An efficient, scalable process for benzphetamine hydrochloride

Article abstract of DOI:10.1021/op400313y

Commercial manufacturing of benzphetamine hydrochloride along with its impurity profiling is disclosed. Deoxygenation of pseudoephedrine is reported with ～100% retention by shielding the amine group as its tert-butyl carbamate, which is very straightforward to eliminate at the end. Four unknown process-related impurities are isolated from the samples of final API and characterized on the basis of their NMR and mass spectral analysis. Structures of the isolated impurities are confirmed by independent syntheses and coinjecting with the isolated one.

Full text of DOI:10.1021/op400313y

Article
pubs.acs.org/OPRD
An Efficient, Scalable Process for Benzphetamine Hydrochloride
Chinmoy Pramanik,*,† Kiran Bapat,† Ashok Chaudhari,*,† Mukund G Kulkarni,‡ Rangarao Kolla,†
Srinivasarao Sompalli,† Narendra K. Tripathy,† and Mukund K. Gurjar†
†API R&D Centre, Emcure Pharmaceuticals Ltd., ITBT Park, Phase-II, MIDC, Hinjewadi, Pune - 411057, India
‡Department of Chemistry, University of Pune, Ganeshkhind, Pune - 411007, Maharashtra, India
S
* Supporting Information
ABSTRACT: Commercial manufacturing of benzphetamine hydrochloride along with its impurity profiling is disclosed.
Deoxygenation of pseudoephedrine is reported with ∼100% retention by shielding the amine group as its tert-butyl carbamate,
which is very straightforward to eliminate at the end. Four unknown process-related impurities are isolated from the samples of
final API and characterized on the basis of their NMR and mass spectral analysis. Structures of the isolated impurities are
confirmed by independent syntheses and coinjecting with the isolated one.
towards development for commercially valuable generic drugs,
we intended to undertake the synthesis of benzphetamine
hydrochloride and come up with a process which would be
devoid of all these harsh conditions and afford the product with
high purity and yield under milder conditions. We envisaged
commercially available ephedrine or pseudoephedrine could be
the best suitable starting point for the manufacturing of
benzphetamine HCl. Benzylic deoxygenation of ephedrine or
pseudoephedrine followed by N-benzylation under mild
conditions would give the desired benzphetamine free base,
which could be easily converted to its hydrochloride salt. It is
noteworthy to mention that ephedrine/norephedrine, meth-
amphetamine, and benzphetamine all are controlled substances
(psychotropic), and their uses are restricted.
INTRODUCTION
Benzphetamine (1, chemically known as (2S)-N-benzyl-N-
methyl-1-phenylpropan-2-amine, figure 1) is an anorectic drug
■
Figure 1. Benzphetamine hydrochloride.
marketed under the brand name ‘Didrex’ in the United States
(USA) by Pharmacia.1 It is used as sympathomimetic appetite
suppressants to manage exogenous obesity by stimulating the
release of norepinephrine and/or dopamine from storage sites
in nerve terminals of the lateral hypothalamic feeding center,
thereby producing a decrease in appetite.
Even though the molecule is known for more than half a
decade, only a few manufacturing processes have been reported
in the literature. The initial synthesis of benzphetamine
hydrochloride by Heintzelman et al.2 in U.S. Patent
2,789,138 (1957) started with d-desoxyephedrine (metham-
phetamine) (2) which on N-alkylation with benzyl chloride
using anhydrous potassium carbonate as base in solvents like
benzene/toluene or xylene under prolonged heating (150 °C)
afforded the crude free base (3) (Scheme 1). Purification of the
crude base by vacuum distillation at high temperature provided
pure benzphetamine free base which was transformed to its
hydrochloride salt using ethanolic HCl in ethyl acetate followed
by crystallization from ether.
The main disadvantages of this process are the extensive high
temperature for reactions (150 °C) and vacuum distillation
(∼127 °C) of the free base and use of ether as solvent during
crystallization of salt. Later on Kolota et al.3 in U.S. Patents
0262268 (2008) and 2,750,187 (2010), reported improved
crystallization process of benzphetamine HCl. Tomazi et al.4
also reported purification methods (U.S. Patents 0124833,
2009 and 0113831, 2010). As a part of our ongoing program
RESULTS DISCUSSION
■
In our initial approach, we planned the direct deoxygenation of
commercially available ephedrine/pseudoephedrine hydro-
chloride; for this purpose, among the various methods available
in the literature5 affecting this transformation, we felt
hydrogenolysis/deoxygenation with Raney Ni could be the
best option for large-scale production instead of using
expensive complex and precious metal hydrogenating catalysts.
