An alternative approach to achieve enantiopure (3S)-4-benzyl-3-(4- fluorophenyl)morpholin-2-one: A key intermediate of aprepitant, an NK1 receptor antagonist

Article abstract of DOI:10.1021/op700030d

An efficient and alternative synthesis of enantiomerically pure (3S)-4-benzyl-3-(4-fluorophenyl)morpholin-2-one (S)-(+)-2), a key intermediate in the synthesis aprepitant (1), is described. The key resolution of N-benzylglycinamide, (±)-9, is achieved via diastereomeric salt crystallization using (+)-di-p-toluoyltartaric acid (DPTTA) as the resolving agent to furnish (S)-(+)-9. Alkylation of (S)-(+)-9 with 2-bromoethanol followed by stereocontrolled cyclization of obtained (S)-(+)-10 afforded the desired enantiomer (S)-(+)-2 with good yields and enantiopurity (>98%). The reaction conditions were optimized to make the process robust in order to implement at the commercial scale.

Full text of DOI:10.1021/op700030d

Organic Process Research & Development 2007, 11, 455−457
An Alternative Approach to Achieve Enantiopure (3S)-4-Benzyl-3-
(4-fluorophenyl)morpholin-2-one: A Key Intermediate of Aprepitant,
an NK1 Receptor Antagonist†
Naveenkumar Kolla,‡ Chandrashekar R. Elati,‡ Muthulingam Arunagiri,‡ Srinivas Gangula,‡ Pravinchandra J. Vankawala,‡
Yerremilli Anjaneyulu,§ Apurba Bhattacharya,‡ Sundaram Venkatraman,‡ and Vijayavitthal T. Mathad*,‡
Research and DeVelopment, Dr. Reddys Laboratories Ltd., IPD, Unit-III, Bollaram, Hyderabad - 502325, Andhrapradesh,
India, and Center for Atmospheric Science, J.N.T. UniVersity, Kukatpally, Hyderabad - 500072, Andhrapradesh, India
Abstract:
An efficient and alternative synthesis of enantiomerically pure
(3S)-4-benzyl-3-(4-fluorophenyl)morpholin-2-one (S)-(+)-2), a
key intermediate in the synthesis aprepitant (1), is described.
The key resolution of N-benzylglycinamide, (()-9, is achieved
via diastereomeric salt crystallization using (+)-di-p-toluoyl-
tartaric acid (DPTTA) as the resolving agent to furnish (S)-
(+)-9. Alkylation of (S)-(+)-9 with 2-bromoethanol followed by
stereocontrolled cyclization of obtained (S)-(+)-10 afforded the
desired enantiomer (S)-(+)-2 with good yields and enantiopurity
(>98%). The reaction conditions were optimized to make the
Figure 1. Structure of aprepitant (1).
process robust in order to implement at the commercial scale.
U.S. FDA in the year 2003 and is currently being marketed
under the brand name of Emend in the dosage of 40-, 80-,
and 125-mg capsules.6 Structurally, aprepitant (1) consists
of three chiral centers, two of which are present on mor-
pholine core, and the third one is on bis-trifluoro ethyl-
benzene (Figure 1). Efficient synthesis of enantiomerically
Introduction
Design of new resolving agents, through both rational
concepts1 and practical experience,2 is an ongoing subject
of research and development. Selective crystallization meth-
ods are still the most important techniques in preparing
optically pure pharmaceutical products.3 Solubility differ-
ences between diastereomers are often achieved by the
selection of suitable resolving agents and/or a solvent systems
pure (S)-morpholinone, (+)-2, is required to support different
synthetic approaches designed for 1.
Dorn et al.7 reported the first synthesis of (+)-2 starting
from (S)-(+)-4-fluorophenylglycine (6) in two steps which
require a strict control of the process parameters such as
during the resolution. In continuation of our interest in
reaction time and temperature to retain chirality during the
resolutions,4 herein we are reporting a synthesis of (3S)-4-
conversion of 8 to (S)-(+)-2, thus making the process
benzyl-3-(4-fluorophenyl)morpholin-2-one ((S)-(+)-2), a cru-
cial and cost-contributing intermediate in the synthesis of
aprepitant (1).
Aprepitant (1), a potent and orally active antiemetic drug
well-known in the class of nonpeptide antagonists to the
tachykinin neurokinin NK1 receptor, having some other
widespread therapeutic activities,5 has been approved by the
impractical at scale8 (Scheme 1, Path A).
