A convergent approach to the synthesis of aprepitant: a potent human NK-1 receptor antagonist

Article abstract of DOI:10.1016/j.tetlet.2007.09.051

A simple and convergent approach to enantiomerically pure 5-[[2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)morpholin-4-yl]methyl]-1,2-dihydro-1,2,4-triazol-3-one 1, a potent orally active antagonist of the human neurokinin-1 (NK-1) receptor, is described. The synthetic procedure starts from p-fluorobenzaldehyde to access the racemic morpholinone 2 via a modified Strecker synthesis and utilizes a diastereomeric salt resolution technique to accomplish the synthesis of 1 in enantiomerically pure form and good yield.

Full text of DOI:10.1016/j.tetlet.2007.09.051

Tetrahedron Letters 48 (2007) 8001–8004
A convergent approach to the synthesis of aprepitant:
a potent human NK-1 receptor antagonistI
Chandrashekar R. Elati, Naveenkumar Kolla, Srinivas Gangula, Anitha Naredla,
Pravinchandra J. Vankawala, Muttu L. Avinigiri, Subrahmanyeswararao Chalamala,
Venkatraman Sundaram, Vijayavitthal T. Mathad, Apurba Bhattacharya and
Rakeshwar Bandichhor*
Research and Development, Dr. Reddy’s Laboratories Ltd., IPD, Unit-III, Bollaram, Medak 502 325, India
Received 21 June 2007; revised 31 August 2007; accepted 7 September 2007
Available online 12 September 2007
Abstract—A simple and convergent approach to enantiomerically pure 5-[[2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluoro-
phenyl)morpholin-4-yl]methyl]-1,2-dihydro-1,2,4-triazol-3-one 1, a potent orally active antagonist of the human neurokinin-1
(NK-1) receptor, is described. The synthetic procedure starts from p-fluorobenzaldehyde to access the racemic morpholinone 2
via a modified Strecker synthesis and utilizes a diastereomeric salt resolution technique to accomplish the synthesis of 1 in enantio-
merically pure form and good yield.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Resolution by diastereomeric salt crystallization is an
important and cost effective tool to obtain chiral mole-
cules.1 It is often the case that, when a molecule pos-
sesses several stereogenic centres, one can envisage
that transformations leading to the synthesis of the
desired isomer, would have occurred through one of
the following general processes: (a) resolution, (b) chiral
pool based transformation using amino acids, carbo-
hydrates, etc. (c) involve temporary installation of a
readily removable chiral auxiliary, which would dictate
facial selectivity in a key stereo defining transformation
or (d) involve an enantioselective catalytic process to
introduce chirality during reactions.
HN
N
O
O
N
CF3
N
O
H
CF3
F
Figure 1. Aprepitant (1).
out a moisture sensitive and reversible imidate reaction
on a large scale, (b) control of the amount of ruthenium
metal, which was used in the form of cis-aminoindano-
Ru (p-cymene) for the preparation of chiral-alcohol
used in the final active pharmaceutical to acceptable
limits, and (c) involving expensive reagents and harsh
conditions.
In this Letter, we report an efficient synthesis of aprep-
itant (1), which possesses three stereogenic centres by
exploiting resolution techniques. Aprepitant (see
Fig. 1) is a drug known to elicit activity against the
human neurokinin-1 (NK-1) receptor.2
Herein, we report a cost-effective and practical approach
for the large scale preparation of aprepitant (1), from
( )-morpholinone (2), 1-(1-bromoethyl)-3,5-bis-tri-
fluoromethylbenzene (11) and chloroacetamidrazone
(Schemes 2–5). This process does not require any chiral
pool starting material, chiral auxiliary, enantioselective
catalyst, pyrophoric or expensive or toxic reagent, and
has the advantage of relative simplicity over the
previously reported approaches.
Aprepitant 1 has been synthesized previously3a–c and the
reported routes have certain disadvantages: (a) carrying
q DRL-IPD Communication No. 00052.
*
Corresponding author. Tel.: +91 8458 2 79485; fax: +91 8458 2
79619; e-mail: rakeshwarb@drreddys.com
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.051

