A practical synthesis of enantiomerically pure N-benzyl-α-methyl benzylamine

Article abstract of DOI:10.1021/op000201n

Optically pure (R)- and (S)N-benzyl-α-methyl benzylamine have been prepared on pilot plant scale from benzaldehyde and α-phenyl-ethylamine via palladium-catalyzed hydrogenation of the intermediate (R)-benzylidene-(1-phenylethyl)amine.

Full text of DOI:10.1021/op000201n

Organic Process Research & Development 2000, 4, 594−595
A Practical Synthesis of Enantiomerically Pure N-Benzyl-r-methyl Benzylamine
Brian K. Huckabee,* Sechoing Lin, Traci L. Smith, and Timothy L. Stuk
Chemical DeVelopment, Parke-DaVis/DiVision of Warner Lambert, 188 Howard AVenue, Holland, Michigan 49424, U.S.A.
Scheme 1
Scheme 2
Abstract:
Optically pure (R)- and (S)-N-benzyl-r-methyl benzylamine
have been prepared on pilot plant scale from benzaldehyde and
r-phenyl-ethylamine via palladium-catalyzed hydrogenation of
the intermediate (R)-benzylidene-(1-phenylethyl)amine.
Introduction
Despite recent advances in asymmetric catalysis, classical
resolution remains prevalent in cost-driven industrial proc-
esses. There are several enantiomerically pure, commercially
available amines that can be used for this purpose; however,
their cost frequently limits their use on an industrial scale.
Our work on the synthesis of improved HIV protease
inhibitors required a method for the synthesis of â-hydroxy
carboxylic acids of structure 1. While screening a range of
chiral amines for the classical resolution of these substrates,
it became apparent that N-benzyl-R-methyl benzylamine1 (3)
proved superior both in terms of yield and % ee of the final
material. The high commercial cost of this amine, however,
prevented its practical use on increased scale. To make the
project cost-effective, we decided to synthesize this com-
pound in-house.
required large amounts of DMPU as the solvent.6 Another
paper7 describes the use of NaBH3CN to reduce the imine
5; unfortunately the yields are low (60%), and some
racemization cannot be avoided even with careful pH
adjustment. Our goal was to develop a high-throughput
process that would yield enantiomerically pure material on
a consistent basis. Herein we report an inexpensive synthesis
of (R)- and (S)-N-benzyl-R-methyl benzylamine starting with
readily available (R)- and (S)-R-phenylethylamine.
Results and Discussion
The formation of the imine (R)-5 in both benzene and
methylene chloride solvents has been previously reported.8
After surveying a number of more EPA-friendly solvents,
we report that the imine formation occurs readily in toluene,
and despite the increased temperature required to remove
the water, no racemization is observed.
Debenzylation of the product during the reduction of the
imine was a serious concern since this could contaminate
the product with both benzylamine and R-phenylethylamine.
The presence of these impurities understandably diminishes
the efficiency of the subsequent resolution. Of the catalysts
screened, 5% Pd/C caused the least hydrogenolysis. We also
observed that debenzylation was suppressed to a greater
extent at higher hydrogen pressures, which is counterintuitive,
but consistent with the observation that hydrogenolysis is
generally a “hydrogen-starved” process. Because of equip-
ment capabilities, we ran these reactions at 50 psig hydrogen.
If the reaction was run for substantially longer than the usual
Enantiomerically pure N-benzyl-R-methyl benzylamine
has found range of utility in addition to its use as a resolving
agent. The lithium amide derived from the amine has been
used for asymmetric deprotonations of prochiral ketones used
in stereoselective aldol reactions.2 The lithium and magne-
sium amides have been used successfully in asymmetric
Michael additions.3
A review of the literature revealed that this amine can be
made via the asymmetric hydrogenation of imine 2 using
either optically active zirconocene4 or iridium complexes,5
but these methods only provide material in 76 and 90% ee,
respectively. The amine was also prepared by the monoalkyl-
ation of 1-phenylethylamine with benzyl bromide but
* To whom correspondence should be addressed. Telephone: 616-392-2375.
Fax: 616-392-8916. E-mail: brian.huckabee@wl.com.
(1) The amine 3 has been used successfully as a resolving agent. (a) Juaristi,
E. Tetrahedron Asymmetry 1998, 9, 715. (b) See also: Japanese Patent JP
05255180A, 1993.
(2) Majewski, M.; Gleave, D. M. J. Org. Chem. 1992, 57(13), 3599-605.
(3) Bunnage, M. E.; Davies, S. G.; Goodwin, C. J.; Walters, I. A. S.;
Tetrahedron Asymmetery 1994, 5(1), 35-36.
(4) Brintzinger, H.; Ringwald, M.; Strumer, R. J. Am. Chem. Soc. 1999, 121,
1524.
(6) Juaristi, E.; Murer, P.; Seebach, D. Synthesis 1993, 12, 1243-6.
(7) Cain, C. M.; Cousins, R. P. C.; Coumbarides, G.; Simpkins, N. S.
Tetrahedron 1990, 46, 523.
(8) Furukawa, M.; Okawara, T.; Noguchi, Y.; Terawaki, Y. Chem. Pharm.
Bull. 1979, 27, 7(11), 2795. (b) Bourzat, J. D.; Comercon, A. Tetrahedron
Lett., 1993 34, 6049.
(5) Tani, K.; Onouchi. J.; Yamagata, T.; Kataoka, Y. Chem. Lett. 1995, 955.
594
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Published on Web 09/27/2000

