Facile Synthesis of Thalidomide

Article abstract of DOI:10.1021/acs.oprd.9b00122

We report a simple and facile procedure for the preparation of thalidomide in two steps with a high overall yield (56%). The preparation was composed of a reaction between anhydride phthalic and l-glutamic acid to form N-phthaloyl-dl-glutamic acid (IV), and a cyclization step using IV reacted with ammonium acetate in diphenyl ether to create thalidomide. Reaction parameters reaction time, temperature, solvent, and molar ratio of reagents in the procedure are optimized so that the reaction performance is highest while ensuring environmental friendliness. Moreover, this process has great potential for the industrial scale of thalidomide. These compounds were identified through IR, MS, ¹H NMR, and ¹³C NMR.

Full text of DOI:10.1021/acs.oprd.9b00122

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Full Paper
A FACILE SYNTHESIS OF THALIDOMIDE
Binh Duong Vu, Ngoc Minh Ho Ba, and Dinh Chau Phan
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00122 • Publication Date (Web): 14 Jun 2019
Downloaded from http://pubs.acs.org on June 14, 2019
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A FACILE SYNTHESIS OF THALIDOMIDE
1
*
1
2*
Binh Duong Vu , Ngoc Minh Ho Ba , Dinh Chau Phan
1The R&D Drug center, Vietnam Military Medical University, No.160, Phung Hung str.,
Phuc La Ward, Ha Dong District, Hanoi 10000, Vietnam.
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2School of Chemical Engineering, Hanoi University of Science and Technology, No.1,
Dai Co Viet str., Bach Khoa ward, Hai Ba Trung District, Hanoi 10000, Vietnam.
*Corresponding Author: vbduong2978@gmail.com and chau.phandinh@hust.edu.vn
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For Table of Contents Only
A Facile Synthesis of Thalidomide
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ABSTRACT
We report a simple and facile procedure for the preparation of thalidomide in two-step
with high overall yield (56%). The preparation was comprised of a reaction between
anhydride phthalic and L-glutamic acid to form N-phthaloyl-DL-glutamic acid (IV), and a
cyclization step using IV reacted with ammonium acetate in diphenyl ether to create
thalidomide. The reaction parameters as reaction time, temperature, solvent, molar ratio of
reagents of procedure are optimized so that the reaction performance is highest while
ensuring environmental friendliness. Moreover, this process has great potential for
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industrial scale of thalidomide. These compounds were identified through IR, MS, H-
1
3
NMR, and C-NMR.
KEYWORDS: Thalidomide, N-phthaloyl-DL-glutamic anhydride, leprosy, rheumatoid
arthritis, neoplastic diseases, multiple myeloma.
INTRODUCTION
Thalidomide (I) (N-phthalimido glutarimide) was first introduced to medical market in
West Germany by Chemie Grunelthal GmbH as a non-barbiturate sedative-hypnotic drug
1
in 1957 . This drug was used therapeutically as sedative-hypnotic from 1958 to 1961.
During that time, it became a frequent sedative drug in Europe, Japan, and Canada with
2
many trade names such as Contergan, Isomin, and Distaval. In 1961, W. Lenz and W. G.
3
Mc Bride discovered the unexpected dominant teratogenicity of thalidomide which
caused birth defects, generated one of the biggest blatant medical disasters in modern
medical history and thalidomide was consequently banned in 1962.
However, the bioactivities of thalidomide toward other diseases such as leprosy,
rheumatoid arthritis, neoplastic diseases, HIV/AIDS, multiple myeloma, mesothelioma,
Crohn's diseases, cancer-related to pathologic angiogenesis have been discovered
gradually. Thus, Celgene was FDA allowed for using thalidomide (Thalomid) in the
treatment of Erythema Nodosum Leprosum (ENL) in 1998. More recently, thalidomide
4
5
has been approved to use for treating several illnesses such as leprosy , AIDS , Crohn’s
6
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diseases , rheumatoid arthritis , cancer associated with pathologic angiogenesis and it is
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still under-study for other diseases . Therefore, the enhancement of new improved
manners of thalidomide and its related structures synthesis are attractive and necessary
which were demonstrated based on the number of publications related to thalidomide
recently.
