An improved and impurity-free large-scale synthesis of venlafaxine hydrochloride

Article abstract of DOI:10.1021/op200221y

An improved and impurity-free synthetic method for large-scale synthesis of venlafaxine hydrochloride was developed using inexpensive reagents. The overall yield obtained from this newly developed process is 55% in a highly pure state with >99.9% purity by HPLC.

Full text of DOI:10.1021/op200221y

COMMUNICATION
pubs.acs.org/OPRD
An Improved and Impurity-Free Large-Scale Synthesis of
Venlafaxine Hydrochloride†
Mohanarangam Saravanan,*,‡,^ Bollikonda Satyanarayana,§ and Padi Pratap Reddy§
‡Research and Development, Dr. Reddy’s Laboratories Ltd., Bachupalli, Hyderabad 500072, Andhra Pradesh, India
§Research and Development, Macleods Pharmaceuticals Ltd., Andheri(E), Mumbai 400093, India
^Department of Chemistry, Institute of Science and Technology, J.N.T. University, Hyderabad 500072, Andhra Pradesh, India
Scheme 1a
ABSTRACT: An improved and impurity-free synthetic
method for large-scale synthesis of venlafaxine hydrochlo-
ride was developed using inexpensive reagents. The overall
yield obtained from this newly developed process is 55% in a
highly pure state with >99.9% purity by HPLC.
’ INTRODUCTION
Venlafaxine,1À3 (RS)-1-[2-(Dimethylamino)-1-(4-methoxy-
phenyl)ethyl]cyclohexanol hydrochloride (1), is a member of
the cycloalkanol ethylamine scaffold and was the first dual-acting
serotonin and norepinephrine reuptake inhibitor (SNRI), used
for the treatment of depression and anxiety disorders. It was
developed by Wyeth laboratories and is currently being marketed
a Reagents and conditions: (i) MeOH, NaOMe, 5 ꢀC, 4 h; (ii) AcOH,
Kalcat C-8030-type Raney-Ni, H2, 10À12 bar, 50 ꢀC, 3 h; (iii) water,
under the trade name Effexor.
37% HCHO, HCOOH, 100 ꢀC, 20 h, toluene, 10% HCl in isopropanol.
’ RESULTS AND DISCUSSION
55%, which has been accomplished by modifying the original
process to one suitable for the large-scale synthesis by addressing
the aforementioned limitations.
Venlafaxine was first synthesized by Yardley and co-workers1
and then by different groups by various methods. The first
reported1 and most common approach for large-scale synthesis
involves neucleophilic addition of 4-methoxyphenyl acetonitrile
(2) with cyclohexanone (3) using LDA at À78 ꢀC to afford (RS)-
1-[cyano-(4-methoxyphenyl)methyl]cyclohexanol (4). Catalytic
hydrogenation of 4 over rhodium on alumina in ethanolic am-
monia to provide (RS)-1-[2-amino-1-(4-methoxypheny) ethyl]-
cyclohexanol (5) then dimethylation of 5 using EschweilerÀ
Clarke procedure and isolation of the resulting venlafaxine as
hydrochloride salt 1 are further stages in this synthesis with an
overall yield <25%. When we have explored this reported syn-
thetic process for the preparation of 1, it was realized that this
method suffered from disadvantages such as: (i) Reaction is at
very low temperature À78 ꢀC, and is particularly unattainable at
tropical conditions. (ii) Usage of pyrophoric reagents such as
n-BuLi and LDA made the process industrially unattractive. (iii)
Excessive load of expensive Rh/alumina catalyst for catalytic
hydrogenation of 4 rendered the process economically non-
viable. (iv) Amine compound 5 was found to be unstable at am-
bient temperature and needed to be processed to the next stage
immediately. (v) Final product 1 was associated with several
impurities and required several purifications. (vi) Overall yield of
this process is less than 30%. Although a few other syntheses have
been reported in the literature,4À8 they were either expensive or
involved tedious workup procedures to isolate the product.
Herein, we report an improved, efficient, cost-effective, and
impurity-free synthesis of venlafaxine with an overall yield of
The first step of our synthesis (Scheme 1) commences with
condensation of 2 with 3 in the presence of sodium methoxide
using methanol as solvent to afford 4 in 91% yield with 99.0%
purity. The selection of methanol as a solvent and sodium meth-
oxide as a base facilitates the carbanion generation from the ben-
zylic position of 2 at 0À5 ꢀC, and thereby addition of 3 allowed
reaction completion in 4 h. Simple addition of water to the
reaction mass assisted the precipitation of 4 as a white, crystalline
solid and thus avoided the use of cryogenic reaction conditions as
well as pyrophoric reagents such as n-BuLi and LDA.
