A synthesis of racemic thalidomide

Article abstract of DOI:10.1081/SCC-120018698

A synthesis of racemic thalidomide is described using formal [3+3] cycloaddition strategy as the key step. The total yield of thalidomide was 30% in three steps from ester 2.

Full text of DOI:10.1081/SCC-120018698

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A Synthesis of Racemic Thalidomide
a
a
b
Meng-Yang Chang , Shui-Tein Chen & Nein-Chen Chang
a
Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei, Taiwan
Department of Chemistry, National Sun Yat-Sen University, Kaohsiung, Taiwan
b
Published online: 15 Aug 2006.
To cite this article: Meng-Yang Chang , Shui-Tein Chen & Nein-Chen Chang (2003): A Synthesis of Racemic Thalidomide,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:8,
1375-1382
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 8, pp. 1375–1382, 2003
A Synthesis of Racemic Thalidomide
1
1
2,
Meng-Yang Chang, Shui-Tein Chen, and Nein-Chen Chang *
1
Institute of Biological Chemistry, Academia Sinica,
Nankang, Taipei, Taiwan
2
Department of Chemistry, National Sun Yat-Sen
University, Kaohsiung, Taiwan
ABSTRACT
A synthesis of racemic thalidomide is described using formal [3þ3]
cycloaddition strategy as the key step. The total yield of thalidomide
was 30% in three steps from ester 2.
Key Words: Thalidomide; Formal [3þ3] cycloaddition; Glutari-
mides; a-sulfonylacetamide; Ester.
*Correspondence: Nein-Chen Chang, Department of Chemistry, National Sun
Yat-Sen University, 70 Lien-hai Rd. Kaohsiung 804, Taiwan; E-mail: ncchang@
mail.nsysu.edu.tw.
1
375
DOI: 10.1081/SCC-120018698
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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1
376
Chang, Chen, and Chang
INTRODUCTION
Glutarimides (2,6-piperidinediones) possess various biological
[
1,2]
activities,
ized, e.g., cycloheximide, actiketal (RK-441S), thalidomide,
therefore, many glutarimide derivatives have been synthes-
[4–6]
[
3]
[3]
and
In particular, interest in the immuno-suppressor
[4–6,7]
aminoglutethimide.
thalidomide has remained constant despite it’s teratogenicity.
[
8]
Thalidomide has been used in the treatment of leprosy, auto-immune
diseases, and body wasting or cachexia and other disorders due to its
immunomodulatory and anti-inflammatory effects. Newly found the
therapeutic uses include its inhibition of angiogenesis and for AIDS-
[9,10]
related disorders.
Thalidomide is currently used therapeutically in
the racemate form. It is the classical example of a racemic drug in which
one isomer, the S-isomer, exerts a devastating negative side effect,
teratogenicity. The pure enantiomer can be obtained by preparative
chiral chromatography, however, it is quickly racemizes in solution
ꢀ
[11]
with a half life of 556 min at pH ¼ 7.4 (37 C). Therefore, thalidomide
is chirally unstable in vitro and in vivo, making the chiral purity issue
moot. To take advantage of previous preclinical and clinical experiences
with thalidomide, we are interested in developing a facile synthesis for
thalidomide and its possible derivatives. Thalidomide has traditionally
[
12]
been prepared in a fairly simple three-step sequence;
the last step
involves a high-temperature melt reaction that yields a crude thalidomide
that requires multiple recrystallizations. Here, we report the synthesis of
racemic thalidomide (1) using a formal [3þ3] cycloaddition strategy that
can avoid the melt reaction, which is not amenable to standard reaction
equipment.
RESULTS AND DISCUSSION
The retrosynthetic strategy for the synthesis of racemic thalidomide
1) is illustrated in Sch. 1. First, the glutarimide ring is established
(
rapidly in a one-step cycloaddition reaction. The cycloaddition reaction
of a-toluenesulfonyl acetamide with a- or b-substituted unsaturated
[
7]
esters produced various glutarimides in good yields. Second, the desul-
fonation and deprotection reactions of a-toluenesulfonyl glutarimides
easily lead to the facile synthesis of target 1.
Formal [3þ3] cycloaddition reaction of a,b-unsaturated methyl ester
[13–15]
2
with the dianion intermediate obtained from p-methoxybenzyl-
a-toluenesulfonyl acetamide 3 and 2.2 equiv. sodium hydride produced

