A synthesis of thalidomide

Article abstract of DOI:10.1002/jccs.200200060

A synthesis of racemic thalidomide (1) was described and the important formal [3+3] cycloaddition strategy was a key step. The total yield of thalidomide (1) was 18% in five steps from known 3.

Full text of DOI:10.1002/jccs.200200060

Journal of the Chinese Chemical Society, 2002, 49, 383-385
383
A Synthesis of Thalidomide
Meng-Yang Changa (
Shui-Tein Chena* (
), Chung-Ho Changa (
),
) and Nein-Chen Changb* (
)
aInstitute of Biological Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan, R.O.C.
bDepartment of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, R.O.C.
A synthesis of racemic thalidomide (1) was described and the important formal [3+3] cycloaddition strat-
egy was a key step. The total yield of thalidomide (1) was 18% in five steps from known 3.
INTRODUCTION
Glutarimides (2,6-piperidinedione) possess various bi-
The elimination result was afforded in 82% yield. Iodide
compound was prepared from serine by known methods.15
Acetamide 4 was furnished by acetylation of chloroacetyl
chloride and N-p-methoxybenzylamine, followed by nu-
cleophilic substitution of p-toluenesulfonic acid sodium salt.
Compound 4 was obtained in 90% yield. As shown in Scheme
II, the acidolysis of the BOC protective group in 2 with
trifluoroacetic acid in methylene chloride gave the amine 5.
The solution of 5 in chloroform appeared an interesting
deep-blue color. We made the skeleton of 2-aminoglutar-
imide by a facile formal [3+3] cycloaddition reaction in two
steps from known 3. Phthaloylation of crude primary amine 5
with phthalic anhydride and triethylamine in reflux tempera-
ture provided compound 6 in 65% yield. Treatment of 6 with
6% sodium amalgam (Na-Hg) in methanol afforded PMB-
thalidomide.7 Desulfonylation of compound 6 must control
the PH value (7.4) to prevent the ring-opening of glutarimide.
Without purification, the crude product 6 was treated with
ceric ammonium nitrate to remove the PMB group16 in 6 and
thalidomide (1) was afforded. The total yield of thalidomide
is 18% in five steps from known 3. In conclusion, the pre-
sented synthesis provided a new strategy for racemic thalido-
mide by formal [3+3] cycloaddition reaction, and the method
could be useful in the search for immunosuppressors. We are
ological activities.1,2 Therefore, the preparation of these im-
ides has attracted attention in organic chemistry, e.g. cyclo-
heximide,3 actiketal,3 thalidomide4-7 and aminogluteth-
imide.4-6,8 The interest in the immuno-suppressor thalido-
mide has been growing regularly.9 It is currently used for
treatment of AIDS.10,11 Its activity against angiogenesis has
been recently discovered.12 Thalidomide (1) is currently used
in therapy as a racemate. The rate of racemization of 1 was
determined by its half life to be 556 min at PH = 7.4 (37 C).13
The pure enantiomer was obtained by preparative chiral chro-
matography.14 In the report we described the synthesis of
racemic thalidomide (1) by formal [3+3] cycloaddition reac-
tion.8
RESULTS AND DISCUSSION
Our strategy for the synthesis of thalidomide (1) is il-
lustrated in Scheme I. The key step was formal [3+3] cyclo-
addition reaction of , -unsaturated ester 3 and N-p-meth-
oxybenzyl- -sulfonyl acetamide 4. The given adduct was the
5-substituted -sulfonyl glutarimide 2 in 62% yield as the
mixture. The 2:1 ratio in the mixture 2 was determined by 1H
NMR spectra. The , -unsaturated ester 3 was prepared from
iodide compound15 and triethylamine in methylene chloride.
Scheme II
Scheme I

