Practical synthesis of a cell adhesion inhibitor by self-regeneration of stereocenters

Article abstract of DOI:10.1016/j.tetasy.2003.08.039

An efficient enantiospecific synthesis of the cell adhesion inhibitor BIRT-377 by self-regeneration of stereocenters has been achieved in 38% overall yield in eight steps. The key transformations involve the stereoselective formation of the trans imidazol

Full text of DOI:10.1016/j.tetasy.2003.08.039

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3495–3501
Practical synthesis of a cell adhesion inhibitor by
self-regeneration of stereocenters
Nathan K. Yee,* Laurence J. Nummy, Rogelio P. Frutos, Jinhua J. Song, Elio Napolitano,
Denis P. Byrne, Paul-James Jones and Vittorio Farina
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368,
Ridgefield, CT 06877-0368, USA
Received 24 July 2003; accepted 28 August 2003
Abstract—An efficient enantiospecific synthesis of the cell adhesion inhibitor BIRT-377 by self-regeneration of stereocenters has
been achieved in 38% overall yield in eight steps. The key transformations involve the stereoselective formation of the trans
imidazolidinone 7, subsequent alkylation, and the efficient hydrolysis of disubstituted imidazolidinone 9. The process is practical,
robust, and cost-effective; it has been successfully implemented in the pilot plant to produce multikilogram quantities of the drug
BIRT-377 1.
© 2003 Elsevier Ltd. All rights reserved.
LFA-1 to ICAM-1 in a reversible manner with a Kd of
25.8 6.3 nM. Additional binding site studies demon-
strated that BIRT-377 binds to the b-subunit (CD11a
chain) of LFA-1 and not to ICAM-1. Furthermore, it
was shown in a mouse model that orally administered
BIRT-377 inhibits the in vivo production of IL-2.
Given the immense therapeutic potential that a small
molecule such as BIRT-377 has to offer for the treat-
ment of immunological disorders, we became involved
in a program designed to develop an efficient, scalable,
and cost-effective route for the synthesis of molecules
like BIRT-377 and analogs. Herein, we report an
efficient enantiospecific synthesis of BIRT-377 based on
a modification of Seebach’s self-regeneration of stereo-
centers strategy in which we extend the original
protocol to achieve complete (>99.9%) overall stereo-
selectivity.5
1. Introduction
LFA-1 (lymphocyte function-associated antigen-1)
belongs to the integrin family and is expressed solely on
leukocytes (white blood cells) and is required for a
variety of important functions in both killer and helper
T cells. The counter receptor to LFA-1 on target cells is
recognized to be ICAM-1 (intercellular cell adhesion
molecule-1).1 ICAM-1 belongs to the immunoglobulin
family of receptors and can be expressed on cells from
a variety of tissues, including endothelial, fibroblastic,
and epithelial cells. Blocking the protein–protein inter-
action of cell adhesion molecules such as LFA-1 to
ICAM-1 could prove beneficial to patients suffering
from immune disorders, and an antisense polynucle-
otide molecule that blocks the expression of ICAM-1 is
currently undergoing tests for the treatment of Crohn’s
disease.2 With the realization that small molecules have
an advantage over protein therapeutics, a high through-
put screening was established by our Discovery team in
an effort to identify low molecular-weight molecules
that act as antagonists to the binding of LFA-1 to
ICAM-1. The structure–activity relationship studies
resulted in the discovery of BIRT-377 1 (Fig. 1).3,4 This
small molecule selectively inhibits the association of
Figure 1.
* Corresponding author. E-mail: nyee@rdg.boehringer-ingelheim.com
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.08.039

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N. K. Yee et al. / Tetrahedron: Asymmetry 14 (2003) 3495–3501
nately, this method has not been widely reported, espe-
cially for industrial large-scale production, probably
due to the reported harsh conditions (aqueous HCl at
150–220°C) required to hydrolyze the resulting 5,5-di-
substituted imidizolidinones,8–18 as well as its modest
diastereoselectivities (70–90% ds) in the formation of
the imidazolidinone template. During our literature sur-
vey, it was found that the stereoselective formation of
either the trans- or cis-imidazolidinones by Seebach’s
method was limited to the a-amino-N-methyl amides as
substrates, and other substitution (such as N-aryl) on
the amide nitrogen atom had not been reported. There-
fore, the utilization of Seebach’s principle to synthesize
a-substituted amino N-aryl amide 2 (Scheme 1) for
BIRT-377 1 is intriguing in relation to the possible
stereochemical outcome.
Scheme 1. Retrosynthetic strategy.
