Synthesis of all enantiomerically pure diastereomers of aprepitant

Article abstract of DOI:10.1080/00397910903221084

Syntheses of all eight enantiomerically pure diastereomers of aprepitant and assignment of absolute configuration at newly generated stereocenters by NMR and X-ray crystallographic analysis were achieved. Copyrigh

Full text of DOI:10.1080/00397910903221084

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Synthesis of All Enantiomerically Pure
Diastereomers of Aprepitant
Srinivas Gangula a , Chandrashekhar R. Elati a , Satish Varma
Mudunuru a , Anitha Nardela a , Ashok Dongamanti b , Apurba
Bhattacharya a & Rakeshwar Bandichhor a
a Innovation Plaza, Dr. Reddy's Laboratories Ltd., Bachupally,
Qutubullapur, India
b Department of Chemistry, Osmania University, Hyderabad, India
Version of record first published: 07 Jul 2010.
To cite this article: Srinivas Gangula , Chandrashekhar R. Elati , Satish Varma Mudunuru , Anitha
Nardela , Ashok Dongamanti , Apurba Bhattacharya & Rakeshwar Bandichhor (2010): Synthesis of
All Enantiomerically Pure Diastereomers of Aprepitant, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 40:15, 2254-2268
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Synthetic Communications1, 40: 2254–2268, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903221084
SYNTHESIS OF ALL ENANTIOMERICALLY PURE
DIASTEREOMERS OF APREPITANT
Srinivas Gangula,1 Chandrashekhar R. Elati,1
Satish Varma Mudunuru,1 Anitha Nardela,1
Ashok Dongamanti,2 Apurba Bhattacharya,1 and
Rakeshwar Bandichhor1
1Innovation Plaza, Dr. Reddy’s Laboratories Ltd., Bachupally,
Qutubullapur, India
2Department of Chemistry, Osmania University, Hyderabad, India
Syntheses of all eight enantiomerically pure diastereomers of aprepitant and assignment
of absolute configuration at newly generated stereocenters by NMR and x-ray crystallo-
graphic analysis were achieved.
Keywords: ICH; spectroscopy; stereoisomers; synthesis; X-ray crystallography
INTRODUCTION
Aprepitant, shown in Fig. 1, is a drug known to elicit activity against the
human neurokinin-1 (NK-1) receptor.[1] In general, during synthesis of desired
species, traces of undesired by-products (e.g., stereoisomers) are observed, which
we refer to as impurities.
According to the International Conference on Harmonization (ICH) guide-
lines, active pharmaceutical ingredient (API) contamination by impurities cannot
be more than 0.05–0.15%. Impurities must be identified by spectroscopy and other
techniques to ensure that the elicited pharmacological or toxicological effects are
not due to impurities and that in the due course of product formulation and market-
ing, impurities will not be generated or elevated. Nevertheless, the impurities may
not always be considered inferior, as they may have better pharmacological and
inferior toxicological properties.[2] In our endeavour to synthesize aprepitant, an
enantiomer and the diastereomers of 1 were found to be potential synthetic impuri-
ties. To meet ICH standards, we synthesized all enantiomerically pure diastereomers
in significant quantities, mainly for characterization. In this article, we describe (i)
the synthesis of all enantiomerically pure diastereomers of aprepitant 1 (Fig. 2)
Received May 18, 2009.
IPDO Communication IPDO-IPM-00129.
Address correspondence to Rakeshwar Bandichhor, Innovation Plaza, Dr. Reddy’s Laboratories
Ltd., Survey Nos. 42, 45, 46, and 54, Bachupally, Qutubullapur, R. R. District 500 073, A.P., India.
E-mail: rakeshwarb@drreddys.com
2254

SYNTHESIS OF DIASTEREOMERS OF APREPITANT
2255
Figure 1. Structure and ORTEP diagram of aprepitant 1.
and (ii) the depiction of the absolute configuration of all stereocenters by employing
NMR and x-ray crystallography techniques.
RESULTS AND DISCUSSION
De novo synthesis of aprepitant 1, confirmed by x-ray crystal analysis (Fig. 1),
was recently reported.[3] As an extension of the previous work, we present a strategy
to synthesize and characterize all the enantiomerically pure diastereomers.
Understanding the physical property differences between two diastereomeric
salts of resolving agent and their corresponding enantioforms led us to isolate and
characterize all the diastereomers of 1.
As reported earlier[3] and shown in Scheme 1, intermediate 5 was successfully
synthesized from hydrochloride salt of N-benzyl protected 5 and further subjected
to the isopropyl alcohol (IPA)–mediated crystallization that afforded the major
diastereomer 6 as a solid. The minor diastereomer 7 (in solution) contaminated with
6 was found to be soluble in IPA (mother liquor). Resolution of 6 was accomplished
Figure 2. Structure of 1, its enatiomer (ent-1), and diastereomers (2, ent-2, 3, ent-3, 4, ent-4).

2256
S. GANGULA ET AL.
Scheme 1. Isolation of trans pairs (8 and ent-8, and 9 and 9) to obtain diastereomers (2 and ent-2, and 3
and ent-3) of 1.
using L-(–)-camphorsulfonic acid in methanol, which gave intermediate 8 in 75%
yield and 97% chiral purity. The structure of the L-(–)-CSA salt of 8 was confirmed
by x-ray analysis[3] (Scheme 1). The free amine 8 served as an advanced intermediate
to synthesize diastereomer 2.
The diastereomeric L-(–)-CSA salt of ent-8, present in methanol (mother liquor),
was subjected to base hydrolysis followed by enantiomeric enrichment employing
D-(þ)-CSA in methanol, which afforded the diastereomeric D-(þ)-CSA salt of ent-8
with 64% yield and 99.0% chiral purity. This, upon basic hydrolysis, yielded free amine
ent-8. The resultant ent-8 was used as a source of diastereomer ent-2.
Diastereomer 7 in mother liquor was found to be contaminated with around
20% of 6. Further crystallization of this mixture with tartaric acid afforded 7 in
85% yield and 99% high performance liquid chromatography (HPLC) purity. The sol-
ution of diastereomer 7 in IPA was subjected to semipreparative normal-phase HPLC
on a Chiracel OD column that afforded 9 and its antipode, ent-9, in quantitative yield
(based on its 50% abundance) and >99% chiral HPLC purity for each.
These two intermediates were separately used to synthesize the other two
diastereomers (3 and ent-3) of aprepitant 1 as per the method described earlier.[4]

SYNTHESIS OF DIASTEREOMERS OF APREPITANT
2257
Scheme 2. Synthesis of cis pairs (12 and ent-12, and 13 and ent-13) through corresponding imines (10 and
ent-10, and 11 and ent-11) to obtain 1, ent-1, 4, and ent-4.
Figure 3. Stereoselective reduction of imine 10.