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Briefly, among the number of publications about the synthesis of thalidomide were
reported, they used the different starting materials such as phthalic anhydride and L-
glutamic acid10,11, phthalic anhydride and L-glutamine12-15, N-carbethoxy-phthalimide and
L-glutamine16-18, phthalic anhydride and 2,6-dioxo-3-amino-pyridine or its derivatives19,20
,
N-phthaloyl-DL-glutamic acid21,22 or N-phthaloyl-DL-glutamic anhydride23,24 phthalic
2
5
26
acid with 2,6-dioxo-3-amino-pyridine , phthalimide and glutamic acid and other
materials27-29. Although these synthetic manners imply to be simple changes, they
remained several weak points on the large-scale production like: (1) Using extravagant
starting reagents/materials in the steps related to the preparation; (2) Carrying-out the
1
reactions at a high temperature requiring multiple recrystallizations or purified by column
1
2
chromatography on silica gel ; (3) Using toxic solvents/materials; (4) Procedure have lot
1,12
11
of steps ; (5) Low overall yields . Generally, in finished step the product applied for
cyclization of the glutarimide-ring including the condensation of the NaNH in solution of
2
1
1
NH
3
/Fe(NO
3
)
3
at high pressure , the reaction urea in melting mixture at a high
1
14
temperature and the cyclization of the amide with CDI/4-DMPA or CDT/4-DMAP .
These steps could be the reasons of low yields, longer reaction time and by-product
formation. Thus, it could not be suitable for scale-up of industrial operations.
Besides, some papers already reported the synthetic routes of thalidomide (I) from
1
,13
phthalic anhydride (II) via three or four steps, however the overall yields were still low .
For example, N-carbethoxylation of II produced N-carbethoxy-phthalimide (III) which
was converted to N-phthaloyl-DL-glutamic acid (IV) with L-glutamic acid and sodium
carbonate in water and then esterificated with methanol and thionyl chloride in reflux
conditions form N-phthaloyl L-glutamic acid dimethyl diester (V). Finally, the compound
V was treated with sodium amide (prepared in-situ combined sodium and ammonia
catalyzed by Fe(NO
3
)
3
in ammonia solution and ammonium chloride) to afford crude
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product and further purified using column chromatography to get thalidomide, with low
overall yields (19% from III) (Scheme 1)11.
Scheme 1*. The synthesis of thalidomide (I) via four steps from phthalic anhydride (II)
and L-glutamic acid11
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O
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O
(a)
(
b)
O
N-COOC H5
2
N
COOH
COOH
O
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II
III
IV
O
O
(
c)
(
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N
COOCH3
COOCH3
N
O
NH
O
O
O
V
I
*
Reagents and conditions: (a) i, NH
3
/high temperature and pressure; ii, ClCOOC
2
H
5
; (b)
o
L-glutamic acid/Na
2
CO
3
/0 C/5min+RT/40min, 60%; (c) methanol/SO Cl /reflux/6h/
2
2
purified on column chromatography,71%; (d) Na/liquid NH
3
/Fe
3
NO , 45%.
3
RESULTS AND DISCUSSION
In this report, a pair of starting materials phthalic anhydride (II) and L-glutamic acid
was chosen for the preparation of intermediate product N-phthaloyl-DL-glutamic acid (IV)
because of the low cost. Compound IV was prepared by treatment of II with L-glutamic
o
acid in pyridine at 115 C for 1.5 hrs and then the mixture was added to water and adjusted
pH to 1.2 by using 6N HCl solution. The precipitated product was separated, filtered and
washed with cold water to afford IV with 86% yield. This product required no further
purification in the next step. The mixture of IV, ammonium acetate (as a source of
o
ammonia) and diphenyl ether was heated at 170-175 C for 45 minutes, then work-up
afforded thalidomide (I) with 65% yield (Scheme 2).
Scheme 2*. The synthesis of thalidomide from phthalic anhydride and L-glutamic acid via
two steps.