2. Results and discussion
2.1. Synthetic strategy
The key structural feature of BIRT-377 is the N-aryl-
substituted hydantoin, which contains a quaternary
stereogenic center. In our retrosynthetic analysis
(Scheme 1), the hydantoin ring can be formed by
cyclization of the corresponding a-substituted alanine
amide 2. In the literature, a variety of synthetic
methodologies have been reported for the asymmetric
synthesis of quarternary a-amino acids as well as their
derivatives, and this important subject had been
recently reviewed by Cativiela.6 Of these known meth-
ods, Seebach’s self-regeneration of stereocenters
principle7 in the preparation of a-substituted amino
acid derivatives was most attractive to us due to its
simplicity in terms of the easy access of the chiral
template imidazolidinones (up to 90% ds), the stability
of its enolate at higher temperature (up to 0°C), and the
predictability of its stereochemical outcome. Unfortu-
2.2. Stereoselective formation of trans-imidazolidinone
Since the complete diastereoselectivity (100% dr) for the
alkylation of the trans-imidazolidinone such as 8
(Scheme 2) had been well documented in literature,8–18
our efforts were first focused on the efficient formation
of trans-N-aryl imidazolidinone 7 in Scheme 2. The
synthesis of BIRT-377 1 started with the commercially
available
D
-N-Boc-alanine 4 (Scheme 2). The amide 5
was prepared by reacting 4 with 3,5-dichloroaniline via
a mixed anhydride intermediate (i-BuOCOCl, N-
methylmorpholine, −15°C to rt, THF). Deprotection of
the crude amide 5 by HCl in methanol afforded amino
N-aryl amide 6. The crude product obtained after
Scheme 2. Synthesis of BIRT-377 1.

N. K. Yee et al. / Tetrahedron: Asymmetry 14 (2003) 3495–3501
3497
neutralization was pure enough to carry on to the next
step without further purification. In our preliminary
laboratory studies,5 amino amide 6 was treated with
pivalaldehyde in refluxing pentane in a manner similar
to that described by Seebach’s original procedure. A
crystalline solid was directly formed from the reaction
mixture and identified as the desired trans-imidazolidi-
none 719 as a single diastereomer in 74% yield. This
observation is in contrast with Seebach’s case for the
corresponding amino acid N-methyl amide. Seebach
reported that the acyclic Schiff base intermediate was
actually obtained as an oil in this step and then cyclized
only when treated with HCl in methanol at 0°C or with
(PhCO)2O at 130°C to generate stereoselectively either
trans- or cis-imidazolidinones in 90% ds and 71% ds,
respectively.8
It is interesting that pure trans-7 was equilibrated to a
mixture of 7/11/12/6 in these solutions over time. How-
ever, both the equilibrium ratios and the rates of equili-
bration were different in different solvents. In polar
solvents, the ratios of 7/11 (91:9 in DMSO-d6 and 80:20
in MeOH-d4) were reached instantaneously and no
change of this ratio was observed over days. In less
polar solvents CDCl3 and benzene-d6, the rate of equili-
bration was much slower. The amount of cis-isomer 11
was slowly increased, in chloroform 7/11 to 77:23 at 22
days and in benzene 7/11 to 88:12 at 3 days. Most
importantly, these apparent equilibration data indicated
that there is no overwhelming thermodynamic factor in
favor of the trans-isomer 7 over the cis-isomer 11.
Therefore, formation of the single trans-isomer 7 dur-
ing the crystallization of a mixture of trans- and cis-
imidazolidinones 7 and 11 in non-polar solvents such as
alkanes is not attributable to the inherent thermody-
namic properties of these trans/cis isomers. Instead, the
phenomenon observed in this case is more consistent
with a crystallization-driven dynamic transformation,20
in which the crystallinity of the trans-isomer 7 is the
driving force for the stereoselective formation of the
single diastereomer. The possible factors contributing
to the stereoselective formation of trans-7 include the
different crystallinity of the respective compounds 7/11/
12 and the lower pKa of the NH group in the N-aryl
amide 6 in comparison with those of the corresponding
N-methyl amide, which facilitates the equilibration
among 7/11/12.
In our later experiments, it was found that a mixture of
trans- and cis-imidazilidinones 7 and 11 and Schiff base
12 (Table 1) was readily formed by treating amino
amide
6
with pivalaldehyde in toluene or
dichloromethane. However, when this oily mixture
(with various 7/11/12 ratios) was allowed to stand neat
over a period of time, or when the mixture of 7/11/12
was stirred in nonpolar solvents such as pentane or
i-octane, it was completely converted to the pure trans-
isomer 7 as a crystalline solid.