2258
S. GANGULA ET AL.
At this stage, conversion of 8 into 12 was carried out following Zhao and
coworkers’[5] procedure. The crystalline imine 10 was reduced with sodium borohy-
dride with complete cis-stereoselectivity[6] to afford 12 as shown in Scheme 2.
The stereochemical outcome, as shown in Fig. 3, of this reduction process is
due to the presence of a bulky 2-alkoxy group in intermediate 10, which directed
the favored attack of hydride from the less hindered face of the plane of the molecule
to afford 12 as a major isomer (cis). Because of the steric hindrance, the hydride
trajectory from the top face afforded the disfavored or minor isomer 8 (trans). This
exercise was performed independently starting from ent-8, 9 and ent-9 to obtain
diastereomers ent-12, 13 and ent-13 respectively. Subsequent condensation of inter-
mediate 12 with chloroacetamidrazone, following a precedented procedure[6] and
in situ cyclization of the resulting intermediate at 120 ꢀC in a closed autoclave
system, gave 1 in 60% yield.[3]
However, the syntheses of other diastereomers of aprepitant, ent-1, 2, ent-2, 3,
ent-3, 4, and ent-4, as shown in Fig. 2, were achieved following a one-pot procedure[4]
that involves the condensation of 8, ent-8, 9, ent-9, ent-12, 13, and ent-13 respectively
with chloromethyltriazolinone.
Figure 4. Comparative values of chemical shifts and coupling constants of a proton present at C-2
position in cis (1 and 4) and trans pairs (2 and 3).

SYNTHESIS OF DIASTEREOMERS OF APREPITANT
2259
The characterization and establishment of stereochemistry at the chiral centers
of all enantiomerically pure diasteriomers pose a great challenge. Through routine
1H NMR studies, we observed that the distereomers (i.e., 2, 3, and 4 of aprepitant
1) have different chemical shifts and characteristic differences in coupling constant
values for protons present at C-1, 2, and 3 centers.
As summarized in Fig. 4, the chemical shift of HC-2 and its coupling constant
present in aprepitant 1 were found to be 4.37 ppm and 2.8 Hz; this indicates that the
protons at C-2 and 3 positions are placed in a cis fashion. However, the chemical
shift and coupling constant values for the same proton in diastereomer 2 were
recorded as 4.19 ppm and 7.2 Hz, which is in agreement with an orientation of
protons at HC-2 and 3 in trans fashion. We believe, based on the analysis, that this
is a pair of diastereomers in which the orientation of methyl group at C-1 center is in
the a-position. With the second pair of diastereomer 4 and 3 in which the orientation
of methyl group at C-1 centre is in b-position, we observed similar patterns in the
chemical shifts and coupling constant values. The chemical shifts and coupling
constants for HC-2 present in 4 and 3 were found to be 4.85 ppm, 2.8 Hz (cis),
and 4.50 ppm and 7.2 Hz (trans), respectively.
The x-ray crystallographic analysis for 8[3] clearly showed that the morpholine
core has a trans arrangement as both the fluorophenyl and alkoxy groups are in
equatorial orientations, and the methyl group is a disposed.
Detailed x-ray analysis for free base of 7 clearly showed, as shown in Fig. 5a,
that the molecules are connected by centrosymmetric N1-H19 ꢁꢁꢁ F1 and C6-H6 ꢁꢁꢁ F1
dimers and propagating along the a axis. The observed configuration of the chiral
centres was SSR and RRS. Based on the x-ray crystallographic studies, it has been
concluded that the crystal of 7 contains racemate.
Additionally, x-ray analysis also revealed that the substituents at adjacent or
nearby chiral centers are relatively disposed in trans fashion as shown in Fig. 5b.
Figure 5. (a) ORTEP diagram and (b) crystal packing of 7.

2260
S. GANGULA ET AL.
CONCLUSIONS
In conclusion, we have successfully synthesized, isolated, and characterized all
the enantiomerically pure diastereomers of aprepitant 1.
EXPERIMENTAL
1
Solvents and regents were used for all the reactions as received. H NMR and
13C NMR spectra were recorded on a Varian Mercury spectrometer at 200 or
400 MHz. The proton signal of residual, nondeutrated solvents (d 7.26 for CDCl3,
2.2 ppm for DMSO-d6) was used as an internal reference for H NMR. Infrared
1
(IR) spectra were recorded as thin films on a Mattson Galaxy Series Fourier trans-
form (FT)–IR 3000 spectrometer referenced to polystyrene standard. Optical rota-
tions were measured on a Perkin-Elmer polarimeter model 341, using a quartz cell
with 5-mL capacity and a 100-mm path length. The electrospray ionization (ESI)
and tandem mass spectrometry (MS-MS) studies were performed on a triple quad-
rupole mass spectrometer PE Sciex model API 3000. CHN analysis was obtained
by using a Perkin-Elmer model 2400 S CHN elemental analyzer, and x-ray powder
diffractometer pattern was been obtained on a Rigaku D=Max-2200 model diffract-
ometer equipped with horizontal goniometer in h=2h geometry. Finally, x-ray data
for the single crystal have been collected on a AFC-7S diffractometer with mercury
˚
CCD detector using graphite monochromated Mo-Ka (k ¼ 0.7107 A) radiation. Dif-
ferential scaning calorimetric (DSC) analysis was carried out on Shimadzu DSC 50.
Diastereomeric purities of all the intermediates and diastereomers of aprepitant were
analyzed by HPLC or chiral HPLC.
Diastereomeric purity of compounds from 5 to 13 were estimated by RSHPLC
analysis (symmetry shield RP=18, 100 ꢂ 4.6 ꢂ 3.5 m and injection load 20 ml, flow rate
1.0 mL=min at 210 nm). Mobile phase A was a mixture of buffer=acetonitrile (70:30);
mobile phase B was a mixture of buffer= acetonitrile (20:80). Buffer was prepared
with 1.36 g of potassium dihydrogen phosphate in 1000 mL of water, pH 6, with
triethylamine. The gradient profile is shown in Table 1.
The enantiomeric purities of 9, ent-9, 13, and ent-13 were determined by using-
normal phase HPLC analysis [chiral cell=OD-H, 150 ꢂ 4.6 mm, injection load 20 mL,
flow 0.8 mL=min at 210 nm; mobile phase: n-hexane, 2-propanol, trifluoroacetic in
the ratio of 980:20:1 (v=v)].
Diastereomeric purities of 1, 2 and 3, 4 were determined by RSHPLC analysis
[Hypersil BDS C-18, 150 ꢂ 4.6 ꢂ 5 mL, injection volume: 20 ml, flow rate 1.0 mL=min
at 210 nm, diluents: mixture of acetonitrile and water in the ratio of 1:1, mobile phase
A: acetonitrile=buffer (20:80), mobile phase B: acetonitrile=buffer (80:20), buffer
preparation: dissolved 1.96 g of 99% solid orthophosphoric acid and 0.34 g of tetra
Table 1. Gradient profile
Time (min)
0.0
25
35
50
52
60
A (%)
B (%)
75
25
75
25
10
90
10
90
75
25
75
25