Accordingly, deoxygenation of ephedrine/pseudoephedrine
HCl with an excess of Raney Ni in isopropanol was attempted
in an autoclave at 50−55 °C (pressure observed up to 2−3 kg);
to our satisfaction, the reaction proceeded to completion within
2−3 h and cleanly afforded the desired product (methamphet-
amine) after filtration of the catalyst. The N-benzylation step
was accomplished using benzyl chloride in the presence of
K2CO3 in toluene which provided benzphetamine free base (3)
in almost quantitative yield and high purity (Scheme 2). For
the hydrochloride salt formation, the free base (oil) was
dissolved in ethyl acetate and treated with anhydrous HCl in
ethyl acetate (8−10%).
Received: November 1, 2013
Published: March 17, 2014
© 2014 American Chemical Society
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Scheme 1
Scheme 2
Figure 2. Chiral purity of methamphetamine of initial and new route. (a) Chiral HPLC purity of methamphetamine in initial route. (b) Chiral HPLC
purity of methamphetamine in new route.
Scheme 3
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Figure 3. Process-related unknown impurities.
The synthetic sequence was repeated and found to be
reproducible on 500-g scale. The final API (benzphetamine
HCl) synthesized by this route was highly pure (>99.5% by
HPLC), but unfortunately, the optical rotation and chiral purity
was found to be fairly low (∼10% racemization was observed).
We were surprised by this result as we never expected
racemization during the deoxygenation reaction using Raney Ni
or the N-benzylation step. When we went back to check the
optical rotation of the intermediate 2 (methamphetamine)
isolated after the deoxygenation step, to our surprise, the SOR
was found to be low, indicating that the racemization really
happened during this transformation. Also, we developed the
chiral HPLC method and found that the chiral purity of
methamphetamine (2) was low (10% racemization, Figure 2),
confirming that the racemization had occurred during the
deoxygenation step.
chloride salt formation was accomplished using HCl in ethyl
acetate (8−10%) which afforded the API (benzphetamine
hydrochloride) in >99.8% HPLC as well as >99.9% chiral purity
in very good yield. The final API was devoid of any impurity
(NMT 0.1%) and satisfied all the ICH guidelines.8
Impurity Profiling. Impurity profile of a drug is very
important for its efficiency and safety point of view. To control
the process impurities it is very important to isolate and
characterize all the impurities present in the drug substance.
After developing the process, we turned our attention to
impurity profile study and tried to isolate and identify all the
possible impurities that could be formed during the process.
For this purpose, the ethyl acetate mother liquor after HCl salt
formation of the final API was injected in HPLC, and several
(six) prominent peaks were observed to the level of 1−5%
(HPLC area). From the LC/MS experiment, two of these
impurities were confirmed to be pseudoephedrine (m/z 165,
SM) and methamphetamine (m/z 149, intermediate) [also
confirmed by coinjection]. For identification/characterization
and structure confirmation with peaks m/z values 255, 245, 259
and 261, we decided to isolate these impurities. By careful and
tedious preparative HPLC, we isolated very small samples of
these four impurities and confirmed the structures (7, 8, 9 and
Hence, at this stage we decided to abandon this route and
work on alternate process which would avoid this problem.