R. J. Alabaster et al.9 reported the synthesis of (S)-
morpholinone, (+)-2, through dynamic diastereomeric salt
resolution of (()-2 using [(1S)-(endo,anti)]-(-)-3-bromo-
camphor-8-sulfonic acid (Scheme 1, Path B). A notable
drawback of this synthesis is the use of expensive and
commercially less viable resolving agent [(1S)-(endo,anti)]-
(-)-3-bromocamphor-8-sulfonic acid.10 With these limita-
tions of reported approaches, development of new synthetic
methods adequate to be carried out at large scale with low
cost and cheaper raw materials is desirable. This paper reports
a simple and economic process for large-scale synthesis of
† DRL-IPD Communication number: IPDO-IPM-00039.
* Corresponding author. E-mail: drvtmathad@yahoo.co.in. Telephone: +91
9822581611. Fax: +91 8458 279619.
‡ Research and Development, Dr. Reddys Laboratories Ltd.
§ Center for Atmospheric Science, J.N.T. University.
(1) Hoeveten, W.; Wynberg, H. J. Org. Chem. 1985, 50, 4508.
(2) Pallavicini, M.; Valoti, E.; Villa, L.; Piccolo, O. Tetrahedron: Asymmetry
1996, 7, 1117.
(6) http://www.rxlist.com/cgi/generic3/emend.htm.
(3) Carey, S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem
2006, 4, 2337.
(7) (a) Dorn, C. P.; Finke, P. E.; Hale, J. J.; Gills, S. G.; Williams, B. J. U.S.
Patent 5,719,147, 1998. (b) Sorbera, L. A.; Castaner, J.; Bayes, M.; Silvestre,
J. Drugs Future 2002, 27(3), 211.
(8) Todd, D. N.; Mahadevan, B. U.S. Patent 6,177,564, 2001.
(9) Alabaster, R. J.; Gibson, A. W.; Johnson, S. A.; Edwards, J. S.; Cottrell, L.
F. Tetrahedron: Asymmetry 1997, 8, 447.
(10) Zhao, M. M.; McNamara, J. M.; Ho, G.-J.; Emerson, K. M.; Song, Z. J.;
Tschaen, D. M.; Brands, K. M. J.; Dolling, U.-H.; Grabowski, E. J. J.;
Reider, P. J.; Cottrell, I. F.; Ashwood, M. S.; Bishop, B. C. J. Org. Chem.
2002, 67, 6743.
(4) Chandrashekar, R. E.; Naveen, K.K.; Pravinchandra, J. V.; Srinivas, G.;
Subrahmanyeswararao, C.; Venkatraman, S.; Bhattacharya, A.; Himabindu,
V.; Mathad, V. T. Org. Process Res. DeV. 2007, 11, 289.
(5) (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.; Eiermann,
G.; Tsou, N. N.; Tattersall, F. D.; Rupniak, N. M. J.; Williams, A. R.;
Rycroft, W.; Hargreaves, R.; MacIntyre, D. E. J. Med. Chem. 1998, 41,
4607. (b) Rupniak, N.M. J. Pharmacol. 1997, 326, 201.
10.1021/op700030d CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/04/2007
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Scheme 1. Reported approaches for the synthesis of (S)-(+)-2
Scheme 2. New approach for (S)-(+)-morpholinone, (S)-(+)-2, synthesisa
a Reagents and conditions: (a) D-(+)-DPTTA/methanol/60-65 °C/30-45 min; (b) 2-bromoethanol/EDIPA/DMF/80-85 °C/12-15 h; (c) acetic acid/55-60 °C/
3-4 h.
(3S)-4-benzyl-3-(4-fluorophenyl)morpholin-2-one (2) through
the resolution of (()-9 with a commercially available
resolving agent. The resolved substrate (+)-9 was subse-
quently converted to the desired chiral intermediate (+)-2
in good yield and purity by simple chemical modifications.
present resolution study. Among the commercially viable
chiral acids (mandelic acid, camphorsulphonic acid, tartaric
acid, dibenzoyl tartaric acid, and di-p-toluoyl tartaric acid)
screened for the resolution of either (()-9 and (()-11, (+)-
DPTTA was found to be the best choice for the resolution
of (()-9 using methanol as a solvent. Interestingly, the
diastereomeric salt having the same podes, (+)-9‚(+)-
DPTTA, is precipitated in methanol in contrast to the
preceding reports.11-12 The final procedure for resolution
(after optimizing solvent, solvent volume, time, temperature,
and molar ratio of DPTTA) is as follows: A mixture of (+)-
DPTTA and methanol was stirred at room temperature until
a clear solution was obtained. A solution of compound (()-9
in methanol was added to the above solution, and the
resulting mixture was heated to reflux for about 45-60 min.