SYNTHESIS OF DIASTEREOMERS OF APREPITANT
2261
butyl ammonium hydrogen sulfate in 1000 mL milli-Q water]. The gradient profile is
shown in Table 2.
Enantiomeric purities of 1, ent-1, 2, ent-2, 8, ent-8, 12, and ent-12 compounds
were determined by using normal-phase HPLC analysis [chiral pack=AD-H,
250 ꢂ 4.6 mm, injection load 20 mL, flow rate 0.5 mL=min at 210 nm; mobile phase:
n-hexane and ethanol 90:10 (v=v)].
Preparation of 2R-[1R-(3,5-Bistrifluromethyl-phenyl)-ethoxy]-3R-
(4-fluoro-phenyl)-morpholine 8[3]
A methanolic solution of L-(–)-camphor-10-sulfonic acid (6.1 kg, 24.4 mol
in 18.0 L methanol) was added slowly to a solution of amine 6 (10.6 kg, 24.3 mol) in
methanol (18 L) at room temperature. The resulting reaction mass was stirred at room
temperature for 2–3 h, and the precipitated solid was filtered off to afford 6.1 kg L-(–)-
camphor-10-sulfonic acid salt of 8 in 75% (yield calculated based on available enan-
tiomer) with 98.5% ee. L-(–)-Camphor-10-sulfonic acid salt of 8 (6.1 kg) was dissolved
in a mixture of water (12.2 L) and toluene (12.2 L), and the suspension pH was
adjusted to 9.5–10.0 by using lye solution. Organic layer was separated; aqueous
phase was extracted with toluene (24.4 L). The combined organic layers were washed
with water (24.4 L) and concentrated under vacuum to obtain compound 8 as free
25
base in 98.5% yield (3.92 kg). Spectral data for free amine: ½aꢃD ¼ ðþÞ 33:35ꢀ (c ¼
1
0.77 MeOH); H NMR (400 MHz, DMSO-d6) d 7.85 (s, 1H), 7.50–7.35 (m, 4H),
7.10 (t, J ¼ 8.8 Hz, 2H), 5.00 (q, J ¼ 6.4 Hz, 1H), 4.15 (d, J ¼ 7.6 Hz, 1H), 3.95 (d,
J ¼ 6.4, 1H), 3.65–3.55 (m, 2H), 2.95–2.75 (m, 2H), 1.35 (d, J ¼ 6.4 Hz, 3H); MS calcd.
for C20H18F7NO2 (Mþ) 437.35; found (MHþ of free amine) 438.
Preparation of 2S-[1S-(3,5-Bistrifluromethyl-phenyl)-ethoxy]-3S-
(4-fluoro-phenyl)-morpholine ent-8
The filtrate (100 mL) from the experiment (preparation of 8) was concentrated
to obtain a mixture of the L-(–)-camphor-10-sulfonic acid salts of 8 (minor) and
ent-8 (major), and a mixture of water (200 mL) and toluene (400 mL) was added.
The reaction mass was adjusted to pH 9.5–10 using lye solution, and the toluene
layer was separated from the aqueous layer. Repeated extraction of the aqueous
layer with toluene (2 ꢂ 200 mL) was performed. Combined toluene layers were
washed with water (2 ꢂ 200 mL) and concentrated to get the thick syrup of mixture
of (8 and ent-8 in the ratio of 1:4). A methanolic solution of D-(þ)-camphor-10-
sulfonic acid (11.5 g, 0.04 mol in 35.0 mL methanol) was added slowly to a solution
of this mixture of amine 8 and ent-8 (20 g, 0.04 mol) in methanol (35 mL) at room
temperature. The resulting reaction mass was stirred at the same temperature for
Table 2. Gradient profile of RSHPLC
Time (min)
0.0
5.0
35
50
52
60
A (%)
B (%)
65
35
65
35
20
80
20
80
65
35
65
35