After careful/extensive literature search, it was found that
recently Gollapudy et al.6 disclosed (U.S. Patent 0293971,
2008) an efficient process for methamphetamine involving
deoxygenation of protected ephedrine/pseudoephedrine (as
amides) without any racemization using Raney Ni. The
protecting groups they chose vary from −CO−H, −CO−Me,
and −CO−Ph which form the corresponding amides and
finally were hydrolyzed after the deoxygenation step under
harsh conditions to release the free amine. We planned to
investigate the utility of tert-butyl carbamate protection (Boc)
for this transformation as the Boc deprotection would require
milder conditions later in the synthesis. Accordingly,
ephedrine/pseudoephedrine HCl was treated with Boc2O in
the presence of NaHCO3 in water (Scheme 3) to afford the
Boc-protected compound (5) which was subjected to the
deoxygenation reaction under our earlier condition of Raney Ni
in IPA. The reaction proceeded smoothly to provide clean
deoxygenated product (Boc-methamphetamine, 6), but at this
stage we were unaware of the effect on chiral purity. Thus, the
Boc group of this intermediate was cleaved using HCl in ethyl
acetate to provide the desired methamphetamine HCl (2). To
our satisfaction, the chiral purity of this was found to be more
than 99.9%, and the optical rotation matched with the reported
values, indicating no racemization. This transformation was
repeated a few times and was scaled up to 0.5 kg scale in the
laboratory (it is currently being performed on commercial
scale). Once we solved the major problem and were able to
avoid/prevent any racemization during the deoxygenation step,
we focused our attention on optimizing the N-benzylation step.
The benzylation step was attempted using various bases in
different solvents; most of the reactions were found to be clean
and gave the product in very good yield. Amongst all the
conditions for the benzylation reaction, we decided to go with
K2CO3 as base and water as the solvent (70−75 °C, 10 h)
which provided the benzphetamine free base after workup in
reasonably good purity and high yield (excess benzyl chloride
and benzyl alcohol that formed during the process could be
easily removed by acid−base workup).7 Finally, the hydro-
1
10) on the basis of mass and H NMR (isolated impurity
samples were not enough for complete characterization) as in
Figure 3.
Hence, we planned to synthesize all these four impurities
which would enable us to provide sufficient quantities of these
impurities to the analytical group to complete all their activities
to include these compounds in the final API as known
impurities. Accordingly, we synthesized all these four impurities
using a straightforward sequence of reactions (Schemes 4 and
5), and generated working standards of these impurities and
completed all the analytical activities including the analytical
method validation of the API.
EXPERIMENTAL SECTION
■
General Procedures. All materials were purchased from
commercial suppliers. Unless specified otherwise, all reagents
and solvents were used as supplied by manufacturers. 1H NMR
spectra and 13C NMR spectra were recorded on a Varian 400
MR spectrometer in CDCl3 and DMSO-d6, and mass spectra
Scheme 4. Synthesis of impurity 7, 9 and 10
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(m, 3H), 7.3−7.1 (m, 5H), 4.3−4.2 (m, 2H), 3.9−3.5 (m, 2H),
2.72 (m, 3H), 2.67−2.56 (m, 1H), 1.3−1.2 (m, 3H). 13C NMR
(CDCl3, 100 MHz, δ ppm): 135.8, 135.4, 130.8, 130.7, 129.6,
129.6, 129, 129, 128.9, 128.8, 128.7, 128.5, 128.4, 126.9, 126.8,
60.2, 60.1, 57.34, 55.7, 37.9, 35.8, 36.02, 34.5, 13.4, 11.3.
C17H21N·HCl, (M+)/z: 239.36, Found: (M + H)/z: 240.0;
Anal. for C17H21N·HCl, calcd: C, 73.49; H, 8.71; N, 5.04;
Found: C, 73.43; H, 7.93; N, 5.05. HPLC purity >99.8%
Identification of the Impurities by LC/MS. The LC/MS
analysis was carried out on hypersil BDS, C8, 250 mm × 4.6
mm, 5 μm particle diameter column. The mobile phase A
contained 0.01 M ammonium acetate in purified water, and the
pH was adjusted to 4.5 with glacial acetic acid. The mobile
phase B consisted of acetonitrile and purified water in the ratio
of 9:1 (v/v). The flow rate of the mobile phase was 1.0 mL
min−1. The column temperature was kept at 25 °C, and the LC
gradient program was set as: time (min)/% solution B: 0/20,
3/20, 30/60, 35/60, 40/90, 45/90, and 46/20, and the
detection was monitored at wavelength of 207 nm. The
injection volume was 20 μL. A mixture of water and acetonitrile
(1:1) was used as diluents. The LC/MS analysis of the
impurities were carried out on a triple quadruple mass
spectrometer (MDS Sciex model API 2000). The analysis
was performed in the positive (+ve) ion mode with electron
spray ionization technique (ESI) interface with the following
conditions: declustering potential at 40 V, entrance potential at
10 V, focusing potential at 325 V, curtain gas 20 L min−1, ion
spray voltage 4500 V, and temperature 450 °C.