This observation was intriguing and led us to conduct
some equilibration experiments for the mixture of 7/11/
12 in solution. Pure trans-imidazolidinone 7 was dis-
solved in deuteriated solvents such as CDCl3,
benzene-d6, DMSO-d6, and MeOH-d4. These samples
were allowed to equilibrate at ambient temperature and
led to the formation of four related compounds, which
are the trans- and cis-imidazolidinones 7 and 11,
acyclic Schiff base 12, and some hydrolyzed free amine
6 (Table 1). The ratio of 7/11/12/6 was monitored by
1H NMR spectroscopy over a period of time. The
results are summarized in Table 1.
After the unique behavior of these trans- and cis-iso-
mers 7 and 11 was identified, the desired trans isomer 7
was easily formed stereoselectively. A solution of amino
amide 6 and pivalaldehyde in toluene was heated at
50°C and a mixture of trans- and cis-7 and 11, and
Schiff base 12 was obtained. Regardless of the 7/11/12
ratio in this mixture, pure trans-7 was selectively pre-
cipitated as a crystalline solid from i-octane (Scheme 2).
It should be noted that this chiral template 7 was the
Table 1. Equilibration of trans-imidazolidinone 7 in organic solvents
Entry
Solvent
CDCl3
Time
7 (%)
11 (%)
12 (%)
6 (%)
1
0
100
0
0
0
2
3
4
5
3 h
6 h
22 days
0
95.0
90.0
48.0
100
0.5
1.0
14.0
0
4.0
8.0
29.0
0
0.5
1.0
9.0
0
C6H6-d6
6
7
8
9
5 h
93.4
68.1
61.0
82.0
69.0
0.2
4.8
8.3
8.0
17.1
4.7
1.7
3.6
3.9
0
2 days
3 days
0 to days
0 to days
23.5
26.8
10.0
13.9
DMSO-d6
MeOH-d4
10
0

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N. K. Yee et al. / Tetrahedron: Asymmetry 14 (2003) 3495–3501
first isolated crystalline intermediate and it served as the
first purification point from the beginning of the syn-
thesis and the overall yield of 7 was 66% for the first
three steps from 4.
3. Conclusion
In conclusion, an efficient enantiospecific synthesis of a
cell adhesion inhibitor BIRT-377 1 has been achieved in
38% overall yield in eight steps. The key transforma-
tions involve the stereoselective formation of the trans-
imidazolidinone 7, subsequent alkylation, and the
efficient hydrolysis of 9. The crude intermediates were
used directly in all steps in this synthetic scheme and
there was no purification step needed in the entire
sequence. A single crystallization of the final product
gave the drug substance in high purity. This process is
practical, robust, and cost-effective, and it has been
successfully implemented in the pilot plant to produce
multikilogram quantities of BIRT-377 1.
Interestingly, when isobutyraldehyde was used to
replace the much more expensive pivalaldehyde, similar
phenomenon in terms of stereoselective formation of
the trans-isomer 13 was also observed (Scheme 3).21
Even though such a change may seem trivial, it has not
been previously documented in the literature that alde-
hyde bearing a-hydrogen can be used in this protocol.
4. Experimental25
Scheme 3. Isobuyyraldehyde-derived trans-imidazolidinone
13.
4.1. (1R)-[1-(3,5-Dichloro-phenylcarbamoyl)-ethyl]-car-
bamic acid tert-butyl ester 5
A solution of
D
-N-Boc-alanine 4 (8.83 kg, 46.7 mol) in
2.3. Synthesis of BIRT-377
90 L of anhydrous THF was prepared in a 50 gallon
reactor. The reaction mixture was cooled to approxi-
mately −15°C and N-methyl-morpholine (4.96 kg, 49.0
mol) was added at a rate to keep the internal tempera-
ture at −15°C. Isobutyl chloroformate (6.67 kg, 48.8
mol) was added into the reaction mixture over a 45 min
period to keep the internal temperature at −15°C. The
resulting mixture was then agitated at this temperature
for 30 min. A solution of 3,5-dichloroaniline (7.57 kg,
46.7 mol) in 25 L of THF was added at a rate to keep
the internal temperature between −15°C and −20°C
over 30 min. THF (5 L) was used to rinse the transfer
line and added to the reaction mixture. The reaction
mixture was then warmed to 20°C over 6 h. The
resulting suspension was filtered and the solids were
washed with THF (2×8 L). The combined filtrate was
stored in a cold room (ꢀ4°C).