Results and Discussion
As part of wider study on the original resolution of (()-
2,9 other commercially available chiral acids (mandelic acid,
camphor sulfonic acid, tartaric acid, dibenzoyl tartaric acid
and di-p-toluoyl tartaric acid) were selected and tested for
the resolution of (()-2 at our end. Among these, resolution
with di-p-toluoyl tartaric acid though successful, yielded
diastereomeric salt in only 10-15% yield with 92-94%
enantiomeric purity. These results on direct resolution of
(()-2 were highly discouraging. We then explored an
alternative approach for the efficient synthesis of (S)-(+)-2.
Careful evaluation of the original synthesis8 of (()-2 led us
to identify two precursors 9 and 11 (Scheme 2) for the
(11) Kozma, D. CRC Handbook of Optical Resolutions Via Diastereomeric Salt
Formation; CRC Press: Boca Raton, FL, 2002.
(12) On the other hand, the diastereomeric salt (-)-9‚(-)-DPTTA is precipitated
in methanol to optionally access (-)-9.
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The reaction mixture was then cooled to 0-5 °C and stirred
for 1-2 h at this temperature. The resulting diastereomeric
salt (+)-9‚(+)-DPTTA was collected by filtration and washed
with chilled methanol. Recrystallization of the wet solid in
methanol furnished the desired isomer (S)-(+)-9 with good
enantiomeric purity13 (>98%) and yield (60%).
(1140 mL) over a period of 15-30 min at 60-65 °C. The
mixture was stirred at the same temperature for an additional
30-45 min. The reaction mixture was cooled to 25-35 °C,
and then the resulting solid was isolated by filtration. The
filtered cake was washed with cold methanol (300 mL) and
vacuum dried to get 144 g of the enriched diastereomeric
salt (S)-(+)-9‚(+) DPTTA (enantiomeric purity, 88%). This
wet salt was recrystallized from methanol (2250 mL) to get
enantiopure (S)-(+)-9 as a DPTTA diastereomeric salt.
Yield: 112 g (30%; 60% of theory). The diastereomeric salt
was hydrolyzed in water by adjusting the pH of the solution
to11-12 using a solution of sodium hydroxide and was
extracted with dichloromethane. Concentration of the organic
layer furnished (S)-(+)-9 free base as a thick syrup. [R]D )
+93.8 (c 1, methanol); chiral purity: 99.1%; MS; m/z 259
Alkylation of the resolved substrate, (S)-amide ((S)-(+)-
9), with 2-bromoethanol at 80-85 °C in DMF offered the
corresponding alkylated product (+)-10. Cyclization of (S)-
(+)-amide (10) in acidic medium furnished the desired
lactone (S)-(+)-2 as a thick syrup. Subsequent conversion
of the resulting lactone (S)-(+)-2 to hydrochloride salt
afforded pure (S)-(+)-2 with >98.0% purity by HPLC.14 The
temperature in the alkylation step is a critical parameter in
the process as alkylation of (S)-(+)-9 with 2-bromoethanol
at >95 °C resulted in 2 as a racemic compound, which could
be due to the deprotonation of benzylic proton under the
reaction conditions. The other process parameters involved
in all the stages were also optimized, and the final process
was successfully implemented in our scale-up facilities.
This newly developed process is around 1.5-fold cost
advantageous over the literature-reported procedures to the
best of our knowledge. We are in the process of recovering
the undesired (R)-(-)-9 and converting it to the desired (S)-
(+)-9 via racemisation and resolution process. This will
further improve the economy of our process.
1
(M+ + H). H NMR (C2D6SO): δ 7.5 (s, 2H), 7.1-7.45
(m, 9H), 4.1 (s, 1H), 3.6 (t, J ) 7.1, 2H), 2.9 (s, 1H).