On the basis of our previous experience in process development of
the catalytic hydrogenation of 49 and the available literature,10À18 we
were very certain that catalytic hydrogenation of 4to 5coupled with a
workup procedure which minimizes the process impurities is crucial
to the success of the synthesis of 1 as per regulatory requirements.19
Among the available reducing agents15 for reduction of 4 to 5, Kalcat
C 8030-type Raney Ni20 was found to be an attractive choice
(Table 1, entries 10 and 11) in view of its low cost and scope for
its recovery and reuse in up to three reaction cycles.
Subsequently, we investigated the effect of different solvents
on the hydrogenation by carrying out the reaction in the fol-
lowing solvents: methanol, isopropyl alcohol, methanolic ammonia,
acetic acid, and aqueous ammoniaÀmethanol using Kalcat C
Received: August 15, 2011
Published: October 20, 2011
r
2011 American Chemical Society
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Organic Process Research & Development
COMMUNICATION
Table 1. Hydrogenation of 4 using different reducing agents
entry
reducing agent (% of load)
solvent
H2 (bar)
temp (ꢀC)
time (h)
% yielda
1
LAH
THF
À
25
50
50
25
50
50
25
45
45
45
45
14
9
55
47
45
68
43
25
67
52
48
76
81
2
Pd/C (10%)
methanolic ammonia
acetic acid
10À12
10À12
6À8
3
wet Pd/C (10%)
7
4
Rh-Al2O3 (25%)
methanolic ammonia
methanolic ammonia
methanolic ammonia
methanolic ammonia
acetic acid
6
5
Raney Ni-type B (50%)
Raney Ni-type F (50%)
Raney Ni-type CORM III (75%)
Raney Ni-type CORM III (75%)
Raney Ni-type CORM III (25%)
Raney Ni-type C 8030 (10%)
Raney Ni-type C 8030 (10%)
8À10
8À10
8À10
8À10
8À10
10À12
10À12
24
11
9
6
7
8
9
9
acetic acid
14
11
3
10
methanolic ammonia
acetic acid
11
a isolated yield.
Table 2. Solvent screening for hydrogenation of 4
took a longer time for reaction completion and led to the
formation of significant amounts of impurities during the longer
reaction time, resulting in lower yield of the product. When the
catalyst load was high, though the reaction was completed in 1 h,
impurity levels were substantially higher, and product yield was
only moderate (Table 3, entry 6) due to reverse aldol reaction.
When catalytic hydrogenation was carried out with 10À12% w/w
catalyst load based on weight of 4, the product was formed in
excellent yield (Table 3, entries 3À5). Finally, using acetic acid as
solvent and Kalcat C 8030-type Raney Ni as catalyst, a systematic
screening of one variable at a time (reaction temperature,
reaction time, hydrogen gas pressure) was carried out, and the
optimum conditions were identified as 55 ( 2.5 ꢀC, 3.5 ( 0.5 h,
10À12 bar hydrogen gas.
entry
solvent
4a
6a
7a
8a
9a % yieldb
1
2
3
4
5
methanol
isopropyl alcohol
methanolic ammonia 10
12
1.62 2.57
8.6 0.02
64
63
72
83
59
14
1.07 1.23 10.1 0.07
1.40 0.78
0.4 0.33 0.14
17 1.93 0.96
6.4 0.06
0.7 0.07
4.8 0.02
acetic acid
aq NH3-methanol
a Result reported on basis of HPLC area %. b Isolated yield.
Table 3. Optimization of Kalcat C 8030-type Raney Ni
quantity for hydrogenation of 4
Raney Ni
entry (% w/w) time (h) 4a
After the completion of reaction, the catalyst was filtered, and
the filtrate was concentrated under reduced pressure to get crude
5 as a thick syrup. The crude 5 contains 6, 7, 8, and 9 as major
impurities (Figure 1). Since these impurities have a free amino
functional group, all these impurities can participate in the
subsequent stage of the venlafaxine synthesis (5 to 1, EschweilerÀ
Clarke reaction) leading to the formation of corresponding 10,
11, 12, and 13 impurities in the final drug substance 1
(Figure 2).21 To remove these impurities, crude 5 was dissolved
in water and washed with various antisolvents such as toluene,
ethyl acetate, and dichloromethane. Among them, toluene was
identified as the ideal solvent to eliminate these impurities very
effectively without losing the desired product. Finally, the pro-
duct was extracted into ethyl acetate after basifying with aqueous
ammonia, and the organic layer was concentrated to provide the
free base of 5. To isolate pure 5 (substantially free from 6À9) in
the form of solid, the free base of 5 was treated with acetic acid in
different solvents such as toluene, methanol, ethyl acetate, and
dichloromethane. Among them, ethyl acetate was found to be an
appropriate solvent to enhance the purity to >99.3%. An im-
portant parameter was observed during establishment of the
isolation procedure, wherein 1.5 mol equiv of acetic acid is
essential to achieve the excellent yield and purity of 5. The ace-
tate salt thus obtained was found to be stable for more than one
year at room temperature, and it can be conveniently converted
into venlafaxine HCl without incorporating any purification. The
optimized process has been validated at kilo scale, and the results
of the batches are reported in Table 4 along with the content of
impurities. Thus, removal of expensive catalyst and achievement
of desired purity, yield, and excellent stability were addressed.