The enantiomerically pure trans-imidazolidinone 7 was
N-protected (TFAA, TEA, toluene, rt, 98% yield). The
resulting imidazolidinone 8 was deprotonated at −5°C
and the resulting enolate was alkylated with bromoben-
zyl bromide from the opposite face to the tert-butyl
group to give a.a-disubstituted imidazolidinone 9 as a
single diastereomer.22
As reported by Seebach and others,8–18 hydrolysis of
dialkylated imidazolidinone 9 was not trivial, pre-
sumably due to steric hindrance of the substrate and its
low solubility in aqueous media. The substrate
remained unreacted under most of the traditional
hydrolysis conditions (aqueous HCl/MeOH at reflux;
aqueous NaOH/MeOH at reflux; or H2NNH2/EtOH at
reflux). After considerable efforts, a practical one-pot
hydrolysis procedure was developed. The trifluoroac-
etamide moiety of 9 was first hydrolyzed (1.5 equiv. of
BnNMe3OH, 2.0 equiv. of 50% NaOH, rt to 40°C,
dioxane) to give a mixture of the corresponding par-
tially hydrolyzed N-unsubstituted aminal of 9, Schiff
base of 2, and 2 itself. Subsequent direct addition of 6
M HCl to the above mixture resulted in complete
hydrolysis to afford amino amide 2 in 96% overall yield
from 8. The smooth hydrolysis of 9 by BnNMe3OH
may be attributed to its unique features acting as a
potent base and a phase transfer catalyst.
The above procedure was repeated in the identical
manner to produce another batch of this compound.
The combined filtrate from these two batches was con-
centrated under reduced pressure (ꢀ200 torr) with
jacket temperature at 30–40°C. After collecting approx-
imate 235 L of the distillate, MeOH (70 L) was added
to the mixture. The mixture was subjected to vacuum
distillation (jacket temp. <60°C). After 50 L of the
distillate were collected, the crude product 5 solution
was transferred to a container with aid of 20 L of
MeOH (total weight: 73.4 kg) and used for next step
directly. An analytically pure sample was obtained by
flash chromatography. Mp 146°C; [h]2D0=+72.0 (c 1.07,
CH2Cl2); 1H NMR (CDCl3, 400 MHz) l 8.81 (br.s,
1H), 7.46 (s, 2H), 7.06 (s, 1H), 4.93 (br. d, J=6.6 Hz,
1H), 4.28 (br. dt, J=7.0 Hz, 1H), 1.47 (s, 9H), 1.42 (d,
J=7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) l 171.5,
156.5, 139.6, 134.9, 123.8, 117.6, 81.0, 50.9, 17.4. Anal.
calcd for C14H18Cl2N2O3: C, 50.46; H, 5.44; N, 8.41.
Found: C, 50.40; H, 5.42; N, 8.27.
Treatment of crude 2 with methyl chloroformate in the
presence of triethylamine gave crude hydantoin 10.
Methylation [LiN(TMS)2, MeI, DMF, rt] of the crude
10 followed by a single crystallization of the crude
product from EtOAc/hexane afforded BIRT-377 1 in
62% overall yield from 2. The drug substance possessed
excellent chemical purity (>99.9% by HPLC23) and
enantiomeric excess (>99.9% ee by chiral HPLC24).

N. K. Yee et al. / Tetrahedron: Asymmetry 14 (2003) 3495–3501
3499
4.2. (2R)-2-Amino-N-(3,5-dichlorophenyl)-propionamide
6
NMR (CDCl3, 100 MHz) l 175.3, 140.5, 135.1, 126.0,
122.8, 82.0, 55.5, 39.5, 26.1, 18.2. Anal. calcd for
C14H18Cl2N2O: C, 55.82; H, 6.02; N, 9.30. Found: C,
55.80; H, 6.05; N, 9.15.
Hydrochloric acid (12 M, 39 L, 468 mol) was charged
into a 50 gallon reactor and diluted with water (39 L)
and MeOH (20 L). The internal temperature rose to
ꢀ30°C. The above solution of crude amide 5 (73.4 kg,
max. 93.4 mol) obtained from the last step was added
into the reaction mixture in two portions over 1 h and
gas evolution started at this point. The reactor jacket
temperature was set to 25°C and the reaction mixture
was agitated for 18 h. The reaction mixture was then
subjected to vacuum distillation with jacket tempera-
ture <60°C. After ꢀ70 L of distillate was collected, the
reaction mixture was cooled to ꢀ15 to 20°C and 60 L
of toluene was added. 50% NaOH solution (ꢀ40 kg)
was added at a rate to keep the internal temperature
below 25°C until the pH reached 13–14 in the aqueous
layer. The layers were separated and the aqueous layer
was extracted with toluene (2×35 L). The combined
organic layers were washed with water (2×30 L) and
concentrated under reduced vacuum (jacket temp.