8002
C. R. Elati et al. / Tetrahedron Letters 48 (2007) 8001–8004
tions. The a-aminonitrile thus obtained was hydrolyzed
H
O
O
with alkaline hydrogen peroxide to furnish amide 7 as a
white crystalline solid in 75% yield. Cyclization of amide
7 in the presence of acetic acid afforded ( )-morpho-
linone 2 in 89% yield. Conversion of 2 to ( )-trans-mor-
pholinol was attempted with reducing agents such as
sodium borohydride and Red-Al. Reduction of 2 using
0.7 equiv of Red-Al was found to be efficient and gave
trans-4 in 88% yield, >96% purity and with <0.1% of
over reduction product 8. The small quantity of over
reduction product is in contrast with Nelson’s study
on morpholinone reduction.5 In our hands, the condi-
tions for the preparation of this key intermediate
trans-4 are ideal with respect to cost, convenience and
scalability and have been demonstrated successfully on
multi kilogram scale.
Ph
N
Ph
N
H+
OH
O
H
F
F
major
trans-4
cis-4 minor
F
O
H
N
H
O
Scheme 1. Acid catalyzed stereoinversion.
The preparation of 11 was achieved by the procedure
shown in Scheme 3. Reduction of the acetophenone
derivative 9 using sodium borohydride in methanol gave
the corresponding hydroxy compound as a crystalline
solid in 98% yield. Subsequent treatment with HBr/
H2SO4 gave the desired bromo compound 11 in 83%
yield.
In our preliminary approach to 1 the isolation of cis-mor-
pholinol (cis-4) was unsuccessful because of the preferred
formation of the thermodynamically stable trans-mor-
pholinol (trans-4) at room temperature (Scheme 1).
This prompted us to investigate the synthesis of 1 start-
ing from trans-4. Taking the advantage of the inherent
tendency of morpholinol (cis-4) to form the stable
trans-isomer (trans-4) we succeeded in developing a sim-
ple, cost effective and scalable process for aprepitant (1).
Treatment of racemic trans-4 with 1-(1-bromoethyl)-3,5-
bis-trifluoromethylbenzene 11 in the presence of potas-
sium carbonate furnished the ether derivative 12 as a
mixture of racemic diastereomers in a 2:1 ratio. The dia-
stereomeric and enantiomeric relationship of the isomers
formed in the reaction was apparent by means of
HPLC6 and LCMS (Scheme 4). Upon hydrogenolysis
of the hydrochloride salt of ether 12 in the presence of
Pd–C/H2amine 3a7 was obtained in the same diastereo-
meric ratio. The major pair of amine enantiomers 3b
was isolated by crystallization from isopropyl alcohol.
Resolution of 3b was accomplished using L-(À)-cam-
phorsulfonic acid in methanol, which gave 3c in 81%
yield and 95% purity. The structure of the L-(À)-CSA
salt of 3c was confirmed by X-ray analysis. The X-ray
structure clearly showed that 3c had the configuration
as indicated in Figure 2, in which the morpholine core
has a trans arrangement, both the fluorophenyl and
alkoxy groups are in equatorial orientations, and the
methyl group is a disposed.
First, ( )-morpholinone 2 was prepared from commer-
cially available p-fluorobenzaldehyde 5 by modifying
the literature procedure4 as presented in Scheme 2. p-
Fluorobenzaldehyde 5 was converted to a-aminonitrile
6 in excellent yield (90%) under standard reaction condi-
OH
CN
CHO
NaCN, NaHSO3
-benzylethanolamine
Ph
N
K2CO3
N
H2O, 35 °C, 16 h
DMSO:50%H2O2
6:1 (v/v)
F
F
5
6 , 90%
OH
O
Ph
N
CONH2
Ph
N
AcOH, toluene
55 °C, 1.5 h
O
O
HO
F
F
NaBH4, MeOH
25 to 35 °C, 2 h
7, 75%
rac-2, 89%
F3C
CF3
F3C
CF3
OH
OH
O
Ph
N
Ph
N
10
9
OH
Red-Al, toluene
0 to 5 °C, 1 h
+
Br
aq. HBr, H2SO4
50-55 °C, 2h
F
F
F3C
CF3
8, < 0.1%
trans-4, 88%
> 96% (purity)
11, 83%
Scheme 2. Synthesis of morpholinol trans-4.
Scheme 3. Synthesis of intermediate 11.