Isolation and Characterization of the Compounds 7,
8, 9 and 10. The compounds 7, 8, 9 and 10 were isolated by
preparative HPLC of the crude mass obtained upon
concentration of mother liquor of benzphetamine hydro-
chloride. A Waters autopurification system equipped with
binary gradient module (Waters 2545), system fluidics
organizer (Waters SFO), photodiode array detector (Waters
2998) and a sample manager (Waters 2767) with Mass lynx
data handling system, and a Waters Symmetry C18 (30 mm ×
100 mm) preparative column packed with 5 μm was employed
for the isolation of impurities. Mobile phase A consisted of
1.0% ammonium acetate pH 4.5 adjusted by acetic acid, and
mobile phase B consisted of methanol. Flow rate was kept at 30
mL/min, and UV detection was carried out at 207 nm.The
gradient program was as follows. Time (min)/A (v/v): B (v/v),
Scheme 5. Synthesis of impurity 8
were determined on an API-2000LCMS mass spectrometer,
Applied Biosystems. Elemental Analysis was done in a VarioEL
III instrument.
Preparation of Methamphetamine Hydrochloride (2).
To a solution of (+)-pseudoephedrine hydrochloride (4, 20 kg,
99.0 mol) in water (100 L) at room temperature, was added
sodium bicarbonate (18.28 kg, 217 mol) with stirring. Boc
anhydride (23.84 kg, 110 mol) was added into the reaction
mixture slowly at room temperature, and stirring was continued
for the next 12 h. After completion of the reaction (monitored
by HPLC), the reaction mixture was extracted with ethyl
acetate (2 × 80 L). The combined ethyl acetate layer was
washed with water (55 L) and concentrated at below 55 °C
under reduced pressure. The residue was redissolved in
isopropanol (55 L) and transferred into an autoclave. Raney
Ni (40 kg) suspension in isopropanol (55 L) was added into
the reaction mixture and heated to 50−55 °C. After completion
of the reaction (by HPLC), the reaction mixture was cooled to
room temperature and filtered through a Hyflo bed. Filtrate was
concentrated at 50−55 °C under reduced pressure to obtain a
crude oil. The crude oil thus obtained was dissolved in ethyl
acetate and cooled to 0−5 °C. Ethyl acetate HCl (96 L) was
added into it, and the reaction mixture was stirred at room
temperature for 20 h. Ethyl acetate was removed under reduced
pressure at 55−60 °C. To the residue was added ethyl acetate
(75 L) and stirred at 10−15 °C for 1 h and filtered. The solid
thus obtained was washed with cold ethyl acetate (10−15 °C,
55 L). Material was dried at 50−55 °C under vacuum to obtain
1
2 (16.5 kg, 90%). H NMR (CDCl3, 400 MHz, δ ppm): 9.73
(bs, 2H), 7.32−7.21 (m, 5H), 3.49 (m, 1H), 3.35 (m, 1H), 2.85
(m, 1H), 2.7 (s, 3H), 1.35 (d, 3H, J = 6.52 Hz). 13C NMR
(CDCl3, 100 MHz, δ ppm): 135.9, 129.1, 128.6, 127.0, 56.9,
39.1, 30.0, 15.2. C10H15N·HCl, (M+)/z: 149.24, Found: (M +
H)/z: 150.0.
Preparation of Benzphetamine Hydrochloride. To a
solution of methamphetamine hydrochloride (2, 11 kg, 59 mol)
in water (55 L), at room temperature, was slowly added
potassium carbonate (24.5 kg, 177 mol) and stirred for 30 min.