2262
S. GANGULA ET AL.
2–3 h, and the precipitated solid was filtered off to afford the product in 64% yield as
salt of D-(þ)-camphor-10-sulfonic acid ent-8 (15.6 g, calculated based on available
enantiomers) with 97.8% ee (98.9 purity by chiral HPLC). D-(þ)-Camphor-10-
sulfonic acid salt of ent-8 (15.6 g) was dissolved in mixture of water (50 mL) and
toluene (50 mL), and suspension pH was adjusted to 9.5–10.0 using a lye solution.
The organic layer was separated; the aqueous phase was extracted with toluene
(100 mL). The combined organic layers were washed with water (100 mL) and
concentrated under vacuum to obtain compound ent-8 as free base in 98.7% yield
25
(10.77 g). Spectral data for free amine: ½aꢃD ¼ ðꢄÞ 35:5ꢀ (c ¼ 0.78, MeOH); 1H
NMR (400 MHz, DMSO-d6) d 7.85 (s, 1H), 7.50–7.35 (m, 4H), 7.10 (t, J ¼ 8.8 Hz,
2H), 5.10 (q, J ¼ 6.4 Hz, 1H), 4.10 (d, J ¼ 7.6 Hz, 1H), 3.95 (d, J ¼ 6.4 Hz, 1H),
3.75–3.55 (m, 2H), 2.95–2.75 (m, 2H), 1.35 (d, J ¼ 6.4 Hz, 3H); 13CNMR
(100 MHz, DMSO-d6) d 162.7, 160.3, 147.6, 136.6, 130.6, 126.4, 124.6, 120.5,
114.2, 102.1, 73.9, 65.7, 63.2, 44.8, 21.6; MS calcd, for C20H18F7NO2 (Mþ) 437.35;
found (MHþ of free amine) 438.
2-[1-(3,5-Bistrifluromethyl-phenyl)-ethoxy]-3-(4-fluoro-phenyl)-
morpholine 7
Isopropyl alcohol mother liquor (500 mL) of 5[3] was concentrated to get syrup
(250 g), and it was subsequently suspended in water (750 mL). The pH was adjusted to
9.5–10 using lye solution. Dichloromethane (1.4 L) was added to extract the com-
pound 7 from aqueous layer. Organic layer was distilled to get 150 g of sec-amine 7.
Further, the sec-amine (150 g, 0.34 mol) was dissolved in isopropyl alcohol (450 mL),
and tartaric acid was added (51.5 g, 0.34 mol) at 25–35 ꢀC and stirred for 2–3 h.
The resulting solid was filtered and washed with isopropyl alcohol (100.0 mL). The
obtained tartarate salt (180 g) was suspended in water (400 mL) and toluene
(400 mL), and the pH was adjusted to 9.5–10 with lye solution. The toluene and aque-
ous layers were separated, and 7 was extracted from the aqueous layer with toluene
(2 ꢂ 200 mL). The organic layers were combined and concentrated to get 7 in 85%
1
yield, with 99.8% purity HPLC: H NMR (400 MHz, DMSO-d6) d 7.92–7.85 (m,
3H), 7.63–7.59 (m, 2H), 7.30–7.10 (m, 2H), 4.85 (q, J ¼ 6.4 Hz, 1H), 4.65 (d,
J ¼ 7.6 Hz, 1H), 3.95 (d, J ¼ 10.8 Hz, 1H), 3.70–3.50 (m, 1H), 3.49 (d, J ¼ 11.2 Hz,
1H), 2.85–2.75 (m, 2H), 1.0 (d, J ¼ 6.4 Hz, 3H); MS calcd. for C20H18F7NO2 (Mþ)
437.35; found (MHþ) 438.
2-[1-(3,5-Bistrifluromethyl-phenyl)-ethoxy]-3-(4-fluoro-phenyl)-
morpholine 9 and ent-9
Racemic free amine 7 (3.2 g, 7.0 mmol) was subjected to semipreparative
normal-phase HPLC on a Chiralcel OD column to obtain enatiomerically pure 9
(1.5 g, 3.4 mmol) and ent-9 (1.5 g, 3.4 mmol) isomers with quantitative yields.
Separation of isomer has been achieved by using Chiralcel OD column (cellulose
tris(3,5-dimethylphenylcarbamate), 250 mm ꢂ 10 mm, 10-mm particle diameter) with
a mobile phase consisting of n-hexane, 2-propanol, and triflouroacetic acid
(980:20:1 v=v), at a flow rate of 3 mL=min at 25 ꢀC and 210 nm wavelength. Data
25
for 9: 98.8% ee (99.4% purity by chiral HPLC); ½aꢃD ¼ ðþÞ 30:2ꢀ (c ¼ 0.78 MeOH);

SYNTHESIS OF DIASTEREOMERS OF APREPITANT
2263
1H NMR (400 MHz, DMSO-d6) d 7.95–7.80 (m, 3H), 7.63–7.59 (m, 2H), 7.15 (t,
J ¼ 8.8 Hz, 2H), 4.85 (q, J ¼ 6.4 Hz, 1H), 4.50 (d, J ¼ 7.6 Hz, 1H), 3.85 (d, J ¼ 10.8 Hz,
1H), 3.70–3.60 (m, 1H), 3.55 (d, J ¼ 11.2 Hz, 1H), 2.90–2.78 (m, 2H), 1.0 (d,
J ¼ 6.4 Hz, 3H); MS calcd for C20H18F7NO2 (Mþ) 437.35; found (MHþ) 438. Data
25
for ent-9: 99% ee (99.5 purity chiral HPLC); ½aꢃD ¼ ðꢄÞ 31:52ꢀ (c ¼ 0.78 MeOH);
1H NMR (400 MHz, DMSO-d6) d 7.92–7.80 (m, 3H), 7.63–7.59 (m, 2H), 7.15 (t,
J ¼ 8.8 Hz, 2H) 4.85 (q, J ¼ 6.4 Hz, 1H), 4.50 (d, J ¼ 7.6 Hz, 1H), 3.85 (d, J ¼ 10.8 Hz,
1H), 3.70–3.60 (m, 1H), 3.45 (d, J ¼ 11.2 Hz, 1H), 2.90–2.78 (m, 2H), 1.0 (d,
J ¼ 6.4 Hz, 3H); 13CNMR (100 MHz, DMSO-d6) d 162.7, 160.3, 147.5, 136.6,
129.9, 127.4, 126.4, 124.7, 120.5, 114.2, 102.1, 73.8, 65.7, 63.2, 44.8, 21.6; MS calcd.
for C20H18F7NO2 (Mþ) 437.35; found (MHþ) 438.
General Procedure for the Preparation of 2, ent-2[4]
Chloromethyltriazolinone solution (3.14 g, 0.02 mol) in dimethylformamide
(DMF) (30 mL) was added dropwise to a solution of sec-amine (8 or ent-8) (10 g,
0.02 mol) and K2CO3 (3.5 g, 0.02 mol), in DMF–water (33 mL) at 0 ꢀC and stirred
for 2 h. After completion of the reaction, water (100 mL) was added, and compound 2
as a solid was obtained after filtration in 99% yield (12 g) with 97.4% ee (98.7% purity
25
by chiral HPLC) and 98.0% purity by HPLC: ½aꢃD ¼ ðþÞ 49:72ꢀ (c ¼ 0.67 MeOH);
1
DSC ¼ 254.2 ꢀC. H NMR (400 MHz, DMSO-d6) d 11.25–11.0 (br, 2H), 7.86 (s,
1H), 7.41–7.35 (m, 4H), 7.07 (t, J ¼ 8.8 Hz, 2H), 5.05 (q, J ¼ 6.4 Hz, 1H), 4.19 (d,
J ¼ 7.2 Hz, 1H), 3.95 (dd, J ¼ 1.6, 2.0 Hz, 1H), 3.67 (dt, J ¼ 2.0, 2.0, 1.6 Hz, 1H),
3.35–3.20 (m, 2H), 2.88 (d, J ¼ 14.8 Hz, 1H), 2.65 (d, J ¼ 11.2 Hz, 1H), 2.42 (t,
J ¼ 2.8 Hz, 1H), 1.35 (d, 3H, J ¼ 6.4 Hz); MS calcd. for C23H21F7N4O3 (Mþ)
534.43; found (MHþ) 535. Ent-2 in 99.2% yield (12 g) with 98.4% ee (99.2% purity
25
by chiral HPLC) and 98.72% purity by HPLC; ½aꢃD ¼ ðꢄÞ 48:9ꢀ (c ¼ 0.68 MeOH);
1
DSC ¼ 254.8 ꢀC; H NMR (400 MHz, DMSO-d6 & CDCl3) d 11.00 (s, 1H), 11.78
(s, 1H), 7.86 (s, 1H), 7.38–7.35 (m, 4H), 7.07 (t, J ¼ 8.8 Hz, 2H), 5.00 (q, J ¼ 6.4 Hz,
1H), 4.19 (d, J ¼ 8.0 Hz, 1H), 3.95 (dd, J ¼ 2.0, 2.0 Hz, 1H), 3.70 (dt, J ¼ 1.6, 1.6,
2.0 Hz, 1H), 3.4 (d, J ¼ 10 Hz, 1H), 3.2 (d, J ¼ 12.4 Hz, 1H), 3.17 (d, J ¼ 12.4 Hz,
1H), 2.88 (d, J ¼ 14.8 Hz, 1H), 2.65 (d, J ¼ 11.2 Hz, 1H), 1.35 (d, J ¼ 6.0 Hz, 3H);
13C NMR (50 MHz, DMSO-d6) d 164.0, 159.2, 156.0, 146.0, 144.1, 133.7, 130.4,
129.6, 126.3, 120.9, 114.6, 101.9, 74.0, 68.5, 63.4, 50.4, 49.2, 24.2; MS calcd. for
C23H21F7N4O3 (Mþ) 534.43; found (MHþ) 535.
General Procedure for the Preparation of 3, ent-3, 4, and ent-4[4]
Chloromethyltriazolinone solution (157 mg, 1.17 mmol) in DMF (1.5 mL) was
added dropwise to a solution of sec-amine (9 or ent-9 or 13 or ent-13) (500 mg,
1.14 mmol) and K2CO3(175 mg, 1.27 mmol) in DMF–water (1.65 mL) at 0 ꢀC and
stirred for 2 h. After completion of the reaction, water (5.0 mL) was added, and com-
pound 3 as a solid was obtained after filtration in 98.6% yield (600 mg) with 98% ee
25
(99% purity by chiral HPLC) and 98.9% purity by HPLC; ½aꢃD ¼ ðþÞ 35:92ꢀ
(c ¼ 0.68 MeOH); DSC ¼ 253.8 ꢀC; 1H NMR (400 MHz, DMSO-d6 & CDCl3) :
d 11.3 (s, 1H), 11.2 (s, 1H), 7.95–7.85 (m, 3H), 7.58–7.55 (m, 2H), 7.00 (t, J¼ 8.8 Hz,
2H), 4.73 (q, J ¼ 6.4 Hz, 1H), 4.49 (d, J ¼ 7.2 Hz, 1H), 3.90 (m, 1H), 3.88