C. R. Elati et al. / Tetrahedron Letters 48 (2007) 8001–8004
8003
O
O
11
Ph
N
CF
3 5% Pd-C
N
CF3
O
MeOH
NCS, DBU, DMF
K2CO3, 0 to 5 °C
O
KOH, acetone
NaBH4, MeOH
trans-4
3c
4.0 kg/cm2
35 °C, 2 h
60 °C, 6 h,aq.HCl,
toluene,n-hexane
0 to 5 °C
1.5 h
CF3
O
HCl
CF3
F
12, 80%
F
13
O
O
N
O
HN
CF3
HN
CF3
O
IPA
25 to 35 °C
Cl
N
H
O
O
HN
CF3
NH2
O
DIPEA, MeCN
35 °C, 3 h
CF3
CF3
HCl
HCl
CF3
3d, yield 86%
NH2
F
F
3a, 78%
3b, 75%
F
(yield based on available diastereomer)
O
O
HN
CF3
O
L(-) camphor-10-sulphonic acid
MeOH, 0 to 5 °C
N
CF3
MeCN
N
O
120 to 130 °C
O
NH
1, 60%
CF3
3 h
O
CF3
F
3c, 81 %
F
(salt of camphor -10-sulfonic acid)
14
Scheme 5. Completion of the synthesis of 1.
(yield based on available enantiomer)
Scheme 4. Synthesis of intermediate 3c.
the synthesized material 1 were in complete agreement
with reported values.
In summary, we have demonstrated an efficient synthesis
of aprepitant without using any chiral starting materials,
except L-(À)-CSA (used for resolution), or expensive
reagents, which has the considerable advantage of
relative simplicity over the reported syntheses.
Acknowledgements
The authors thank the management of Dr. Reddy’s
Laboratories Ltd. for supporting this work. Coopera-
tion from the project colleagues is highly appreciated.
The X-ray crystallography division of DRF is also
acknowledged.
Figure 2. ORTEP representation of the L-(À)-CSA salt of 3c.
At this stage conversion of 3c into 3d was carried out
according to Zhao and co-workers3b (Scheme 5). The
crystalline imine 13 was reduced with sodium boro-
hydride with complete cis-stereoselectivity8 to afford
3d. The stereochemical outcome of this reduction pro-
cess is due to the presence of a bulky 2-alkoxy group
in 13, which directed the addition of hydride from the
opposite face of the plane of the molecule. Subsequent
condensation with chloroacetamidrazone following a
known process9 and in situ cyclization of the resulting
intermediate 14 at 120 ꢁC in a closed autoclave system
gave 5-[[2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-
fluorophenyl)morpholin-4-yl]methyl]-1,2-dihydro-1,2,4-
triazol-3-one 1 in 60% yield.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.09.051.
References and notes
1. Carey, S.; Laffan, D.; Thomson, C.; Williams, M. T. Org.
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Ber, E.; Hale, J. J.; Mills, S. G.; MacCoss, M.; Seward, E.;
1
DSC (differential scanning calorimetry), H NMR, IR,
SOR (specific optical rotation) and chiral HPLC10 of

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C. R. Elati et al. / Tetrahedron Letters 48 (2007) 8001–8004
Huscroft, I.; Owen, S.; Swain, C. J.; Hill, R. G.;
Hargreaves, R. J. Eur. J. Pharmacol. 1997, 326, 201–209.
mobile phase—B: mixture of Buffer and acetonitrile in the
ratio of 20:80; 1.0 mL/min; 210 nm.
Gradient profile:
3. (a) Hale, J. J.; Mills, S. G.; MacCoss, M.; Finke, P. E.;
Cascieri, M. A.; Sadowski, S.; Ber, E.; Chicchi, G. G.;
Kurtz, M.; Metzger, J.; Eiremann, G.; Tsou, N. N.;
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6. The diastereopurity of 12 was estimated by HPLC analysis
with symmetry shield RP/18, 100 · 4.6 mm · 3.5 lL;
mobile phase—A: mixture of buffer (1.36 g of potassium
dihydrogen phosphate in 1000 mL of water, adjust pH to 6
with triethylamine) and acetonitrile in the ratio of 70:30;
Time (min)
A (%)
B (%)
00
75
25
25
75
25
35
10
90
50
10
90
52
75
25
60
75
25
7. This compound is a mixture of diastereomers as HPLC
data indicated.
8. The enantiopurity of 3d was determined by using chiral
HPLC analysis with chiral cell/ODH, 150 · 4.6 mm,
20 lL; mobile phase: n-hexane, 2-propanol, trifluoroacetic
acid and diethylamine in the ratio of 980:20:1:0.2 (v/v);
0.8 mL/min; 210 nm.
9. Conard, P. D.; Paul, E. F.; Jeffrey, J. H.; Malcolm, M.;
Sander, G. M.; Shrenik, K. S.; U.S. Patent 5,719,147,
1998.
10. (a) The enantiopurity of 1 was determined by using chiral
HPLC analysis with chiral cell/ADH, 250 · 4.6 mm,
20 lL; mobile phase: n-hexane and ethanol 90:10
(v/v); 0.5 mL/min; 210 nm; (b) The title compound could
be obtained in 100% ee by single crystallization from
MeCN.