6a
7a
8a
9a % yieldb
1
2
3
4
5
6
7
9
7.0
4.0
3.0
3.0
2.5
1.0
5.21 0.24 0.32
0.40 0.23 0.19
0.47 0.14 0.13
0.21 0.12 0.12
0.32 0.17 0.10
4.3 0.02
2.1 0.07
1.8 0.06
1.5 0.07
3.5 0.02
73
78
82
81
79
69
10
11
12
18
0.15 0.32 0.22 10.2 0.02
a Result reported on the basis of HPLC area %. b Isolated yield.
Figure 1. Structure of impurities 6À9.
8030-type Raney Ni at 45À55 ꢀC under 10À12 bar hydrogen gas
pressure. Among these, acetic acid was found to be the best solvent
of choice in terms of conversion and yield (Table 2, entry 4).
Further, the impact of catalyst load on yield and quality of the
product was studied. At a low load of catalyst (Table 3, entry 1), it
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Organic Process Research & Development
COMMUNICATION
Table 6. Organic volatile impurities results of 1
content of residual solvent in 1a in ppm
entry MeOH IPA DCM EtOAc toluene AcOH HCOOH
1
2
3
ND
ND
ND
25
88
75
ND
ND
ND
ND
ND
ND
ND
ND
15
ND
ND
ND
ND
ND
ND
a Residual solvent limits in ppm: MeOH NMT 2000, IPA NMT 3000,
DCM NMT 600, toluene NMT 300, AcOH NMT 1500, HCOOH
NMT 1500, NMT = not more than.
eliminate the impurities 14, 15, and 16. Finally, the product was
extracted into toluene after basifying the reaction mass to pH
9À10 with 20% NaOH solution. The toluene layer was dried
over anhydrous sodium sulfate to remove water, since the pro-
duct 1 is highly soluble in water, then treated with 10% HCl in
isopropyl alcohol solution followed by recrystallizing the product
from isopropyl alcohol to get 82% of 1 as a highly pure (Tables 5
and 6), white crystalline compound with purity >99.9% (by a
validated HPLC method).
Figure 2. Structures of impurities 10À16.
Table 4. Results of scaled-up batches of 5
’ CONCLUSION
HPLC purity (%)
In conclusion, we have provided an improved, impurity-free,
cost-effective, and scalable process for the production of
venlafaxine HCl with an overall yield of 55% in a highly pure
state (>99.9% purity by HPLC) by switching to cheaply
available Kalcat C8030-type Raney Ni in place of expensive
Rh/alumina for hydrogenation and sodium methoxide in place
of LDA.
entry input 4 (kg)
5a
6a
7a
8a
9a
4a % yieldb
1
2
3
60
60
60
99.42 0.04 0.19 0.02 0.003 ND
73.1
68.6
71.7
99.33 0.03 0.16 0.04 ND
99.35 0.05 0.12 0.04 ND
a Result reported on the basis of HPLC area %. b Isolated yield; ND = not
detected.
ND
ND
’ EXPERIMENTAL SECTION
All the solvents and reagents were used as received without
further purification. The H NMR spectra were recorded on a
1
Table 5. Results of scaled-up batches of 1
Varian Mercury plus 400 MHz FT NMR spectrometer, the
chemical shifts are reported in δ (ppm) relative to TMS. The
13C NMR spectra were recorded on a Varian Mercury plus
200 MHz FT NMR spectrometer, the chemical shifts are re-
ported in δ (ppm) relative to CDCl3. The IR spectra were
recorded in the solid state as a KBr dispersion using a Perkin-
Elmer FT-IR spectrometer. The mass spectra were recorded on a
Shimadzu LCMS-QP8000 and Micromass LCT Premier XE
mass spectrometer. Elemental analysis for CHN was performed
on a Perkin-Elmer model 2400 CHNS/O analyzer.