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O
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(a)
(
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COOH
COOH
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NH
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II
IV
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Reagents and conditions: (a) L-Glutamic acid/pyridine/115 C/1.5 hrs, 86% (b) Amoni
acetate/diphenyl ether/170-175 C/45 min, 65%.
o
Synthesis of N-phthaloyl-DL-glutamic acid (IV). Compound IV was prepared from
phthalic anhydride (II) to react with L-glutamic acid. In this reaction, the solution of II, L-
o
glutamic acid and pyridine were stirred and heated to 115 C for 1.5 hrs. This method
avoids the carbethoxylation of II to III (Scheme 1, step a), thus can skip the step for
preparation of N-carbethoxy-phthalimide (III). This change reduced one step of the
procedure. In addition, various reaction parameters of procedure including solvent types
(see Table S1); reaction temperatures (see Table S2); the water volume used in isolation
of N-phthaloyl-DL-glutamic acid (IV) from reaction mixture (see Table S3); the molar
ratio between reactants (see Table S4); the pyridine volume used in reaction (see Table
S5) were optimized.
Synthesis of thalidomide (I): Compound I was prepared in one step from IV by heating
mixture of IV, ammonium acetate (ammonia donor source), diphenyl ether instead of two
steps that involved the esterification of IV with methanol/SO
then the formation glutarimide-ring from V by using the NaNH
NH /Fe(NO
11. The parameters of this step were also optimized for cyclization of
2
Cl
2
to afford ester V and
2
in solution of
3
)
3 3
o
glutarimide-ring. The results showed that the reaction temperature was at 170-175 C and
the reaction time was 45 min. The parameters of the ammonia donor source and the
reaction temperature; the molar ratio between ammonium acetate and compound IV; the
solvent types used in reaction; and the diphenyl ether volume used in reaction were
tabulated (see Table S6-S10). Finally, the method for separation and purification of
thalidomide has been investigated. The structure of synthetic thalidomide was also
determined by IR, MS, NMR spectra. As the result, there was no need to purify final
product by column chromatography as the earlier reported11, 12
.
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CONCLUSION
A facile synthesis for thalidomide (I) has been established (Scheme 2). It produced
overall yield of 56% through two steps (extremely higher than 19% through three steps
1
1
from compound III ). The synthesis of IV from II was completed in only one step
reaction. The subsequent transition of IV to I was done under relatively simple conditions
without using toxic solvents. Input chemicals in this procedure are economic. The
parameters of each step were developed to save the reagents and solvents as well as
eliminate the toxic chemicals. The reaction time also was optimized to reduce compared to
the methods described above. The results demonstrated our development is much more
economically advantageous than the before manners in term of overall yields and raw
materials. These enhancements aid the efficient, cost-effective and industrial production of
thalidomide.
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EXPERIMENTAL SECTION
General Procedures: The commercial chemicals were used without repurification.
Reactions were magnetically stirred with reflux heating and tracked by thin-layer
chromatography (TLC). The melting points (mp) of compounds were determined on
Stuart SMP-10 system. The NMR spectrum were given in CDCl on Bruker-AV500
3
system at 500 MHz. The FT-IR spectrum were obtained in the solid state as KBr
dispersion using JASCO FTIR-7400 spectrometer (Japan). Mass spectra (MS) data were
acquired on AutoSpec Premier system. Sineo Microware Chemistry Technology UWare-
1
000 (China).
Synthesis of N-phthaloyl-DL-glutamic acid (IV). A solution of phthalic anhydride II
(
149.5 g, 1.0 mole), L-glutamic (147.4 g, 1.0 mole) and pyridine (375 mL) in a round–
o
bottom flask was heated to 115 C for 1.5 hrs with stirring. After the reaction was finished
o
(
1.5 hrs), the reaction temperature was reduced to 75 C and ice-cold water (1000 mL) was
added with stirring, the mixture was acidified using 6N HCl until pH = 1.2 and stirring at
o
10-15 C for 2 hrs. The white solid was separated, filtered, washed with cool water (3 x 30
mL) and vacuum dried to afford N-phthaloyl-DL-glutamic acid (IV) (237.7g, 85.78%),
mp: 191-193ºC; R
f
= 0.42 (benzene : dioxane : formic acid = 75 : 20 : 5).
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-1
IR (KBr) υmax (cm ): 3476 (O-H); 3065 - 2914 (C-H); 1715 (C=O, C1 and C3); 1611
C=O, C13 and C14).
