7
12
prepared as outlined in Scheme 1. This is a fairly simple
mide as a white solid. This material is normally of greater
1
3
three-step sequence. The last step in this synthesis involves
a high-temperature melt reaction that affords a crude thali-
domide requiring multiple recrystallizations. In our synthesis,
we wished to avoid the melt reaction, which is not amenable
to standard equipment.
The synthesis in Scheme 1 begins with L-glutamic acid,
but a synthesis starting with L-glutamine would allow a more
direct two-step synthesis to be developed. In a 1965 paper,
the use of 1,1′-carbonyldiimidazole (CDI) for 4 days at room
temperature in DMF for the cyclization of N-phthaloyl-L-
isoglutamine to form (S)-thalidomide in low yield (41%) was
than 99% purity. The racemic nature of this material was
confirmed by chiral HPLC.
1
4
In conclusion, a synthesis was developed which fulfilled
our initial requirements of readily available starting materials,
no purifications, a good yield, and ability be done in standard
glassware and pilot plant equipment. The procedure can
easily be used to prepare thalidomide at the 100-g scale in
the laboratory, and it was successfully scaled up to the
multikilogram scale.
Experimental Section
All reactions were run under a nitrogen atmosphere unless
otherwise noted. All of the final compounds synthesized were
8
reported. In the same paper, under similar conditions,
N-phthaloyl-L-glutamine was cyclized to afford a 31% yield
of racemic thalidomide. In an earlier paper, acetic anhydride
was used for this cyclization; however, again the cyclization
afforded a low yield (33%) of thalidomide.9
1
13
characterized by H and C NMR, C, H, N elemental
1
13
analysis, and melting point for solids. H and C NMR were
determined on a Bruker AC250 FT instrument in an
appropriate deuterated solvent. Elemental analyses and
melting point determinations were done by Quantitative
Technologies Inc., Whitehouse, NJ. Reagents and solvents
were used as received from commercial suppliers.
N-Phthaloyl-L-glutamine (4). To a stirred solution of
L-glutamine (43.8 g, 300 mmol) and Na CO (33.4 g, 315
2 3
mmol) in 750 mL of water was rapidly added N-carbethoxy-
phthalimide [65.8 g (97% pure, 67.8 g), 300 mmol] as a solid.
After 1 h, the reaction mixture was filtered to remove
unreacted N-carbethoxyphthalimide. The pH of the stirred
filtrate was adjusted to 3-4 with 6 N HCl. The mixture was
then seeded with N-phthaloyl-L-glutamine and the pH
adjusted to 1-2 with 6 N HCl. The resulting slurry was
stirred for 1 h. The slurry was filtered and the solid washed
with copious amounts of water. The solid was air-dried and
We felt the approach starting from L-glutamine instead
of L-glutamic acid afforded a more direct route (Scheme 2).
Glutamine was chosen over isoglutamine because of cost
and the desire for racemic material. N-Phthaloyl-L-glutamine
(4) was prepared by a standard technique using N-carbe-
thoxyphthalimide. Treatment of L-glutamine with Na CO
2
3
then dried in vacuo (60 °C, <1 mmHg) overnight to afford
in water followed by the addition of N-carbethoxyphthalimide
afforded, after workup, a 50-70% yield of 4 as a white
powder. During the acidification, the reaction mixture is
seeded with solid 4 to ensure solidification of the product.
This material requires no purification. Use of N-carbethox-
yphthalimide produces chirally pure 4. This is as expected
from literature precedent10 and was confirmed in our
laboratories by conversion of the material to (S)-thalidomide
using the previously published cyclization method of Casini
and Ferappi.11 The cyclization of 4 is accomplished using
CDI in THF. Racemization of the product occurs in this step.
THF was used since thalidomide has a low solubility in THF
and the imidazole byproduct from CDI is soluble in THF.
A stirred mixture of 4 and CDI (1.05 equiv) in the presence
of a catalytic amount of DMAP in THF is heated to reflux
for 15-18 h. Further work demonstrated that DMAP is not
required for this cyclization to occur. Thalidomide crystallizes
out of the reaction mixture during reflux. The cooled reaction
mixture is filtered to produce an 85-93% yield of thalido-
1
5
1.8 g (67%) of 4 as a white powder: mp 169-171 °C; H
NMR (dmso-d
H, Ar), 7.22 (s, 1 H, CONH
dd, 1 H, CH), 2.50-1.95 (m, 4 H, CH
m, 1 H, CH ); C NMR (dmso-d
2 6
1
6
) δ 13.22 (br s, 1 H, COOH), 8.05-7.75 (m,
), 6.74 (s, 1 H, CONH ), 4.76
CH ), 2.15-2.00
) δ 173.0, 170.4, 167.3,
34.7, 131.2, 123.3, 51.2, 31.3, 23.9. Anal. Calcd for
: C, 56.52; H, 4.38; N, 10.14. Found: C, 56.64;
4
(
(
2
2
2
2
1
3
13 12 2 5
C H N O
H, 4.33; N, 10.10.
Thalidomide (1). A stirred mixture of 4 (125 g, 452
mmol), CDI (76.1 g, 469 mmol), and 4-DMAP (0.20 g, 1.6
mmol) in anhydrous THF (750 mL) was heated to reflux
for 16 h. The reaction slurry was filtered and the solid washed
2 2
with CH Cl (200 mL). The solid was air-dried and then dried
in vacuo (60 °C, <1 mmHg) to afford 106 g (91%) of the
1
product as a white powder: mp 274-276 °C; H NMR
(dmso-d
6
) δ 11.16 (s, 1 H, NH), 8.05-7.80 (br s, 4 H, Ar),
5
.18 (dd, 1 H, J ) 12, 5 Hz, CHCO), 3.05-2.85 (m, 1 H,
CH
2
CO), 2.70-2.45 (m, 2 H, CH
2
CH
) δ 172.8, 169.8, 167.1, 134.9,
131.2, 123.4, 49.0, 30.9, 22.0. Anal. Calcd for C13
C, 60.47; H, 3.90; N, 10.85; O, 24.78. Found: C, 60.42; H,
.82; N, 10.81; O, 24.98.
2
), 2.15-2.00 (m, 1
1
3
2 6
H, CH ); C NMR (dmso-d
(9) Kig, F. E.; Clark-Lewis, J. W.; Wade, R.; Swindon, W. A. J. Chem. Soc.
10 2 4
H N O :
1
957, 873-880.
(
10) Bodanszky, M.; Bodanszky, A. The Practice of Peptide Synthesis; Springer-
Verlag: New York-Heidelburg-Berlin-Tokyo, 1984; pp 10-11.
11) Casini, G.; Ferappi, M. Farmaco, Ed. Sci. 1964, 563-56.
12) Additional material can be obtained from the mother liquor.
13) The major impurity is 4.
3
(
(
(
(
Received for review April 10, 1998.
OP980201B
14) The racemic nature of the material was determined on a Daicel Chemical
Industries Chiralpak OJ column using ethanol as the eluent.
140
•
Vol. 3, No. 2, 1999 / Organic Process Research & Development
Muller, George W.