2264
S. GANGULA ET AL.
(d, J ¼ 10.0 Hz, 1H), 3.70 (dt, J ¼ 1.6, 1.6, 2.0 Hz, 1H), 3.41 (d, J ¼ 14.4 Hz, 1H), 2.95
(d, J ¼ 14.4 Hz, 1H), 2.75 (d, J ¼ 11.6 Hz, 1H), 2.41 (dt, J ¼ 2.4, 3.2, 2.4 Hz, 1H),
0.95 (d, J ¼ 6.4 Hz, 3H); MS calcd. for C23H21F7N4O3 (Mþ) 534.43; found (MHþ)
535; ent-3 in 98.6% yield (600 mg) with 97.0% ee (98.5% purity by chiral HPLC)
25
and 98.60% purity by HPLC; ½aꢃD ¼ ðꢄÞ 35:20ꢀ (c ¼ 0.68 MeOH); DSC ¼ 253.8 ꢀC;
1H NMR (400 M Hz, DMSO-d6 & CDCl3): d 11.3 (s, 1H), 11.2 (s, 1H), 7.90–7.84 (m,
3H), 7.65–7.55 (m, 1H), 7.22–7.0 (m, 2H), 4.73 (q, J ¼ 6.4 Hz, 1H), 4.57 (d,
J ¼ 7.2 Hz, 1H), 3.95 (m, 1H), 3.86 (d, J ¼ 10.0 Hz, 1H), 3.70 (dt, J ¼ 1.6, 1.6,
2.0 Hz, 1H), 3.41 (d, J ¼ 14.4 Hz, 1H), 2.95 (d, J ¼ 14.4 Hz, 1H), 2.75 (d, J ¼ 11.6 Hz,
1H), 2.41 (dt, J ¼ 2.4, 3.2, 2.4 Hz, 1H), 0.95 (d, J ¼ 6.4 Hz, 3H); 13C NMR (100 MHz,
DMSO-d6): d 162.8, 160.4, 156.2, 146.4, 143.7, 133.1, 130.9, 129.9, 127.0, 124.3,
121.6, 114.6, 95.4, 71.5, 67.6, 58.6, 51.4, 50.3, 24.3; MS calcd. for C23H21F7N4O3
(Mþ) 534.43; found (MHþ) 535; 4 in 98% yield (590.0 mg) with 96.8% ee (98.0%
25
purity by chiral HPLC) and 98.4% purity by HPLC; ½aꢃD ¼ ðþÞ 39:52ꢀ (c ¼ 0.68
MeOH); DSC ¼ 254.8 ꢀC;1H NMR (400 MHz, DMSO-d6 & CDCl3) d 11.36 (s,
1H), 11.25 (s, 1H), 7.98–7.91(m, 3H), 7.62–7.59 (m, 2H), 7.15 (t, J ¼ 8.8 Hz, 2H),
4.87 (d, J ¼ 2.8 Hz, 1H), 4.74 (q, J ¼ 6.4 Hz, 1H), 3.87 (t, J ¼ 9.2, 9.2 Hz, 1H), 3.61
(d, J ¼ 2.8 Hz, 1H), 3.48 (d, J ¼ 11.2 Hz, 1H), 3.35 (d, 1H, J ¼ 14.4 Hz), 2.85 (d,
J ¼ 14.0 Hz, 1H), 2.72 (d, J ¼ 11.6 Hz, 1H), 2.36 (t, J ¼ 2.0, 2.8 Hz, 1H), 1.02 (d,
J ¼ 6.4 Hz, 3H); MS calcd. for C23H21F7N4O3 (Mþ) 534.43; found (MHþ) 535;
ent-4 in 98.2% yield (600.0 mg) with 97.4% ee (98.7% purity by chiral HPLC) and
25
1
99.1% purity by HPLC; ½aꢃD ¼ ðꢄÞ 38:52ꢀ (c ¼ 0.68 MeOH); DSC ¼ 254.8 ꢀC; H
NMR (400 M Hz, DMSO-d6) d 11.36 (s, 1H), 11.25 (s, 1H), 7.98–7.91 (m, 3H),
7.62–7.59 (m, 2H), 7.15 (t, J ¼ 8.8 Hz, 2H), 4.87 (d, J ¼ 2.8 Hz, 1H), 4.74 (q,
J ¼ 6.4 Hz, 1H), 3.87 (t, J ¼ 9.6, 9.6 Hz, 1H), 3.61 (d, J ¼ 2.8 Hz, 1H), 3.48 (d,
J ¼ 11.6 Hz, 1H), 3.40 (d, J ¼ 14.4 Hz, 1H), 2.98 (d, J ¼ 14.0 Hz, 1H), 2.73 (d,
J ¼ 11.6 Hz, 1H), 2.37 (dt, J ¼ 3.2, 2.8, 3.2 Hz, 1H), 1.02 (d, J ¼ 6.4 Hz, 3H); 13C
NMR (50 MHz, DMSO-d6) d 159.0, 156.1, 147.5, 143.7, 133.4, 131.4, 130.3, 126.5,
125.9, 120.7, 114.5, 96.4, 73.3, 67.4, 59.2, 50.6, 50.2, 21.4; MS calcd. for
C23H21F7N4O3 (Mþ) 534.43; found (MHþ) 535.
2R-[1R-(3, 5-Bistrifluromethyl-phenyl)-ethoxy]-3S-(4-fluoro-phenyl)-
morpholine 12[3]
N-chlorosuccinimide (NCS) (1.1 kg, 8.23 mol) was added in portions to a mix-
ture of sec-amine 8 (3.26 kg, 7.45 mol), DMF (18.6 L), and K2CO3 (0.4 kg, 2.9 mol)
at 0–5 ꢀC. After the mixture was stirred for 30–45 min, 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) (1.35 kg, 8.9 mol) was added. The mixture was allowed to warm to room
temperature and stirred for 3 h. Water (50 L) and toluene (31 L) were added, and the
organic layer was separated and washed with water (10 L). The resulting organic layer
was distilled off below 50 ꢀC to afford 3.1 kg of imine compound 10. Crude imine
compound (3.1 kg, 7.12 mol) was dissolved in methanol (24.8 L), and sodium borohy-
dride (0.46 kg, 12.2 mol) was added lotwise at 0–5 ꢀC. The reaction mixture was stir-
red for 1.5–2.0 h at 0–5 ꢀC. After completion of the reaction, it was distilled off
completely, water (31 L) and toluene (15.5 L) were added, and the organic layer
was separated and washed with water (2 ꢂ 9.3 L). The organic layer was distilled
off completely under vacuum to afford 12 as thick syrup in 85.6% yield (2.8 kg).