HPLC purity (%)
input 5
%
(kg)
1a
10a 11a 12a 13a 14a
15a
16a yieldb
60
60
60
99.94 ND ND 0.01 ND ND ND
99.91 ND ND ND ND ND ND
0.002 76.5
ND
81.6
78.2
99.92 ND ND 0.01 ND ND 0.002 ND
a Result reported on the basis of HPLC area %. b Isolated yield; ND = not
detected.
Synthesis of 1-(Cyano-(4-methoxyphenyl)methyl)cyclo-
hexanol (4). To a solution ofsodium methoxide powder (45.9 kg,
0.850 kmol) in methanol (250.0 L) was added 4-methoxyphenyl
acetonitrile (2, 50.0 kg, 0.340 kmol) at 5 ꢀC, and the resultant
suspension was stirred at 0À5 ꢀC for 2 h. Cyclohexanone (3,
43.3 kg, 0.442 kmol) was added and stirred at 0À5 ꢀC for 4 h.
Water (500.0 L) was added while maintaining the temperature
below 10 ꢀC and stirred for 1 h. The separated solid was filtered
and washed with water (75.0 L). The resulting wet compound
was taken in toluene (500.0 L) and heated at 65 ( 3 ꢀC, followed
by washing the toluene layer twice with water (2 Â 125 L). The
reaction mass was cooled to 5À10 ꢀC and maintained at 5À
10 ꢀC for 2 h. The separated solid was filtered, washed with
toluene (25 L), and dried at 45 ( 2.5 ꢀC to afford 4 as a white
crystalline solid. Yield: 75.8 kg (91%); HPLC purity: 99.1%; MS:
m/z 246 (M+ + 1); 1H NMR (400 MHz, CDCl3): δ 7.21 (d, 2H,
ArÀH); 6.85 (d, 2H, ArÀH), 3.74 (s, 3H, OCH3), 3.66 (s, 1H,
The isolated acetate salt 5 is then treated with 6.1 equiv of
formic acid and 3 equiv of 37À40% aqueous formaldehyde in the
presence of water as the reaction medium at near reflux tem-
perature for 22 h. HPLC analysis of reaction mass indicated that
product 1 was associated with about 0.5À2.0% of 14, 15 and 16
as major impurities (Figure 2), which are intermediates in the
conversion of 5 to 1. Since these impurities have a nitrogen atom,
all these impurities can form the corresponding HCl salt while
making the HCl salt of free base 1 and lead to unacceptable levels
of impurities in the final API 1. Hence, these impurities need
to be removed to a negligible amount before treating with the
HCl source. To remove these impurities, efforts were made
to wash the aqueous reaction mass with various solvents such
as toluene, ethyl acetate, dichloromethane, and ethers. Among
them, dichloromethane was identified as the best solvent to
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Organic Process Research & Development
COMMUNICATION
CHÀCN), 1.0À1.6 (m, 10H, cyclohexyl); 13C NMR (200 MHz,
CDCl3): δ 21.4, 21.5, 25.1, 34.7, 34.8, 49.2, 55.2, 72.6, 114.0,
119.8, 123.6, 130.5, 159.6.
’ AUTHOR INFORMATION
Corresponding Author
E-mail: saravananm@drreddys.com; saravanan_jaishu@yahoo.
com. Telephone: +91 9000770751. Fax: +91 40 44346285.