MS: m/z 276 [M-H]+.
(
1H-NMR (DMSO) δ (ppm): 12.65 (s, 2H, COOH); 7.88-7.90 (m, 4H: C5-H, C6-H, C7-H,
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C8-H); 4.79- 4.82 (m, 1H, C10-H); 2.25 – 2.51 (m, 4H, C11-H2 and C11-H2).
13C-NMR (DMSO) δ (ppm): 173.7 (C13); 170.3 (C14); 167.4 (C1, C3); 134.8 (C6 and
C7); 131.3 (C4 and C9); 123.4 (C5 and C8); 51.1 (C10); 30.4 (C12); 23.7 (C11).
Synthesis of thalidomide (I). In a round-bottom flask, the mixture of N-phthaloyl-DL-
glutamic acid (IV) (233 g, 0.8 mole), ammonium acetate (256 g, 2.8 mole) and diphenyl
o
ether (200 ml) was added. The mixture temperature was raised to 170-175 C and
o
maintained for 45 min with stirring. The reaction temperature was reduced to 90 C and
ice-cold water (600 mL) was added. After stirred for 20 min, the mixture was maintained
o
at 5-10 C for 1 hrs, separated, filtered, and cleaned with cool water (3 x 40 mL) received a
solid product. To this product, methanol (300 mL) was added, stirring and heating to
o
reflux for 20 min, distilling out solvent ½ volume, cooling to 10-15 C for 2 hrs, filtering to
give a crude product. This process was repeated two times in 150 mL methanol to give
raw thalidomide. Recrystallization of raw thalidomide from DMF-ethanol. The obtained
o
product was cleaned with cool ethanol and vacuum dried (60 C, <1mmHg) to afford
thalidomide (135.46 g, 65.57%), mp: 269-271ºC.
-
1
IR (KBr) υmax (cm ): 3205 (N-H); 3098 (CH) and 2924 (CH
697 (C=O, C13 and C14).
MS: m/z 257 [M-H]+.
2
); 1776 (C=O, C1 and C3);
1
1H-NMR (500 MHZ, DMSO) δ (ppm): 11.12 (s, 1H, NH); 7.88-7.94 (m, 4H, C5-H, C6-
H, C7-H, C8-H); 5.14-5.20 (1H, C10-H, J=13.0 Hz and J = 5.5 Hz); 2.86-2.94 (m, 1H,
C12-Ha); 2.05-2.10 (m, 2H, C11-H2); 2.05-2.10 (m, 1H, C12-Hb).
13C-NMR (125 MHz, DMSO) δ (ppm): 171.7 (C13); 169.8 (C14); 167.1 (C1 and C3);
134.9 (C6 and C7); 131.2 (C4 and C9); 123.4 (C5 and C8); 49.0 (C10); 30.9 (C12); 22.0
(C11).
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SUPPORTING INFORMATION AVAILABLE
Experimental procedures and analytical data (IR, MS, NMR) of compounds IV and I.
This material is available free of charge via ACS Publications website at
http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
*
E-mail: vbduong2978@gmail.com and chau.phandinh@hust.edu.vn
Notes
The authors declare no competing financial interest.
ORCID
Binh Duong Vu: 0000-0002-1055-3181
Ngoc Minh Ho Ba: 0000-0001-6040-3694
Dinh Chau Phan: 0000-0002- 4232-7023
PRESENT ADDRESSES
1
*
1
2*
Binh Duong Vu , Ngoc Minh Ho Ba , Dinh Chau Phan
The R&D Drug center, Vietnam Military Medical University, No.160, Phung Hung str.,
1
Phuc La Ward, Ha Dong District, Hanoi 10000, Vietnam.
2School of Chemical Engineering, Hanoi University of Science and Technology, No.1,
Dai Co Viet str., Bach Khoa ward, Hai Ba Trung district, Hanoi 10000, Vietnam.
AUTHOR CONTRIBUTIONS
The manuscript was written with contributions from all authors. All authors have given
approval to the final version of the manuscript.
ACKNOWLEDGEMENT
This research was financially supported by The R&D Drug center, Vietnam Military
Medical University.
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