SYNTHESIS OF DIASTEREOMERS OF APREPITANT
2265
The crude was dissolved in methanol (16.8 L), oxalic acid (800 g, 6.4 mol) was added
at 25–35 ꢀC. Then the mass was stirred for 1–2 h at the same temperature. Precipitated
salt filtration and methanol (2.8 L) washings afforded 12 as oxalate salt in 85%
(2.8 kg) yield. Oxalate salt of 12 (2.8 kg) was dissolved in a mixture of water (2.8 L)
and toluene (2.8 L), and suspension pH was adjusted to 9.5–10.0 using lye solution.
Organic layer was separated and concentrated under vacuum to obtain compound
12 as free base in 90% yield (2.1 kg) with >99% ee (>99% purity by chiral HPLC)
25
1
and >99% purity by HPLC; ½aꢃD ¼ ðþÞ 92:9ꢀ (c ¼ 0.78 MeOH). Data for 10: H
NMR (400 MHz, DMSO-d6) d 8.12–7.85 (m, 3H), 7.62 (d, J ¼ 6.2 Hz, 2H), 7.05 (t,
J ¼ 6.0 Hz, 2H), 5.52 (s, 1H), 5.25 (q, J ¼ 6.4 Hz, 1H), 3.95–4.10 (m, 4H), 1.5 (d,
J ¼ 6.4 Hz, 3H); MS calcd. for C20H16F7NO2 Mþ) 435.34; found (MHþ) 436. Data
1
for 12: H NMR (400 MHz, DMSO-d6); d 7.82 (s, 1H), 7.63–7.59 (m, 4H), 7.15 (t,
J ¼ 6.0 Hz, 2H), 5.0 (q, J ¼ 6.4 Hz, 1H), 4.50 (d, J ¼ 2.8 Hz, 1H), 4.12–3.90 (m, 2H),
3.55 (d, J ¼ 2.8 Hz, 1H), 3.15–2.95 (m, 2H), 1.5 (d, J ¼ 6.4 Hz, 3H); MS calcd. for
C20H18F7NO2 (Mþ) 437.35; found (MHþ) 438.
5-[{(2R,3S)-2-(1R)-1-3,5-Bis(trifluoromethyl)phenylethoxy-3-
(4-fluorophenyl)-4-morpholinyl}methyl]-1, 2-dihydro-3H-1, 2,4-
triazol-3-one 1[3]
A mixture of sec-amine 12 (5.0 kg, 11.4 mol), N-N-diisoprpopylethylamine
(4.27 kg, 33.0 mol), acetonitrile (42.0 L), and N0-(1-amino-2-chloro-ethylidene)-
hydrazine carboxylic acid methyl ester (2.5 kg, 14.8 mol) was stirred at room tempera-
ture for 2.5–3.0 h. After reaction completion, it was distilled off completely, and water
(56 L) and DCM (56 L) were added. The resulting organic layer was separated, washed
with water (2 ꢂ 28 L), and distilled off completely to afford 6.5 kg of carbamate com-
pound as an amorphous solid. A mixture of compound (6.5 kg, 11.5 mol) and acetoni-
trile (42 L) were heated at 120–125 ꢀC for 6–8 h in a closed autoclave system. After
reaction completion, it was distilled off completely to afford 4.7 kg of crude aprepitant
as a cream-colored solid. The obtained crude aprepitant was treated with charcoal in
methanol (56 L) at 60–65 ꢀC for 0.5 h. The reaction mass was filtered on Celite, and the
filtrate was distilled completely to afford white solid product, which was recrystallized
from acetonitrile (42 L) to give pure aprepitant 1 as white crystalline product in 60.4%
yield (3.7 kg) with 98.12% ee (>99% purity by chiral HPLC) and 99.55% purity by
25
1
HPLC; ½aꢃD ¼ ðþÞ 66:24ꢀ (c ¼ 0.66 MeOH; DSC ¼ 254.8 ꢀC; H NMR (400 M Hz,
DMSO-d6&CDCl3) d 11.4 (s, 1H), 11.2 (s, 1H), 7.84 (s, 1H), 7.51 (t, J ¼ 6.0 Hz,
2H), 7.38 (s, 2H), 7.07 (t, J ¼ 8.8 Hz, 2H), 4.94 (q, J ¼ 6.4 Hz, 1H), 4.36 (d, J ¼ 2.8 Hz,
1H), 4.14 (td, J ¼ 2.0, 2.0, 2.4 Hz, 1H), 3.63 (dd, J ¼ 2.0, 2.0 Hz, 1H), 3.50 (d,
J ¼ 2.4 Hz, 1H), 3.37 (d, J ¼ 14.4 Hz, 1H), 2.85 (d, J ¼ 11.6 Hz, 1H), 2.77 (d, 1H,
J ¼ 14.4 Hz), 2.40 (t, J ¼ 3.2, 3.6, 3.2 Hz, 1H), 1.37 (d, J ¼ 6.0 Hz, 3H); MS calcd.
for C23H21F7N4O3 (Mþ) 534.43; found (MHþ) 535. Anal. calcd. for C23H21N4O3F7
(534.43): C, 51.69; H, 3.96; N, 10.48. Found: C, 51.64; H, 3.75; N, 10.57.
2S-[1S-(3,5-Bistrifluromethyl-phenyl)-ethoxy]-3R-(4-fluoro-phenyl)-
morpholine ent-12
NCS (3.51 g, 0.026 mol) was added in portions to a mixture of sec-amine ent-8
(10 g, 0.02 mol) in DMF (60 mL) and K2CO3 (1.26 g, 9.15 mmol) at 0–5 ꢀC. After the