Benzyl chloride (9.74 kg, 76.9 mol) was added into the reaction
mixture, and the reaction mixture was heated at 70−75 °C for
10 h. After completion of the reaction, it was cooled to room
temperature and extracted with toluene (55 L). The toluene
layer was acidified with dil HCl (55 L, 6.6 N) at 5−10 °C. The
layer was separated; the aqueous layer was washed with toluene
(44 L). The aqueous layer was then basified with sodium
hydroxide solution (11.78 kg in 11.78 L water) to pH ∼12. The
product was then extracted with toluene (3 × 55 L). The
combined toluene layers were concentrated at 50−55 °C under
reduced pressure to get the benzphetamine free base. The free
base was then dissolved in ethyl acetate (6 L) and cooled to 5−
10 °C, and to this was added ethyl acetate HCl (32 L, 8−10%),
and the reaction mixture was stirred at 25−30 °C for 10 h. The
solid thus obtained was filtered and slurry washed with ethyl
acetate to obtain API grade benzphetamine hydrochloride (1,
15 kg, 93%) after drying at 55−60 °C under vacuum. 1H NMR
(CDCl3, 400 MHz, δ ppm): 12.56 (bs, 1H), 7.8 (m, 2H), 7.5
T
0.01/80:20, T5.00/80:20, T25.00/40:60, T30.00/10:90, T36.00/
80:20, T40.00/80:20. A 500 mg/mL solution was prepared in a
mixture of water and acetonitrile (1:1), 900 μL solutions were
injected through auto-injector, and the elution was carried out.
Initially, one pilot run was carried out for simulation of the
auto-fraction collector parameter. Collected fractions were also
monitored for the chromatographic purity. In a similar way ∼40
injections were made. All the fractions from the 40 injections of
>95% chromatographic purity for a particular impurity were
mixed together. The mixed fractions of impurities were
concentrated under reduced pressure to remove the solvents,
and the product was extracted with dichloromethane under
basic conditions. The dichloromethane layer was concentrated
and used for further spectral studies. The structure of the
isolated compound was confirmed by independent synthesis,
and the compound was used for a reference standard for the
analysis of the benzphetamine hydrochloride.
Preparation of (1S,2S)-2-(Benzyl(methyl)amino)-1-phenyl-
propan-1-ol (7). To a solution of (+)-pseudoephedrine
hydrochloride (5.0 g, 24.78 mmol) in water (25 mL) were
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added potassium carbonate (6.85 g, 49.56.mmol) followed by
benzyl chloride (3.76 g, 29.74 mmol). The reaction mixture was
heated at 70−75 °C for 10 h. The reaction mixture was cooled
at room temperature. The product was extracted with toluene
(30 mL × 2). The toluene layer was washed with DM water
(20 mL). Toluene was removed under vacuum at 50 °C to
obtain a crude mass. The crude mass was then diluted with
ethyl acetate and dil HCl (1 N, 60 mL). The reaction mass was
stirred for 15 min, and the layers were separated. The aqueous
layer was basified with NaHCO3 and extracted with ethyl
acetate (2 × 30 mL). The combined organic layer was
concentrated under reduced pressure to obtain a sticky mass.
To this anhydrous ethyl acetate HCl (50 mL, 8−10%) was
added and stirred at room temperature for 30 min. The
reaction mass was concentrated under reduced pressure to
13.4. C17H27N, MS m/z [M+]+ 245.41, Found: (M + H)/z:
246.
Preparation of (1S,2S)-1-Cyclohexyl-2-(methylamino)-
propan-1-ol (11). To a solution of (+)-pseudoephedrine
hydrochloride (4, 5.0 g, 24.8 mmol) in water (50 mL) was
added Pd/C (1.0 g, 5% w/w), and the mixture was
hydrogenated under pressure (75−80 psi) at 55 °C for 6 h.
After completion of the reaction, the reaction mixture was
degassed with nitrogen and was filtered over a Hyflo bed. The
filtrate was diluted with aqueous sodium carbonate and stirred
for 30 min. The product was extracted with dichloromethane (2
× 30 mL). The combined dichloromethane layer was
concentrated under reduced pressure at below 45 °C to obtain
a crude mass. To this crude mass, anhydrous ethyl acetate HCl
(30 mL, 8−10%) was added and stirred for 30 min. The
reaction mixture was then concentrated under reduced pressure
1
obtain 7 (6.6 g, 91%) as a white solid. H NMR (CDCl3, 400
1
to yield 11 (4.0 g, 94%) as hydrochloride salt. H NMR
MHz, δ ppm): 9.17 and 9.48 (br s, 1H), 7.17−7.66 (m, 10H),
6.63−6.79 (m, 1H), 4.11−4.92 (m, 3H), 3.53 and 3.04 (m,
1H), 2.86−2.70 (m, 3H), 1.05−0.94 (m, 3H), 13C NMR
(CDCl3, 100 MHz, δ ppm): 140.5, 139.6, 131.1, 130.6, 129.8,
129.5, 129.2, 129, 128.5, 128.4, 127.2, 127.0, 74.4, 72.8, 63.7,
62.6, 58.2, 56.3, 36.8, 35.0, 11.5, 9.5. C17H21NO, [M+]+ 255.36,
Found: (M + H)/z: 256.2.