Synthesis of [RS]-1-[2-Amino-1-(4-ethoxypheny)ethyl]cyclo-
hexanol Acetic Acid (5). A mixture of 4 (60.0 kg, 0.24 kmol)
and acetic acid (360.0 L) was placed in an autoclave equip-
ped with hydrogen gas induction system. Kalcat C 8030-
type Raney-Ni (9.0 kg, 15% w/w based on 4) was added
(CAUTION! The catalyst is extremely pyrophoric when exposed
to the air in a dry condition; it should be kept with solvent at all
times!), and the reaction mixture was flushed twice with 2 bar
hydrogen gas pressure. The reaction was maintained at 55 (
2.5 ꢀC with 10À12 bar hydrogen gas pressure for 3 h and then
cooled to 25 ꢀC. The catalyst was filtered (CAUTION! Fire
hazard! See above precaution.), and then the filtrate was
concentrated under reduced pressure below 60 ꢀC. The
residual mass was dissolved in water (300.0 L) and then
washed with toluene (120.0 L). The product was extracted
into ethyl acetate (360.0 L) by adjusting the pH 7.5À8.0 using
25% aqueous ammonia (60.0 L). The organic layer was then
concentrated under reduced pressure to dryness and then
dissolved in ethyl acetate (300.0 L). Acetic acid (22 kg, 0.36
kmol) was added, heated at 75 ꢀC for 15 min, and then stirred
at 20À25 ꢀC for 2 h. The separated solid was filtered, washed
with ethyl acetate (30.0 L), and dried at 70 ꢀC to afford 5 as a
white crystalline solid. Yield: 54.3 kg (71.7%); HPLC purity:
99.3%; MS: m/z 250.3 (M+ + 1); 1H NMR (400 MHz,
CD3OD): δ 7.2 (d, 2H, ArÀH); 6.9 (d, 2H, ArÀH), 3.8
(s, 3H, OCH3), 3.5 (dd, 1H, ArÀCHÀCH2), 3.3 (m, 2H,
CH2ÀNH2), 1.9 (s, 3H, AcOH), 0.9À1.5 (m, 10H, cyclo-
hexyl); 13C NMR (200 MHz, CDCl3): δ 20.9, 21.1, 22.4, 25.3,
33.0, 36.5, 54.5, 54.9, 71.8, 112.9, 130.0, 131.7, 157.6, 173.2;
Anal. Calcd for C17H27NO4: C, 65.99; H, 8.80; N, 4.53. Found:
C, 65.91; H, 8.75; N, 4.49.
Notes
†IPDO-IPM Communication No. 00165
’ ACKNOWLEDGMENT
Weare thankfultothemanagementof Dr. Reddy’sLaboratories
Limited and the colleagues of Research and Development (R&D)
for their constant encouragement and excellent cooperation.
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Synthesis of [RS]-1-[2-Dimethylamino-1-(4-methoxyphenyl)-
ethyl]cyclohexanol Hydrochloride (1). To a stirred solution
of 5 (60.0 kg, 0.194 kmol) in water (300.0 L) was added
37À40% formaldehyde (96.0 kg, 1.18 kmol) and formic acid
(26.8 kg, 0.582 kmol), and the reaction mixture was heated at
100 ꢀC for 22 h. The reaction mixture was cooled to 25 ꢀC and
then washed with dichloromethane (300.0 L). The product
was extracted into toluene (540.0 L) after basifying the
reaction mass pH 8.0À9.0 using 20% NaOH solution. The
organic layer was washed with water (180.0 L) followed by
drying with sodium sulfate. The pH of the organic layer was
adjusted to 3.0À4.5 using 8À10% IPA.HCl and stirred at
0À5 ꢀC for 2 h. The separated solid was filtered and washed
with toluene (25.0 mL). The resulting wet product was taken
in isopropyl alcohol (360.0 L) and heated to reflux for
15À30 min. The reaction mass was cooled to 0À5ꢀCandmaintained
at 0À5 ꢀC for 1À2 h. The separated product was filtered, washed
with chilled isopropyl alcohol (60.0 L), and dried at 70 ꢀC in a
cone vacuum drier to afford 1 as a white crystalline solid.
Yield: 47.4 kg (78%); HPLC purity: 99.93%; MS: m/z 278
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(20) Activated alloy catalyst Kalcat C-8030 Raney Ni is a fine black
powder suspended in water, and its pH is between 9 to 11. This catalyst,
having 84À88% nickel content, nitrobenzene activity 40À60 mL of H2/
g/min, and bulk density between 0.60 to 0.85 g/cm3, is procured from
Monarch Catalyst Private Ltd., A-94 MIDC phase I, Dombivli, Thane -
421203, India.
1
(M+ + 1); H NMR (400 MHz, CD3OD): δ 7.22 (d, 2H,
J = 8.6 Hz, ArÀH); 6.96 (d, 2H, J = 7.8 Hz, ArÀH), 3.79 (s, 3H,
OCH3), 3.60À3.72 (m, 2H, CH2ÀN(CH3)2), 3.03 (dd, 1H,
ArÀCHÀ CH2), 2.82 (s, 6H, N(CH3)2), 0.9À1.5 (m, 10H,
cyclohexyl); 13C NMR (200 MHz, CDCl3): δ 21.0, 21.4, 25.2,
31.2, 36.5, 42.5, 44.9, 52.3, 55.1, 60.1, 73.4, 113.9, 130.0, 131.2,
158.7; Anal. Calcd for C17H28ClNO2: C, 65.05; H, 8.99; N, 4.46.
Found: C, 65.11; H, 8.96; N, 4.47.
(21) Saravanan, M.; Suresh Kumar, K.; Pratap Reddy, P.; Satyanarayana,
B. Synth. Commun. 2010, 40, 1880–1886.
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