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Synthesis of Racemic Thalidomide
1377
Scheme 1. Retrosynthesis of racemic thalidomide (1).
Scheme 2. Synthesis of thalidomide (1) in three steps.
the 5-phthalimido a-sulfonyl glutarimide 4 in 58% yield (Sch. 2). The
a,b-unsaturated methyl ester 2 was prepared from propynoic acid methyl
[
16]
ester and phthalimide in 78% yield.
amalgam (Na–Hg)
Treatment of 4 with 6% sodium
and sodium phosphate in methanol produced
[17]
crude PMB-thalidomide. The pH value in the buffer solution for the
desulfonation of 4 must be controlled at 7.4 to prevent the ring-opening
of glutarimide. Desulfonation under more basic condition (pH>10) in
absence of sodium phosphate, produced many side products. Without
further purification, the crude PMB-thalidomide was treated with ceric
[
18]
ammonium nitrate (MeCN/H O ¼ 3:1)
in aliquots added over 5 h to
2
produce racemic thalidomide 1. Because the deprotection of PMB-
thalidomide by ceric ammonium nitrate did proceed according to
stoichiometric ratios, excess ceric ammonium nitrate had to be added to
the reaction mixture. After six equal aliquots added at a rate of one aliquot
about every hour, the PMB-thalidomide was completely transformed to 1.
The reaction progress was monitored by TLC. Thalidomide (1) was pro-
duced in three steps from ester 2 in 30% yield. This procedure easily
produces racemic thalidomide in moderate yield on a small scale

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1
378
Chang, Chen, and Chang
(
ca. 5.0 mmol). The scale-up of the cycloaddition reaction to 10 g or
greater create many other complex products aside from glutarimide in
disproportionate ratios, thus making it difficult to efficiently synthesize
thalidomide in large quantities.
CONCLUSION
The presented synthesis provides a new and simple strategy to
synthesize racemic thalidomide using the formal [3þ3] cycloaddition
reaction. This cycloaddition method can be extended using different
substituents at the 3-position of glutarimide skeleton in a one-pot reac-
tion for synthesizing thalidomide derivatives in the search for improved
activity and potency. Our method may allow for rapid synthesis of
thalidomide and derivatives, but is not effective for high yield, large-scale
[19]
production.
EXPERIMENTAL
General
Tetrahydrofuran was distilled prior to use from a deep-blue solution
of sodium-benzophenone ketyl. All other reagents and solvents were
obtained from commercial sources and used without further purification.
Reactions were routinely carried out under an atmosphere of dry nitrogen
with magnetic stirring. The combined organic extracts of products were
dried with anhydrous magnesium sulfate before concentration in vacuo.
Crude products were purified by open column chromatography using
silica gel (MN Kieselgel 60, 70–230 mesh) at room temperature and
normal pressure. All reported temperatures are uncorrected.
2-Phthalimido-acrylic Acid Methyl Ester (2)
A stirred solution of phthalimide (740 mg, 5.0 mmol), triphenylpho-
sphine (130 mg, 0.5 mmol), and sodium acetate (210 mg, 2.5 mmol) in
toluene (5 mL) was heated at refluxed temperature for 10 min. Acetic
acid (150 mg, 5.0 mmol) and methyl propiolate (420 mg, 5.0 mmol) were
added to above solution then were continued to reflux for 18 h. The cooled
reaction mixture was chromatographed on silica gel (100 g) (hexane/ethyl
ꢀ
acetate ¼ 1/1, 500 mL) to yield 900 mg (78% yield) of 2. M.p. 108–110 C;

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Synthesis of Racemic Thalidomide
1379
þ
1
Electrospray-MS: C H NO m/z (%) ¼ 232 (M þ 1, 100); H NMR
1
2
9
4
(
400 MHz, CDCl ) ꢀ 7.91–7.89 (m, 2H), 7.77–7.75 (m, 2H), 6.67 (s, 1H),
3
5.98 (s, 1H), 3.80 (s, 3H); Anal. calcd. for C H NO : C, 62.34; H, 3.92.
Found: C, 62.44; H, 3.96.
12 9 4
N-p-Methoxybenzyl-2-Toluenesulfonyl Acetamide (3)
Chloroacetic acid chloride (1.2 g, 10.6 mmol) dissolved in tetrahydro-
furan (20 mL) was added to a stirred solution of p-methoxybenzylamine
(
1.37 g, 10.0 mmol) and triethylamine (1.06 g, 10.5 mmol) in tetrahydro-
furan (30 mL) at ice bath. The solution was cooled (ice bath) and stirred
for 30 min then stirred at room temperature for 4 h. The mixture was
concentrated under reduced pressure to form a viscous gum at room
temperature. The viscous gum 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 to give
the crude a-chloroacetamide at room temperature. Without further
purification, the crude product was refluxed with p-toluenesulfonic acid
sodium salt (3.2 g, 16.5 mmol) in dioxane (70 mL) and water (70 mL) for
1
0 h. The mixture was concentrated under reduced pressure to obtain
ꢀ
a brown solid at 50 C and 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 to give the
crude a-sulfonyl acetamide at room temperature. Purification on silica
gel (200 g) (hexane/ethyl acetate ¼ 1/2, 900 mL) afforded 3.0 g (90%) of 3.
þ
1
Electrospray-MS: C H NO S m/z (%) ¼ 334 (M þ 1, 100); H NMR
1
7
19
4
(
7
400 MHz, CDCl ) ꢀ 7.65 (d, J ¼ 8.3 Hz, 2H), 7.28 (d, J ¼ 8.3 Hz, 2H),
3
.21–7.18 (m, 2H), 6.93 (brs, 1H), 6.88–6.85 (m, 2H), 4.36 (d, J ¼ 5.8 Hz,
2H), 3.98 (s, 2H), 3.81 (s, 3H), 2.43 (s, 3H); Anal. calcd. for C H NO S:
C, 61.24; H, 5.74. Found: C, 61.18; H, 5.76.
1
7
19
4
1-p-Methoxybenzyl-3-Phthalimido-5-Toluenesulfonyl-
Piperidine-2,6-Dione (4)
A solution of acetamide 3 (333 mg, 1.0 mmol) in tetrahydrofuran
10 mL) was added to a rapidly stirred suspension of sodium hydride
60%, 88 mg, 2.2 mmol) in tetrahydrofuran (10 mL). After the mixture
(
(
was stirred at room temperature for 5 min, a solution of ester 2 (231 mg,
.0 mmol) in tetrahydrofuran (10 mL) was added. The resulting mixture
was refluxed for 20 min, quenched with saturated ammonium chloride
1