(CDCl3, 400 MHz, δ ppm): 3.0 (m, 1H), 2.5 (m, 1H), 2.4 (s,
3H), 1.8 (m, 2H), 1.6 (m, 3H), 1.5−1.1 (m, 6H), 1.0 (d, 2H, J
= 6.3 Hz). 13C NMR (CDCl3, 100 MHz, δ ppm): 77.9, 56.6,
39.6, 32.8, 30.7, 26.7, 26.4, 26.3, 25.5, 15.2. C10H21NO, (M+)/z:
171.28, Found: (M + H)/z: 172.1.
Preparation of (1S, 2S)-2-(Benzyl(methyl)amino)-1-cyclo-
hexyl-propane-1-ol (9). To a solution of 11 (3.5 g, 20.5 mmol)
in water (20 mL) was added potassium carbonate (5.64 g,
40.86 mmol), followed by benzyl chloride (3.1 g, 24.5 mmol) at
room temperature. The reaction mixture was heated at 70−75
°C for 8 h. After completion of the reaction, it was cooled at
room temperature and extracted with toluene (2 × 20 mL).
The combined toluene layers were washed with water (20 mL).
Toluene was removed under reduced pressure at below 50 °C
to obtain a crude mass. The crude mass was then diluted with
ethyl acetate and dil HCl (1 N, 50 mL). The reaction mass was
stirred for 15 min, and the layer was separated. The aqueous
layer was basified with NaHCO3 and extracted with ethyl
acetate (2 × 25 mL). The combined organic layer was
concentrated under reduced pressure to obtain a sticky mass.
To this anhydrous ethyl acetate HCl (20 mL, 8−10%) was
added and stirred at room temperature for 30 min. The
reaction mass was concentrated under reduced pressure to
Preparation of (S)-1-Cyclohexyl-N-methylpropan-2-amine
(13). To a solution of methamphetamine HCl (2.5 g, 13.45
mmol) in water was added 5% Pd/C (0.25 g), and the reaction
mixture was hydrogenated at 75−80 psi and at 55 °C for 6 h.
After complete consumption of the starting material, the
reaction mixture was filtered over a Hyflo bed. Aqueous sodium
carbonate was added to the filtrate and stirred for 30 min. The
product was extracted with dichloromethane (30 mL × 2). The
combined dichloromethane layer was concentrated under
reduced pressure at below 45 °C to get the product as free
1
base 13 (1.7 g, 82%); H NMR (CDCl3, 400 MHz, δ ppm):
9.34 (bm, 2H), 3.20 (m, 1H), 2.63 (S, 3H), 1.79−1.7 (m, 7H),
1.6−1.5 (m, 1H), 1.40 (d, J = 6.5 Hz, 3H), 1.29−1.12 (m, 3H),
1.0−0.89 (m, 2H). 13C NMR (CDCl3, 100 MHz, δ ppm):
135.9, 129.1, 128.6, 127.0, 96.9, 39.1, 30.0, 15.2. C10H21N, MS
m/z[M+]+ 155.29, Found: (M + H)/z: 156.
Preparation of (S)-N-Benzyl-1-cyclohexyl-N-methylpro-
pan-2-amine (8). To a solution of 13 (5.0 g, 32.19 mmol)
in water was added potassium carbonate (8.9 g, 64.39 mmol),
followed by benzyl chloride (4.89 g, 38.63 mmol). The reaction
mixture was heated to 70−75 °C for 10 h and then cooled to
room temperature. The product was extracted with toluene (25
mL × 2). The combined toluene layers were washed with DM
water (20 mL). Toluene was removed at below 50 °C under
reduced pressure to obtain a crude mass. The crude mass was
then diluted with ethyl acetate and dil HCl (1 N, 70 mL). The
reaction mass was stirred for 15 min and layer was separated.