384 J. Chin. Chem. Soc., Vol. 49, No. 3, 2002
Chang et al.
currently studying the scope of this process as well as addi-
tional application of the methodology to the synthesis of dif-
ferent heterocyclic atoms at the 2-position of glutarimide.
tetrahydrofuran (10 mL) was added. The resulting mixture
was heated at reflux temperature for 20 min, quenched with
saturated ammonium chloride solution (1 mL) and the mix-
ture was concentrated under reduced pressure. Then the
crude product was extracted with ethyl acetate (3 20 mL)
and the combined organic layers were washed with brine (2
20 mL), dried over anhydrous magnesium sulfate, filtered
and evaporated. Purification on silica gel (hexane/ethyl ace-
tate = 4/1) afforded 300 mg (62%) of 2 as a solid: mp 83-84
C. Electrospray-MS: C25H30N2O7S m/z (%) = 447 (100), 503
(M+, 44). IR (film) 1720 cm-1. 1H NMR (400 MHz, CDCl3)
7.74 (d, J = 8.3 Hz, 4/5H), 7.55 (d, J = 8.3 Hz, 6/5H), 7.33-
7.19 (m, 4H), 6.82-6.76 (m, 2H), 5.50-5.20 (brs, 1H), 5.00-
4.74 (m, 3H), 4.30-4.10 (m, 1H), 3.77 (s, 9/5H), 3.76 (s,
6/5H), 3.20-2.95 (m, 1H), 2.44 (s, 3H), 2.30-2.17 (m, 1H),
1.45 (s, 9H). Anal. Calcd. for C25H30N2O7S: C, 59.75; H,
6.02. Found: C, 59.80; H, 6.06.
EXPERIMENTAL SECTION
General
Tetrahydrofuran was distilled prior to use from a deep-
blue solution of sodium-benzophenone ketyl. All other re-
agents and solvents were obtained from commercial sources
and used without further purification. Reactions were rou-
tinely carried out under an atmosphere of dry nitrogen with
magnetic stirring. The organic layer was dried with anhy-
drous magnesium sulfate before concentration in vacuo.
Crude products were purified by column chromatography on
silica gel. All reported temperatures are uncorrected.
N-p-Methoxybenzyl-2-toluenesulfonyl acetamide (4)
1-p-Methoxybenzyl-3-phthalimido-5-toluenesulfonyl-
piperidine-2,6-dione (6)
To a solution of p-methoxybenzylamine (1.37 g, 10.0
mmol) and triethylamine (1.06 g, 10.5 mmol) in tetrahydro-
furan (30 mL) was added to chloroacetyl chloride (1.2 g, 10.6
mmol) in tetrahydrofuran (20 mL) in an ice bath for 30 min.
After the reaction mixture was stirred at room temperature
for 4 h, the mixture was concentrated under reduced pressure.
Then the crude product was extracted with ethyl acetate (3
50 mL) and the combined organic layers were washed with
brine (2 20 mL), dried over anhydrous magnesium sulfate,
filtered and evaporated. Without purification, the crude prod-
uct was refluxed with p-toluenesulfonic acid sodium salt (3.2
g, 16.5 mmol) in dioxane (70 mL) and water (70 mL) for 10 h.
Then the mixture was concentrated under reduced pressure
and the residue was extracted with ethyl acetate (3 100 mL).
The combined organic layers were washed with brine (2 20
mL), dried over anhydrous magnesium sulfate, filtered and
evaporated. Recrystallization on hexane and ethyl acetate
afforded 3.0 g (90%) of acetamide 4. Electrospray-MS:
C17H19NO4S m/z (%) = 334 (M++1, 100); 1H NMR (400 MHz,
CDCl3) 7.65 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H),
7.21-7.18 (m, 2H), 6.93 (brs, 1H), 6.88-6.85 (m, 2H), 4.36 (d,
J = 5.8 Hz, 2H), 3.98 (s, 2H), 3.81 (s, 3H), 2.43 (s, 3H).
Compound 2 (486 mg, 1.0 mmol) was dissolved in
methylene chloride (10 mL). Trifluoroacetic acid (3 mL) was
added into the solution and the mixture was stirred for 30 min
at room temperature. Methylene chloride and excess trifluo-
roacetic acid were removed under reduced pressure to get the
crude amine 5 in 88% yield as a viscous oil. Electrospray-
MS: C20H22N2O5S m/z (%) = 403 (M++1, 100). Triethylamine
(600 mg, 5.93 mmol), phthalic anhydride (170 mg, 1.15
mmol) and 4 Å MS were added. After heating for 2 h, the mix-
ture was filtered and the solvent was removed under reduced
pressure to get the crude amine 6. Purification on silica gel
(hexane/ethyl acetate = 2/1) afforded 450 mg (65%) of 6 as a
solid: mp 110-111 C. Electrospray-MS: C28H24N2O7S m/z
(%) = 403 (100), 533 (M++1, 42). IR (film) 1743, 1704 cm-1.
1H NMR (400 MHz, CDCl3) 7.89-7.74 (m, 4H), 7.53 (d, J =
8.2 Hz, 4/3H), 7.33-7.26 (m, 4H), 7.17 (d, J = 8.7 Hz, 2/3H),
6.84 (d, J = 8.2 Hz, 4/3H), 6.72 (d, J = 8.7 Hz, 2/3H), 5.78 (dd,
J = 6.4, 13.1 Hz, 2/3H), 5.03-4.76 (m, 7/3H), 4.34 (dd, J =
8.4, 13.7 Hz, 1/3H), 4.21 (dd, J = 1.4, 6.0 Hz, 2/3H), 3.78 (s,
2H), 3.73 (s, 1H), 3.19-3.04 (m, 1H), 2.96-2.92 (m, 2/3H),
2.73-2.70 (m, 1/3H), 2.44 (s, 3H). Anal. Calcd. for C28H24N2O7S:
C, 63.15; H, 4.54. Found: C, 63.19; H, 4.55.
1-p-Methoxybenzyl-3-tert-butoxycarbonylamino-5-toluene
sulfonyl-piperidine-2,6-dione (2)
Thalidomide (1)
A solution of 4 (333 mg, 1.0 mmol) in tetrahydrofuran
(10 mL) was added to a rapidly stirred suspension of sodium
hydride (60%, 2.2 mmol) in tetrahydrofuran (10 mL). After
the reaction mixture was stirred at room temperature for 5
min, a solution of benzyl ester 3 (260 mg, 1.0 mmol) in
To a solution of compound 6 (133 mg, 0.25 mmol) and
Na2HPO4 (142 mg, 1 mmol) in HPLC-grade methanol (5 mL)
was added 6% sodium amalgam (360 mg, 0.95 mmol). The
mixture was vigorously stirred for 1 h at room temperature.
After concentration of the solution, methylene chloride (10

A Synthesis of Thalidomide
J. Chin. Chem. Soc., Vol. 49, No. 3, 2002 385
mL) was added to the residue, washed with water (4 10
mL), dried over anhydrous magnesium sulfate, and concen-
trated to get the crude desulfonyl compound. The crude com-
pound was dissolved in acetonitrile (3 mL) and water (1 mL).
Excess ceric ammonium nitrate reagent (6 eq, 1.5 mmol) was
added (in six portions) into the solution. The reaction was
stirred 5 h at room temperature. After concentration of the so-
lution, methylene chloride (3 mL) was added to the residue
and was placed in the flash column directly. Purification on
silica gel (hexane/ethyl acetate = 1/2) afforded 34 mg (52%)
of thalidomide (1) as a solid: mp 275-277 C. Electrospray-
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Key Words
Glutarimides; Thalidomide; Formal [3+3]
cycloaddition reaction; Phthaloylation.
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