2266
S. GANGULA ET AL.
mixture was stirred for 30–45 min, DBU (4.52 g, 0.029 mol) was added. The mixture
was allowed to warm to room temperature and stirred for 3 h. Water (200 mL) and
toluene (200 mL) were added, and the organic layer was separated and washed with
water. The resulting organic layer was distilled off completely below 50 ꢀC to afford
in 97.55% yield (9.95 g) of imine compound ent-10. Crude imine compound ent-10
(9.5 g, 0.022 mol) thus obtained was dissolved in methanol (80 mL), and sodium
borohydride (1.45 g, 0.038 mol) was added lotwise at 0–5 ꢀC. The reaction mixture
was stirred for 1.5–2.0 h at 0–5 ꢀC. After completion of the reaction, it was distilled
off completely, water (100 mL) and toluene (300 mL) were added, and the organic
layer was separated and washed with water (2 ꢂ 200 mL). The resulting organic layer
was distilled off completely under vacuum to afford ent-12 as thick syrup in 89%
yield (8.9 g) with 98.6% ee (99.3 purity by chiral HPLC) and 99% purity by HPLC;
25
½aꢃD ¼ ðꢄÞ 92:1ꢀ (c ¼ 0.76 MeOH). Data for ent-10: 1H NMR (400 MHz, DMSO-d6)
d 8.12 (s, 1H), 7.93 (s, 2H), 7.67–7.60 (m, 2H), 7.15 (t, J ¼ 6.0 Hz, 2H), 5.52 (s, 1H),
5.20 (q, J ¼ 6.4, 1H), 4.15–4.0 (m, 2H), 3.95–3.89 (m, 2H), 1.5 (d, J ¼ 6.4 Hz, 3H);
1
MS calcd. for C20H16F7NO2 (Mþ) 435.34; found (MHþ) 436. Data for ent-12: H
NMR (400 MHz, DMSO-d6) d 7.82 (s, 1H), 7.53–7.35 (m, 4H), 7.15 (t, J ¼ 6.0 Hz,
2H), 5.0 (q, J ¼ 6.4 Hz, 1H), 4.4 (d, J ¼ 2.8 Hz, 1H), 4.0–3.90 (m, 2H), 3.55 (d, 1H,
J ¼ 2.8 Hz), 3.15–2.95 (m, 2H), 1.45 (d, J ¼ 6.4 Hz, 3H); 13C NMR (100 MHz,
DMSO-d6) d 163.7, 158.9, 146.8, 136.0, 131.6, 130.0, 128.9, 126.3, 114.6, 95.4,
71.6, 61.0, 58.9, 48.6, 24.3; MS calcd. for C20H18F7NO2 (Mþ) 437.35; found
(MHþ) 438.
5-[{(2S,3R)-2-(1S)-1-3,5-Bis(trifluoromethyl)phenylethoxy-
3-(4-fluorophenyl)-4-morpholinyl}methyl]-1, 2-dihydro-3H-
1,2,4-triazol-3-one ent-1
Chloromethyltriazolinone solution (3.14 g, 0.02 mol) in DMF (30 mL) was
added dropwise to a solution of sec-amine ent-12 (8.0 g, 0.01 mol) and K2CO3
(2.8 g, 0.02 mol) in DMF–water (33 mL) at 0 ꢀC and stirred for 2 h. After completion
of the reaction, water (100 mL) was added, and isolation of the resulting precipitate
afforded compound 3 in 98% yield (9.6 g) with >99% ee (>99% purity by chiral
25
HPLC) and 99.32% purity by HPLC; ½aꢃD ¼ ðꢄÞ 65:9ꢀ (c ¼ 0.68 MeOH); DSC ¼
1
254.8 ꢀC; H NMR (400 MHz, DMSO-d6 & CDCl3) d 11.10–10.95 (br, 2H), 7.84
(s, 1H), 7.61 (m, 2H), 7.25 (s, 2H), 7.07 (t, J ¼ 8.8 Hz, 2H), 4.94 (q, J ¼ 6.4 Hz,
1H), 4.36 (d, J ¼ 2.8 Hz, 1H), 4.14 (td, J ¼ 2.0, 2.0, 2.4 Hz, 1H), 3.63 (dd, J ¼ 2.0,
2.0 Hz, 1H), 3.50 (d, J ¼ 2.4 Hz, 1H), 3.37 (d, J ¼ 14.4 Hz, 1H), 2.85 (d, J ¼ 11.6 Hz,
Hz, 1H), 2.77 (d, J ¼ 14.4 Hz, 1H), 2.40 (t, J ¼ 3.2, 3.6, 3.2 Hz, 1H), 1.37 (d, 3H,
J ¼ 6.4 Hz); 13C NMR (100 MHz, DMSO-d6) d 162.9, 160.5, 156.3, 146.5, 143.8,
133.1, 130.1, 126.5, 123.0, 120.1, 114.5, 95.4, 71.6, 67.7, 58.7, 51.5, 50.4, 24.3;
MS calcd. for C23H21F7N4O3 (Mþ) 534.43; found (MHþ) 535.
2R-[1S-(3,5-Bistrifluromethyl-phenyl)-ethoxy]-3S-(4-fluoro-phenyl)-
morpholine 13
NCS (350 mg, 2.63 mmol) was added in portions to a mixture of sec-amine 9
(1.0 g, 2.28 mmol) in DMF (6.0 mL) and K2CO3 (126 mg, 0.91 mmol) at 0–5 ꢀC.