<50°C). After ꢀ110 L of distillate was collected, the
crude product 6 solution was transferred to a container
with aid of 10 L of toluene (total weight: 40.3 kg) and
used for next step directly. Analytically pure sample
was obtained by flash chromatography. Oil; [h]2D0=+0.4
4.4. (2R,5R)-2-tert-Butyl-3-(3,5-dichlorophenyl)-5-
methyl-1-trifluoroacetyl-imidazolidin-4-one 8
Imidazolidinone 7 (18.3 kg, 60.7 mol) was charged into
a 50 gallon reactor followed by 130 L of toluene. The
resulting solution was subjected to vacuum distillation
to collect ꢀ20 L of distillate in order to ensure the
dryness of the material. The reaction mixture was
cooled to 0°C and triethylamine (7.07 kg, 69.9 mol) was
added over 15 min at this temperature. Trifluoroacetic
anhydride (14.68 kg, 69.9 mol) was added to the reac-
tion mixture over 1 h at a rate to keep the internal
temperature at −5°C. The reaction mixture was agitated
at ꢀ0°C for 1 h and then warmed to 20°C over 1 h.
The reaction was complete and the reaction mixture
was cooled to 10°C and water (20 L) was added at this
temperature. The layers were separated and the organic
layer was washed with water (20 L and then 10 L). The
organic layer was concentrated under reduced pressure
(jacket temp. <65°C). After ꢀ110 L of distillate was
collected. i-Octane (150 L) was added and the distilla-
tion continued until ꢀ100 L of distillate was collected.
The crystalline solids were collected by filtration and
washed with i-octane (2×12 L) to give 22.30 kg of pure
8. Concentration of the filtrate to dryness and treating
the residue with 5 L of i-octane afforded additional
1.20 kg of 8. The total yield of 8 was 23.50 kg (98%).
1
(c 1.10, CH2Cl2); H NMR (CDCl3, 400 MHz) l 9.66
(br. s, 1H), 7.56 (s, 2H), 7.06 (s, 1H), 3.60 (q, J=7.0
Hz, 1H), 1.62 (br. s, 2H), 1.41 (d, J=7.0 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) l 174.0, 139.5, 135.1, 123.8,
117.4, 51.0, 21.4. Anal. calcd for C9H10Cl2N2O: C,
46.37; H, 4.32; N, 12.02. Found: C, 46.14; H, 4.32; N,
11.89.
1
Mp 131°C; [h]2D0=+119.1 (c 1.25, CH2Cl2); H NMR
(CDCl3, 400 MHz) l 7.48 (s, 2H), 7.28 (s, 1H), 6.20 (br.
s, 1H), 4.52 (q, J=6.6 Hz, 1H), 1.68 (d, J=6.3 Hz, 3H),
0.87 (s, 9H); 13C NMR (CDCl3, 100 MHz) l 169.5,
138.6, 135.6, 127.0, 122.2, 117.3, 114.5, 79.0, 57.8, 42.1,
26.3. Anal. calcd for C16H17Cl2F3N2O2: C, 48.38; H,
4.31; N, 7.05. Found: C, 48.31; H, 4.36; N, 6.79.
4.3. (2S,5R)-2-tert-Butyl-3-(3,5-dichlorophenyl)-5-
methyl-imidazolidin-4-one 7
A solution of the crude amino amide 6 (40.3 kg, max.
93.4 mol) was added into a 50-gallon reactor and
diluted with 48 L of toluene. A solution of pivalalde-
hyde (8.17 kg, 94.86 mol) in 10 L of toluene was added
to the reaction mixture over 30 min and the internal
temperature rose from 21°C to 27°C. The transfer line
was rinsed with 15 L of toluene. After the reaction
mixture was heated to 50°C and agitated at this temper-
ature for ꢀ20 h, the reaction mixture was subjected to
vacuum distillation (jacket temp. <65°C) to collect ꢀ95
L of distillate over ꢀ4 h. The vacuum was released and
i-octane (77 L) was added to the mixture. The reaction
mixture was cooled to ꢀ0°C and stirred for 2 h during
which crystalline solids were formed in the reaction
mixture. The solids were collected by filtration and the
cake was rinsed with i-octane (2×12 L) to give 17.65 kg
of pure 7 as first crop. The combined filtrate was
concentrated to dryness and then treated with 16 L of
i-octane. The crystalline solids were formed and
filtered. The solids were rinsed with i-octane (2×1.5 L)
to give 0.91 kg of pure 7 after drying. The total yield of
7 was 18.56 kg (66%). Mp 126°C; [h]2D0=−12.1 (c 1.30,
4.5. (2R,5R)-5-(4-Bromo-benzyl)-2-tert-butyl-3-(3,5-
dichlorophenyl)-5-methyl-1-trifluoroacetyl-imidazolidin-
4-one 9
A solution of 8 (12.74 kg, 32.07 mol) in 48 kg of
anhydrous THF was prepared in a 50-gallon reactor.
