz, Ar H); 7.95 (s, 1H,
---
---
OH); 4.1 (d, 2H, J = 24 Hz, CH2 N C); 2.92
---
--- ---
(t, 1H, Ar CH Cyclo).
Analysis Calcd. for C24H32N2O2: C, 75.78;
H, 8.4; N, 7.3. Found: C, 75.54; H, 8.49; N,
7.286%. Recrystallization of the compound 2 for
purification yielded crystals of two different mor-
phologies as observed under the microscope. In
this paper, we report the comparative study of
−1
1435 ( C N), 3454 ( OH), 2988 cm
1H
---
---
---
---
NMR (400 MHz, CDCl3): δ 1.02–1.08 (d, 1H,
◦
˚
Table 2. Hydrogen Bonding Geometry of 2a, 2b, and 4 (A, )
---
---
Compound
D
H
A
D
H
H· · ·A
D· · ·A
D
H· · ·A
2a
O7
C8
O7
O7
H7
H8
N10i
O7ii
0.820
0.980
0.820
0.820
2.170
2.350
2.280
2.120
2.915(2)
3.272(2)
2.925(3)
2.748(4)
151.00
157.00
136.00
133.00
2b
4
H7 N10iii
H7
N10
Note. Symmetry code: (i) 1/2 − x, 3/2 − y, 1 − z; (ii) x, 1 + y, z; (iii) 1 − x, −1/2 +
y, 1/2 − z.

Synthesis and molecular structure
961
Fig 4. Packing of 2b showing hydrogen bonds which form
one-dimensional chain as viewed down a-axis.
Fig 3. ORTEP of 2b at 50% probability.
ature. The details of data collection and crystal
structures of the compounds are given in Table 1.
The structures were solved using SHELXS-
9715 and refined using SHELXL-97.15 The hy-
drogen atoms were fixed at chemically suitable
positions.
structures of both forms, namely 2a and 2b in
order to study their molecular conformation.
Results and discussion
Single crystals of 2a, 2b, and 4 suitable for
X-ray diffraction studies were picked. The X-ray
diffraction data were collected at room temper-
The compound 2a is found to exist as dimer
and crystallizes in the monoclinic crystal class
under the space group C2/c. Figure 1 shows the
Fig 5. ORTEP of 4 at 50% probability.

962
Kavitha et al.
Table 3. Comparison of Some Torsion Angles in 2a, 2b, and 4 (◦)
2a
2b
4
O(7), C(4), C(8), C(9)
O(7), C(4), C(8), C(11)
C(4), C(8), C(11), C(16)
C(4), C(8), C(11), C(12)
C(15), C(14), O(17), C(18)
−57.6(2)
66.4(2)
109.2(2)
−72.0(2)
−177.5(2)
−53.4(2)
70.4(2)
110.9(2)
−70.99(3)
0.0(4)
68.8(3)
−163.3(2)
−78.5(3)
99.0(3)
−177.7(3)
of 2a and 2b packing diagrams clearly shows the
loss of mirror symmetry in 2b.
ORTEP of the molecule 2a at 50% probability.
The compound 2a possesses hydrogen bonds of
the type OH · · · N with the angle about the H atom
being 151◦. Table 2 gives the hydrogen bonding
geometry of 2a, 2b, and 4. Figure 2 shows the
NH · · · O bonds in 2a. Also, intermolecular con-
tact of the type CH · · · O is seen with the angle
about the H atom being 157◦, where the car-
bon atom (C8) is the chiral center. The ring: C1,
C2, C3, C4, C5, C6 is in a chair configuration
with weighted average ring bond distance being
The compound 4 crystallizes in triclinic crys-
tal class. Figure 5 shows the ORTEP of 4. The
compound exhibits intramolecular hydrogen bond
of the type OH · · · N with the angle about the hy-
drogen atom being 133◦.
The torsion angle in 2a and 2b about
--- --- ---
O7 C4 C8 C9 indicates gauche—which has
changed to gauche+ in compound 4 1-[2-
1-(4-dimethylaminophenyl)-ethylideneaino] sub-
stitute. A detailed comparison is given in
Table 3.
˚
1.5208 A.
Figure 3 shows the ORTEP of 2b. The
compound 2b possesses intermolecular hydrogen
bond of the type OH · · · N with the angle about the
hydrogen atom being 136◦. There is a formation
of an infinite one-dimensional chain along the b-
axis (Fig. 4). The intermediates 2a and 2b exhibit
chirality. The bond distances of 2a and 2b are
identical.
The cyclohexyl ring C1, C2, C3, C4, C5,
C6 conforms in boat and chair configurations
with weighted average ring bond distance being
˚
1.5223 A. The molecules appear to be stacked
when veiwed down a-axis (Fig. 6).
The ring: C1, C2, C3, C4, C5, C6 conforms
to chair configuration with weighted average ring
˚
bond distance being 1.5224 A.
The CH · · · O bonding in 2a, where the hy-
drogen bond about O7 is bifurcated.16 is absent in
the case of 2b. Even though the geometry around
C8 looks similar in 2a and 2b one obvious differ-
---
---
---
ence is seen in the C15 C14 O17 C19 con-
formation angle. In the former it is in the antiperi-
planar domain while in the latter it changes to
syn-periplanar. This change is sufficient to break
the weak intermolecular CH · · · O hydrogen bond
in 2a so that the molecule gains extra freedom and
subsequently the dimer breaks away and crystal-
lizes in the higher lattice symmetry with less num-
ber of molecules in the 2b unit cell. Superposition
Fig 6. Packing of 4 down a-axis.

Synthesis and molecular structure
963
Supplementary material CCDC reference numbers contain the
supplementary crystallographic data for this paper. These data can
be obtained free of charge via www.ccdc.cam.ac.uk/data request/cif,
by e-mailing data request@ccdc.cam.ac.uk, or by contacting
The Cambridge Crystallographic Data Center, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44(0)1223-336033.
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Acknowledgments
We are grateful to CSIR, New Delhi for finan-
cial support under the project 01(1904)/03/EMR-II and
DST, Government of India for financial assistance un-
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