SYNTHESIS OF DIASTEREOMERS OF APREPITANT
2267
After the mixture was stirred for 30–45 min, DBU (452 mg, 2.97 mmol) was added.
The mixture was allowed to warm to room temperature and stirred for 3 h. Water
(20 mL) and toluene (20 mL) were added, and the organic layer was separated and
washed with water. The resulting organic layer was distilled off completely below
50 ꢀC to afford 97.6% yields (970.0 mg) of imine compound 11. Crude imine
compound 11 (950 mg, 2.0 mmol) was dissolved in methanol (8.0 mL), and sodium
borohydride (145 mg, 3.82 mmol) was added lotwise at 0–5 ꢀC. The reaction mixture
was stirred for 1.5–2.0 h at 0–5 ꢀC. After completion of the reaction, the reaction mass
was distilled off completely, water (10.0 mL) and toluene (30.0 mL) were added, and
the organic layer was separated and washed with water (2 ꢂ 20.0 mL). The resulting
organic layer was distilled off under vacuum to afford 13 as thick syrup in 89.0% yield
(850 mg) with 96.6% ee (98.0% purity by chiral HPLC) and 99% purity HPLC;
25
1
½aꢃD ¼ ðþÞ 48:27ꢀ (c ¼ 0.78 MeOH). Data for 11: H NMR (400 MHz, DMSO-d6)
d 8.12–7.95 (m, 5H), 7.45–7.20 (m, 2H), 5.80 (s, 1H), 5.25(q, J ¼ 6.4 Hz, 1H),
3.85–3.25 (m, 4H), 1.56 (d, J ¼ 6.4 Hz, 3H); MS calcd. for C20H16F7NO2 (Mþ)
435.34; found (MHþ) 436. Data for 13: H NMR (400 MHz, DMSO-d6) d 8.0–7.90
1
(m, 3H), 7.65–7.45 (m, 2H), 7.20–7.0 (m, 2H), 4.95 (d, J ¼ 2.8 Hz, 1H), 4.87 (q,
J ¼ 6.4 Hz, 1H), 4.0 (d, J ¼ 2.8 Hz, 1H), 3.75–3.60 (m, 1H), 3.0–2.8 (m, 3H), 1.20
(d, J ¼ 6.4 Hz, 3H); MS calcd. for C20H18F7NO2 (Mþ) 437.35; found (MHþ) 438.
2R-[1S-(3,5-Bistrifluromethyl-phenyl)-ethoxy]-3R-(4-fluoro-phenyl)-
morpholine ent-13
NCS (350 mg, 2.63 mmol) was added in portions to a mixture of sec-amine
ent-9 (1.0 g, 2.28 mmol) in DMF (6.0 mL) and K2CO3 (126 mg, 0.91 mmol) at
0–5 ꢀC. After the mixture was stirred for 30–45 min, DBU (452 mg, 2.97 mmol)
was added, and the mixture was allowed to warm to room temperature and stirred
for 3 h. Subsequently, a mixture of water (20 mL) and toluene (20 mL), was added
and the organic layer was separated and washed with water. The resulting organic
layer was distilled off completely below 50 ꢀC to afford imine compound ent-11 in
97.6% yield (995 mg). This crude imine compound ent-11 (995 mg, 2.28 mmol) was
dissolved in methanol (8.0 mL), and sodium borohydride (145 mg, 3.82 mmol) was
added lotwise at 0–5 ꢀC. The reaction mixture was stirred for 1.5–2.0 h at 0–5 ꢀC.
After completion of the reaction, the reaction mass was distilled off completely,
and a mixture of water (10 mL) and toluene (30 mL) was added. The organic layer
was separated and washed with water (2 ꢂ 20 mL). The resulting organic layer was
distilled off under vacuum to afford ent-13 as thick syrup in 90% yield (850 mg) with
25
97.4% ee (98.7% purity by chiral HPLC) and 99% purity by HPLC, ½aꢃD
¼
1
ðꢄÞ 47:53ꢀ (c ¼ 0.78 MeOH). Data for ent-11: H NMR (100 MHz, DMSO-d6) d
8.12–7.95 (m, 5H), 7.45–7.20 (m, 2H), 5.80 (s, 1H), 5.25 (q, J ¼ 6.4 Hz, 1H),
3.85–3.25 (m, 4H), 1.5 (d, J ¼ 6.4 Hz, 3H); MS calcd. for C20H16F7NO2 (Mþ)
435.34; found (MHþ) 436. Data for ent-13: 1H NMR (100 MHz, DMSO-d6) d
8.0–7.90 (m, 3H), 7.65–7.45 (m, 2H), 7.22–7.20 (m, 2H), 4.95 (d, J ¼ 2.8 Hz, 1H),
4.85 (q, J ¼ 6.4 Hz, 1H), 4.0 (d, J ¼ 2.8 Hz, 1H), 3.75–3.60 (m, 1H), 3.0–2.8 (m,
3H), 1.25 (d, J ¼ 6.4 Hz, 3H);13C NMR (100 MHz, DMSO-d6) d 163.7, 158.9,
146.8, 135.5, 130.6, 128.8, 126.0, 120.8, 114.1, 95.3, 71.6, 61.0, 58.8, 48.5, 24.3; MS
calcd. for C20H18F7NO2 (Mþ) 437.35; found (MHþ) 438.

2268
S. GANGULA ET AL.
Supporting Information
Spectral data of all compounds are included in supporting information
document separately.
ACKNOWLEDGMENTS
The authors thank management of the Dr. Reddy’s Laboratories for support.
We acknowledge the technical support extended by the AR&D and CRAAI
divisions. We also thank the team of Dr. Moses Babu, Dr. Vishweshwar Peddy,
and Mr. R. Vasu Dev of the analytical research laboratory of the Discovery
Research Foundation.
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