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Chang, Chen, and Chang
solution (1 mL) then concentrated under reduced pressure to give a
viscous oil at room temperature. The viscous oil 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 to give the crude product at room temperature. Purification
on silica gel (200 g) (hexane/ethyl acetate ¼ 4/1, 600 mL) afforded 310 mg
ꢀ
(
58%) of 4 as a solid: M.p. 110–111 C; Electrospray-MS: C H N O S
7
2
8
24
2
þ
1
m/z (%) ¼ 403 (100), 533 (M þ 1, 42); H NMR (400 MHz, CDCl )
3
ꢀ
(
2
7.89–7.74 (m, 4H), 7.53 (d, J ¼ 8.2 Hz, 4/3H), 7.33–7.26 (m, 4H), 7.17
d, J ¼ 8.7 Hz, 2/3H), 6.84 (d, J ¼ 8.2 Hz, 4/3H), 6.72 (d, J ¼ 8.7 Hz,
/3H), 5.78 (dd, J ¼ 6.4, 13.1 Hz, 2/3H), 5.03–4.76 (m, 7/3H), 4.34 (dd,
J ¼ 8.4, 13.7 Hz, 1/3H), 4.21 (dd, J ¼ 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 C H N O S: C, 63.15; H, 4.54. Found: C,
2
8
24
2
7
63.10; H, 4.49.
Thalidomide (1)
To a solution of compound 4 (133 mg, 0.25 mmol) and sodium
phosphate (142 mg, 1.0 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 under reduced pressure to give a viscous oil at room temperature,
methylene chloride (10 mL) was added to the viscous oil, washed with
water (4 ꢁ 10 mL), dried over anhydrous magnesium sulfate, and con-
centrated to get the crude desulfonyl compound. The crude compound
was dissolved in acetonitrile (3 mL) and water (1 mL). Excess ceric
ammonium nitrate reagent (6 eq, 1.5 mmol) was added in six equal
aliquots into the solution over 5 h. The reaction was monitored after
each addition using TLC. After concentrating the solution under reduced
pressure, methylene chloride (3 mL) was added the residue and the mixture
placed in the flash column. Purification on silica gel (50 g) (hexane/ethyl
acetate ¼ 1/2, 300 mL) afforded 34 mg (52%) of thalidomide (1) as a solid:
ꢀ
þ
M.p. 275–277 C; Electrospray-MS: C H N O m/z (%) ¼ 259 (M þ 1,
1
3
10
2
4
1
00); H NMR (400 MHz, CDCl ) ꢀ 7.99 (brs, 1H), 7.89–7.86 (m, 2H),
1
3
7
2
.78–7.75 (m, 2H), 4.98 (dd, J ¼ 5.3, 12.4 Hz, 1H), 2.93–2.71 (m, 3H),
1
.18–2.12 (m, 1H); C NMR (100 MHz, CDCl ) ꢀ 170.74, 167.89,
3
3
167.33, 134.59 (2x), 134.44, 131.82, 123.91 (2x), 123.80, 49.43,
31.49, 22.3. Anal. calcd. for C H N O : C, 60.47; H, 3.90. Found:
C, 60.41; H, 3.86.
1
3
10
2
4

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Synthesis of Racemic Thalidomide
ACKNOWLEDGMENT
1381
The authors would like to thank the National Science Council of the
Republic of China for financial support.
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Received in the USA June 15, 2002