The aqueous layer was basified with NaHCO3 and extracted
with ethyl acetate (2 × 30 mL). The combined organic layer
was concentrated under reduced pressure to obtain sticky mass.
To this anhydrous ethyl acetate HCl (50 mL, 8−10%) was
added and stirred at room temperature for 30 min. Reaction
mass was concentrated under reduced pressure to obtain 8
1
obtain 9 (5.2 g, 86%) as white solid. H NMR (CDCl3, 400
MHz, δ ppm): 7.31−7.25 (m, 5H), 3.68 and 3.39 (ABq, J = 13
Hz, 2H), 3.26 (m, 1H), 2.72 (m, 1H), 2.13 (s, 3H), 1.8−1.15
(m, 11H), 0.93 (d, 3H, J = 6.6 Hz), 13C NMR (CDCl3, 100
MHz, δ ppm): 138.9, 128.8, 128.3, 127.0, 74.8, 59.5, 57.8, 39,
35.8, 31.5, 27.0, 26.5, 26.4, 24.5, 7.6. C17H27NO, (M+)/z:
261.41, Found: (M + H)/z: 262.2.
Preparation of (S)-1-Cyclohexyl-2-(methylamino)propan-
1-one (12). To a solution of 11 (1.5 g, 8.8 mmol) in
dichloromethane (15 mL) was added Dess−Martin period-
inane (3.9 g, 9.2 mmol) at 5−10 °C. The reaction mixture was
stirred for 4 h at room temperature. After completion of the
reaction, it was quenched with aqueous sodium sulfite (20 mL)
and stirred for 1 h. The product was then extracted with
dichloromethane (2 × 20 mL). The combined organic layer
was washed with water (20 mL) and concentrated under
reduced pressure at below 40 °C to obtain a crude mass. To
this crude mass, anhydrous ethyl acetate HCl (20 mL, 8−10%)
was added and stirred for 30 min. The reaction mixture was
then concentrated under reduced pressure to yield 12 (1.0 g,
1
(5.68 g, 62%) as white solid. Molecular formula: H NMR
(CDCl3, 400 MHz, δ ppm): 7.30−7.20 (m, 5H), 3.50 (ABq,
2H, J = 13.3 Hz), 2.82 (m, 1H), 2.11 (s, 3H), 1.48−1.40 (m,
2H), 1.3−1.1 (4H), 1.0 (d, J = 6.5 Hz 3H), 0.88 (m, 1H). 13C
NMR (CDCl3, 100 MHz, δ ppm): 140.6, 128.7, 128.1, 126.6,
57.7, 54.4, 41.7, 41.6, 36.3, 36.3, 34.5, 33.6, 26.8, 26.4, 13.61,
1
65%). H NMR (CDCl3, 400 MHz, δ ppm): 9.67 (br s, 2H),
4.17 (q, 1H, J = 7.2 Hz), 2.72 (s, 3H), 2.59−2.52 (m, 1H),
2.0−1.9 (m, 2H), 1.8−1.7 (m, 4H), 1.67 (d, 3H, J = 7.2 Hz),
499
dx.doi.org/10.1021/op400313y | Org. Process Res. Dev. 2014, 18, 495−500

Organic Process Research & Development
Article
1.5−1.4 (m, 1H), 1.4−1.16 (m, 4H). 13C NMR (CDCl3, 100
MHz, δ ppm): 208.0, 60.5, 47.0, 30.8, 28.8, 27.3, 25.4, 25.3,
24.7, 13.8; C10H19NO, MS m/z[M+]+ = 169.27, Found: (M +
H)/z: 170.1, (M + Na)/z: 192.3.
(3) (a) Kalota, D. J.; Tomazi, K. G. U.S. Patent 0262268, 2008. (b) .
Kalota, D. J.; Tomazi, K. G. U.S. Patent 2,750,187, 2010.
(4) (a) . Tomazi, K. G. U.S. Patent 0124833, 2009. (b) . Tomazi, K.
G., Nichols, G. A., Menze, M. R., Kalota, D. J. U.S. Patent 0113831,
2010.
(5) (a) Marco, J. L.; Royer, J.; Husson, H. P. Synth. Commun. 1987,
17 (6), 669−676. (b) . Aktiengesesellschaft, K. Ger. 968,545, 1958.