The solution was subjected to vacuum distillation to
collect ꢀ20 L of distillate to ensure the anhydrous
conditions. The reaction mixture was cooled at −5°C to
+5°C and a solution of LiHMDS (1.0 M, 29.65 kg, 33.3
mol) was added at this temperature over 45 min. After
the addition, the reaction mixture was agitated at −5°C
to 0°C for 1 h. A solution of 4-bromobenzyl bromide
(8.34 kg, 33.4 mol) in 18 L of THF was added at −5°C
to 0°C over 40 min. The reaction mixture was agitated
at this temperature for 2 h. Saturated ammonium chlo-
ride solution (9 L) was added to quench the reaction.
The reaction mixture was subjected to vacuum distilla-
tion. After collecting ꢀ55 L of distillate, a slurry was
formed in the mixture and water (40 L) was added to
dilute the slurry. Additional 30 L of distillate was
collected by vacuum distillation. At this point, toluene
1
CH2Cl2); H NMR (CDCl3, 400 MHz) l 7.32 (s, 2H),
7.19 (s, 1H), 4.85 (s, 1H), 3.76 (q, J=6.8 Hz, 1H), 2.05
(br. s, 1H), 1.36 (d, J=6.8 Hz, 2H), 0.84 (s, 9H); 13C

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N. K. Yee et al. / Tetrahedron: Asymmetry 14 (2003) 3495–3501
(50 L) was added to the mixture for extraction. The
layers were separated, the organic layer was washed
with water (40 L), and concentrated under reduced
pressure. After collecting ꢀ30 L of distillate, the mix-
ture became a slurry. Toluene (20 L) was added to
dissolve the slurry and the solution was then transferred
into a container with aid of 12 L of toluene. The total
weight of this solution was 75.45 kg and this material
was used for next step directly. The crude alkylated
product 9 was estimated to be 17.50 kg (96%). Analyti-
cally pure sample was obtained by flash chromatogra-
phy. Mp 164°C; [h]2D0=+89.8 (c 1.01, CH2Cl2); 1H
NMR (CDCl3, 400 MHz) two rotamers l 7.23–7.29 (m,
3H), 6.93 (s, 1H), 6.76–6.79 (m, 3H), 5.66 (s, 0.4H),
5.40 (s, 0.6H), 3.72 (d, J=14 Hz, 0.6H), 3.26 (d, J=14
Hz, 0.4H), 3.08 (t, J=15 Hz, 1H), 1.96 (s, 0.6H), 1.93
(s, 0.4H), 0.86 (s, 6.4H), 0.73 (s, 3.6H). Anal. calcd for
C23H22BrCl2F3N2O2: C, 48.79; H, 3.92; N, 4.95. Found:
C, 49.02; H, 3.95; N, 4.88.
dichloromethane (72 L) was concentrated under
reduced pressure to remove dichloromethane, which
was replaced with THF. The resulting solution of 2 in
THF (40 L) was cooled to 10°C and triethylamine (4.32
kg, 42.7 mol) was slowly added. The internal tempera-
ture was then adjusted to 0°C and methyl chlorofor-
mate (3.054 kg, 32.3 mol) was added at a rate to keep
the internal temperature below 10°C. The temperature
was then increased and the mixture was stirred at reflux
(68°C) for 14 h and quenched with water (3.5 L). The
mixture was then concentrated under reduced pressure
keeping the jacket temperature at 57–60°C until
approximately 43 L of distillate was collected. Water
(28 L) was added and the internal temperature was
adjusted to 20–23°C. The product was extracted with
dichloromethane (2×19 L), the combined organic por-
tions were washed with water (14 L) and concentrated
under reduced pressure. Methanol (30 L) was added
and the mixture was again concentrated under reduced
pressure keeping the jacket temperature at 60–65°C
until 43 L of distillate was collected. Afterwards, tri-
ethylamine (4.34 kg, 42.9 mol) and methanol (19 L)
were added and the mixture was stirred and heated at
reflux for 14 h. The mixture was concentrated under
reduced pressure keeping the jacket temperature at
60°C. After 39 L of distillate were collected, the distilla-
tion was stopped and mixture was cooled to 20°C. The
total weight of the crude 10 solution was 20.05 kg and
used for next step directly. An analytically pure sample
was obtained by flash chromatography. foam; [h]2D0=
−120.0 (c 1.02, CH2Cl2); 1H NMR (CDCl3, 400 MHz) l
7.46 (d, J=8.3 Hz, 2H), 7.34 (s, 1H), 7.06 (d, J=8.3
Hz, 2H), 6.98 (s, 2H), 6.84 (br. s, 1H), 3.13 (d, J=13
Hz, 1H), 2.91 (d, J=13 Hz, 1H), 1.60 (s, 3H); 13C
NMR (CDCl3, 100 MHz) l 174.1, 154.7, 135.2, 132.8,
132.7, 131.7, 128.5, 124.5, 122.0, 62.7, 43.5, 23.3. Anal.
calcd for C17H13BrCl2N2O2: C, 50.46; H, 5.44; N, 8.41.