30 min, debenzylation was observed. The reaction kinetics
under these conditions, however, proved to be such that the
reduction greatly outpaced hydrogenolysis.
(R)-5 was not isolated and was carried into the hydrogenation
reaction.
(R)-N-Benzyl-r-methyl Benzylamine. (R)-3. The solu-
tion containing (R)-5 was charged to a reactor containing
50% water-wet 5% palladium on carbon (4.8 kg). The
reactor was pressurized with hydrogen to 50 psig, and the
reaction was hydrogenated at 20 °C. The maximum tem-
perature reached during the hydrogenation was 25 °C. The
reaction was continued until no more hydrogen uptake was
observed (about 30 min). The solution was filtered to remove
the palladium catalyst and concentrated in vacuo to afford a
yellow oil (52.9 kg, 97.8%). 1H NMR (CDCl3, 200 MHz) δ
7.36-7.22 (m, 10H), δ 3.78 (q, 1H, J ) 7 Hz), δ 3.63 (d,
1H, J ) 15 Hz), δ 3.61 (d, 1H, J ) 15 Hz), δ 1.35 (d, 3H,
J ) 7 Hz); Chiral HPLC10 99.4% R : 0.6% S; Anal. Calcd.
for C15H17N: C, 85.26; H, 8.11; N, 6.63. Found: C, 85.4%;
H, 8.0%; N, 6.58%.
This procedure produces material of >95% overall purity
in a consistent manner and can be run at the scale shown in
one 8-h shift. No racemization is observed, and the final ee
is the same as that of the initial R-phenethylamine. The only
significant impurity is benzyl alcohol, which can be removed
with further distillation, if desired, to give material of 99%
purity. Importantly, this process also minimizes solvent,
eliminates some hazardous materials, and produces consistent
low-cost material.
Experimental Section
General Methods. Reagents and solvents were com-
mercial and used as received. 1H NMR was recorded at 200
MHz.
(S)-N-Benzyl-r-methyl Benzylamine. (S)-3. (S)-3 was
prepared as described above in the preparation of (R)-3 using
(S)-R-phenylethylamine. The (S)-3 synthesis was carried out
on the same scale.
(R)-Benzylidene-(1-phenylethyl)amine. (R)-5. (R)-R-
phenylethylamine (98.8% ee, 31 kg, 256 mol), toluene (260
L),9 and benzaldehyde (29 kg, 273 mol) were combined at
ambient temperature. The solution was heated to reflux.
Water was removed in a water separator (approximately 2
h). The reaction solution was cooled to 20 °C. The imine
Received for review January 17, 2000.
OP000201N
(9) The formation of the imine R-5 and the hydrogenation to give R-3 have
been run at double this concentration at the 20 gm scale. Furthermore,
water was not removed from the reaction prior to hydrogenation. The
reaction behaved identically.
(10) Chiracel OD-H column (250 × 4.6 mm), 1000:20:1 (hexane:iPrOH:Et2NH);
0.5 mL per minute, 254 nm. Elution time: 14.5 min. (R), 15.8 min. (S).
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