(c) Larizza, A.; Brancaccio, G.; Segre, A. J. Med. Chem. 1966, 9, 966−
967. (d) Gero, A. J. Org. Chem. 1951, 16, 1731−1735. (e) Tsutsumi,
M. Sci. Crime Detect. (Japan) 1953, 6, 50−52. (f) Skinner, H. F.
Forensic Sci. Int. 1990, 48 (2), 123. (g) . Boswell, R. F., Lo, Y. L. U.S.
Patent 6,399,828, 2002.
(6) Gollapudy, S., Venkata, R. N. U.S. Patent 0293971, 2008.
(7) Gurjar, M. K., Tripathy, N. K., Bapat, K. A., Rao, V.P. K. V.,
Biswas, S. B., Mehta, S. S. U.S. Patent 0046416, 2011.
(8) International Conferences on Harmonizations Guidelines:
(a) ICH Guidelines, Q3A (R2), Impurities in New Drug Substances,
October 2006. (b) ICH Guidelines, Q3B (R2), Impurities in New Drug
Products, June 2006. (c) ICH Guidelines, Q3C, (R5), Guidelines for
Residual Solvents, February 2011.
Preparation of (S)-2-(Benzyl(methyl)amino)-1-cyclohexyl-
propan-1-one (10). To a solution of 12 (1.0 g, 5.90 mmol) in
water (10 mL) was added potassium carbonate (1.63 g, 11.81
mmol) followed by benzyl chloride (0.9 g, 7.09 mmol). The
reaction mixture was heated at 70−75 °C for 8 h. The reaction
mixture was cooled at room temperature and was extracted
with toluene. The combined toluene layers were washed with
water (20 mL) and concentrated under reduced pressure at
below 40 °C to obtain a crude mass. The crude mass was then
diluted with ethyl acetate and dil HCl (1 N, 20 mL). The
reaction mass was stirred for 15 min, and the layer was
separated. The aqueous layer was basified with NaHCO3 and
extracted with ethyl acetate (2 × 25 mL). The combined
organic layer was concentrated under reduced pressure to
obtain a sticky mass. To this anhydrous ethyl acetate HCl (20
mL, 8−10%) was added and stirred at room temperature for 30
min. The reaction mass was concentrated under reduced
1
pressure to obtain 10 (1.2 g, 69%) as white solid. H NMR
(CDCl3, 400 MHz, δ ppm): 7.34−7.24 (m, 5H), 3.55−3.38 (m,
2H), 3.47 (q, J = 6.7 Hz, 1H), 2.96−2.91(m, 1H), 2.2 (s, 3H),
1.8−1.7 (m, 5H), 1.4−1.18 (m, 5H), 1.1 (d, J = 6.7 Hz, 3H).
13C NMR (CDCl3, 100 MHz, δ ppm): 215.7, 139.4, 128.7,
128.3, 127.1, 64.2, 58.8, 47.0, 37.9, 29.6, 28.1, 26.1, 25.9, 25.5,
7.9. C17H25NO, MS m/z[M+]+ 259.39, Found: (M + H)/z:
260.3.
CONCLUSION
■
A practical, efficient and scalable process for the manufacture of
benzphetamine hydrochloride has been described. The process
is mild, industrially reliable and capable for delivering high
quality API with high enantimeric excess even in multi kg scale.
The process is presently being used for the commercial
production in our organization.
ASSOCIATED CONTENT
■
S
* Supporting Information
Spectral data of selected intermediates and final compound.
This information is available free of charge via the Internet at
http://pubs.acs.org/.
AUTHOR INFORMATION
■
Corresponding Authors
*Fax: +91-20-39821445. E-mail: Chinmoy.Pramanik@emcure.
co.in.
*E-mail: Ashok.Chaudhari@emcure.co.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Mr. Samit Mehta, our management, and
ARD group of Emcure Pharmaceuticals Ltd. for their willing
support and constant encouragements.
REFERENCES
■
(1) Veldkamp, W.; Tazelaar, A. P.; Freyburger, W. A.; Keasling, H. H.
Toxicol. Appl. Pharmacol. 1964, 6, 15−22.
(2) Heinzelman, R. V.; Asporgren, B. D. U.S. Patent 2,789,138, 1957.
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