Found: C, 50.40; H, 5.42; N, 8.27.
4.6. (2R)-2-Amino-3-(4-bromophenyl)-N-(3,5-dichloro-
phenyl)-2-methyl-propionamide 2
A solution of 9 in toluene (75.45 kg, max. 32.07 mol)
from last step was transferred into a 50-gallon reactor
with aid of 15 L of toluene. The solution was subjected
to vacuum distillation (jacket temp. <65°C) to collect
ꢀ80 L of distillate. At this point, 1,4-dioxane (80 L)
was added and distillation continued to collect ꢀ16 L
of distillate. At 20°C, an aqueous 40% (w/w)
BnMe3NOH (20.15 kg, 48.2 mol) was added to the
reaction mixture followed by 50% NaOH (5.13 kg, 64
mol). The reaction mixture was then heated to 40°C
and vigorously agitated at this temperature for 12 h. An
HCl solution (prepared by mixing 19.40 kg of conc.
HCl and 10 L of water) was added to the reaction
mixture. The reaction mixture was then heated to 50°C
and stirred for 4 h. The reaction mixture was subjected
to vacuum distillation (jacket temp. <65°C). After ꢀ65
L of distillate was collected, toluene (50 L) was added
and the mixture was cooled to ꢀ10°C. A 50% NaOH
solution was added at a rate to keep the internal
temperature below 20°C until the pH of aqueous layer
reached 13–14 (ꢀ10.5 kg of 50% NaOH was used). The
layers were separated, the organic layer was washed
with water (2×40 L) and concentrated under reduced
pressure to give 13.33 kg of crude 2 which contained
7% by weight of residual toluene. The yield of 2 was
12.4 kg (96%). Analytically pure sample was obtained
by flash chromatography. Mp 81°C; [h]2D0=+176.6 (c
4.8. (5R)-5-(4-Bromobenzyl)-3-(3,5-dichlorophenyl)-1,5-
dimethyl-imidazolidine-2,4-dione 1
The above solution containing crude hydantoin 10
(20.05 kg, max. 19.65 mol) was concentrated under
reduced pressure to remove methanol. Toluene (60 L)
was added and distilled to remove the residual
methanol. DMF (25 L) was added and the internal
temperature was adjusted to 7.5 2.5°C as lithium
bis(trimethylsilyl)amide (21.03 kg, 1.0 M in THF, 20.4
mol) was slowly added. The internal temperature was
adjusted to 15 2°C and a solution of iodomethane
(3.82 kg, 29.9 mol) in DMF (5.0 L) was slowly added at
a rate to keep the internal temperature at 15–20°C. The
mixture was then stirred at 20°C for 3 h. The reaction
was then quenched with water (105 L) at 25°C. The
product was extracted from the above aqueous mixture
with ethyl acetate (3×15 L) and the combined organic
layers were then washed with water (60 L). The result-
ing solution was filtered to remove any solid particle
The resulting solution was concentrated under reduced
pressure with a jacket temperature at 55-60°C until 32
L of distillate was collected. Crystallization was carried
1
1.07, CH2Cl2); H NMR (CDCl3, 400 MHz) l 9.74 (br.
s, 1H), 7.52 (d, J=1.9 Hz, 2H), 7.41 (d, J=8.3 Hz, 2H),
7.08 (t, J=1.9 Hz, 1H), 7.05 (d, J=8.3 Hz, 2H), 3.47
(d, J=13 Hz, 1H), 2.61 (d, J=13 Hz, 1H), 1.45 (s, 3H);
13C NMR (CDCl3, 100 MHz) l 174.7, 139.4, 135.3,
135.1, 131.8, 131.6, 123.9, 121.2, 117.5, 58.8, 45.6, 28.0.
Anal. calcd for C16H15BrCl2N2O: C, 47.79; H, 3.76; N,
6.97. Found: C, 47.89; H, 3.81; N, 6.75.
4.7. (5R)-5-(4-Bromobenzyl)-3-(3,5-dichlorophenyl)-5-
methyl-imidazolidine-2,4-dione 10
A solution of intermediate 2 (7.90 kg, 19.65 mol) in

N. K. Yee et al. / Tetrahedron: Asymmetry 14 (2003) 3495–3501
3501
out by heating the above ethyl acetate solution of the
product to reflux and then slowly adding hexane (60 L).