(2S)-2-[Benzyl(2-hydroxyethyl)amino]-2-(4-fluoro-
phenyl)acetamide (10). A mixture of (S)-(+)-9 (100 g, 0.38
mol), N,N-diisopropylethylamine (220 g, 1.7 mol), and
2-bromoethanol (384 g, 3.0 mol) in DMF (1000 mL) were
heated at 80-85 °C for 12-15 h. After completion of the
reaction, the contents were cooled to room temperature, and
water (1000 mL) was added and then extracted with ethyl
acetate (2 × 750 mL). The combined organic layers were
washed with water (2 × 1000 mL) and concentrated under
vacuum to obtain 10 as thick syrup. Yield: 88 g (75.2%);
MS; m/z 303 (M+ + H). 1H NMR (CDCl3): δ 7.0-7.4 (m,
9H), 5.6 (s, 2H), 4.4 (s, 1H), 3.8 (s, 2H), 3.5-3.9 (m, 2H),
2.6 (t, 2H), 1.7 (s, 1H).
Conclusion
In conclusion, we have developed an efficient, alternative,
and industrially scaleable process for the preparation of (S)-
(+)-4-benzyl-3-(4-fluorophenyl)morpholin-2-one ((S)-(+)-
2), a key and cost-contributing intermediate of aprepitant
(NK1 receptor antagonist).
(3S)-4-Benzyl-3-(4-fluorophenyl)morpholin-2-one ((S)-
(+)-2). A mixture of 10 (200 g, 0. 66 mol) and acetic acid
(200 mL) was heated at 50-60 °C for 3-4 h. After
completion of the reaction (monitored by TLC), the reaction
mixture was cooled to 25-35 °C, water (1000 mL) was
added and then extracted with toluene (2 × 1000 mL). The
combined organic layers were washed with aqueous 5%
Na2CO3 (2 × 1000 mL) solution followed by water (2 ×
1000 mL). The organic layer was concentrated under vacuum
to obtain a thick residue of (S)-(+)-2 as a free base which
was subsequently converted to the corresponding pure-white,
crystalline hydrochloride salt using concentrated HCl(65 mL)
in toluene(200 mL)/hexane(1800 mL) medium. Yield: 182
g (94.5%); purity by HPLC: 98.56%; enantiomeric purity
by HPLC: 98.7%; [R]D ) +63.8 (c 1, methanol); MS; m/z
Experimental Section
The 1H NMR spectra were measured in CDCl3 and
DMSO-d6 on a Varian Gemini 2000 (200 MHz) FT NMR
spectrometer; the chemical shifts are reported in δ ppm
relative to TMS. The FT-IR spectra were recorded in the
solid state as a KBr dispersion using Perkin-Elmer 1650 FT-
IR spectrophotometer. The mass spectrum (70 eV) was
recorded on an HP-5989A LC/MS spectrometer. The melting
points were determined by using the capillary method on a
POLMON (model MP-96) melting point apparatus. The
solvents and reagents were used without further purification.
(2S)-2-(Benzylamino)-2-(4-fluorophenyl)acetamide ((S)-
(+)-9). To a stirred and clear solution of intermediate (()-9
(150 g, 0.58 mol) in methanol (1500 mL) was slowly added
a solution of (+)-DPTTA (224 g, 0.58 mol) in methanol
1
286 (M+ + H). H NMR (C2D6SO): δ 7.0-7.6 (m, 9H),
4.7 (s, 2H), 4.4 (s, 1H), 3.8 (s, 2H), 3.5-3.9 (m, 2H), 2.6 (t,
2H), 1.7 (s, 1H).
Acknowledgment
We thank the management of R&D-IPDO, Dr. Reddy’s
Laboratories Ltd., for supporting this work. Support from
the colleagues from analytical research and development is
highly appreciated.
(13) Enantiopurity of (S)-(+)-9 was determined by chiral HPLC analysis with
Chiralpak ODH, 5.0 µm, 250 mm × 4.6 mm; mobile phase: n-hexane,
ethanol, and diethylamine in the ratio of 95:5:0.01 (v/v); 1.0 mL/min; 210
nm. The retention times of (S)-(+)-9 and (R)-(-)-9 were around 33.23 and
28.14 min, respectively.
(14) Enantiopurity of (S)-(+)-2 was determined by chiral HPLC analysis with
Chiralpak ODH, 5.0 µm, 250 mm × 4.6 mm; mobile phase: n-hexane,
ethanol, and diethylamine in the ratio of 95:5:0.01 (v/v); 0.8 mL/min; 210
nm. The retention times of (S)-(+)-2 and (R)-(-)-2 were around 23 and 19
min, respectively.
Received for review February 8, 2007.
OP700030D
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