The temperature of the resulting slurry was adjusted to
0°C and the mixture was stirred for 1 h. The product
was collected by filtration and the filter cake was
washed twice with a 4:1 ethyl acetate/hexane solution
and once with hexane (6 L). The crystalline material 1
was then dried in a vacuum oven at ambient tempera-
ture for 24 h to afford 5.35 Kg (62% yield from 2) of
BIRT-377 1 as a white solid. Both chemical purity and
enantiomeric excess were >99.9%.23,24 Mp 135–136°C;
7. Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2708.
8. Naef, R.; Seebach, D. Helv. Chim. Acta 1985, 68, 135.
9. Seebach, D.; Aehi, J. D.; Naef, R.; Weber, T. Helv. Chim.
Acta 1985, 68, 144.
10. Aehi, J. D.; Seebach, D. Helv. Chim. Acta 1985, 68, 1507.
11. Seebach, D.; Dziadulewicz, E.; Behrendt, L.; Cantoreggi,
S.; Fitzi, R. Liebigs Ann. Chem. 1989, 1215.
12. Grozinger, K. G.; Kriwacki, R. W.; Leonard, S. F.;
Pitner, T. P. J. Org. Chem. 1993, 58, 709.
13. Seebach, D.; Gees, T.; Schuler, F. Liebigs Ann. Chem.
1993, 785.
1
[h]2D5=+127.3 (c 0.78, EtOH); H NMR (CDCl3, 400
14. Kazmierski, W. M.; Urbanczyk-Lipkowska, Z.; Hruby,
MHz) l 7.42 (br. d, J=8.3 Hz, 2H), 7.28 (t, J=1.8 Hz,
1H), 6.94 (br. d, J=8.3 Hz, 2H), 6.84 (d, J=1.8 Hz,
2H), 3.08 (d, J=14 Hz, 1H), 3.06 (s, 3H), 2.96 (d,
J=14 Hz, 1H), 1.61 (s, 3H); 13C NMR (CDCl3, 100
MHz) l 173.3, 153.4, 135.0, 132.9, 132.8, 131.8, 131.0,
128.3, 124.4, 121.9, 65.6, 40.6, 25.2, 21.0. Anal. calcd
for C18H15BrCl2N2O2: C, 48.90; H, 3.42; N, 6.34; Br,
18.07; Cl, 16.04. Found: C, 48.98; H, 3.40; N, 6.38; Br,
18.33; Cl, 16.07.
V. J. J. Org. Chem. 1994, 59, 1789.
15. Studer, A.; Seebach, D. Liebigs Ann. Chem. 1995, 217.
16. Ma, D.; Tian, H. J. Chem. Soc., Perkin Trans. 1 1997,
3493.
17. Jaun, B.; Tanaka, M.; Seiler, P.; Kuehnle, F. N. M.;
Braun, C.; Seebach, D. Liebigs Ann. Chem. 1997, 1697.
18. Damhaut, P.; Lemaire, C.; Plenevaux, A.; Brihaye, C.;
Christiaens, L.; Comar, D. Tetrahedron 1997, 53, 5785.
19. The corresponding cis isomer of 8 was independently
prepared by deprotonation of trans-8 with LiN(TMS)2 at
0°C followed by quenching the enolate with saturated
aqueous NH4Cl at the same temperature. The trans/cis
stereochemistry was determined by NOESY experiment.
The chemical shifts for the N,N-acetal methine protons at
the C-3 position in trans- and cis-8 are characteristically
different: l 6.39 ppm (for trans isomer); l 6.20 ppm (for
cis-isomer).
References
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1
22. In H NMR spectrum, the disubstituted imidazolidinone
9 exists as a mixture of two rotamers, as reported by
Seebach. See Ref. 7 and cited references.
23. HPLC column, Novapak C18 (30 cm×3.0 mm); mobile
phase, 70% MeCN in aqueous 0.1% TFA; flow rate, 1.0
mL/min; ambient temperature.
24. Chiral HPLC column, Chiralpak AD (30 cm×4.6 mm);
mobile phase, 5% EtOH and 0.5% Et2NH in hexane; flow
rate, 1.0 mL/min; ambient temperature; retention time,
(+)-1 (BIRT-377), 11.38 min; (−)-1, 13.36 min.
6. Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron:
Asymmetry 1998, 9, 3517.
25. For general experimental procedure, see: Ref. 21.