Efficient acylation and one-pot synthesis of dehydroandrographolide succinate on a large scale assisted with microwave radiation

Article abstract of DOI:10.1080/00397910902777987

A rapid and convenient method for acylation and large-scale synthesis of dehydroandrographolide succinate has been developed under microwave irradiation. It is a one-pot condensation and is compatible with dehydration and rearrangement of double bond in mild reaction conditions with good yield, high purity (up to 99.8%), time-savings, few pollutants and low cost. In addition, a number of acylation derivatives were synthesized under microwave irradiation.

Full text of DOI:10.1080/00397910902777987

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Efficient Acylation and
One-Pot Synthesis of
Dehydroandrographolide
Succinate on a Large Scale
Assisted with Microwave
Radiation
Xin-Feng Luo a , Ling He a , Hai-Bin Yin b , Hu Zheng
a , Di Bei a , Jin-Jin Deng b & Wen-Cai Huang c
a Department of Medicinal Chemistry and Key
Laboratory of Drug-Targeting of Education Ministry
of China , West China School of Pharmacy, Sichuan
University , Chengdu, Sichuan, China
b Guangzhou Yuantong Pharmaceutical Technology
Co., Ltd. , China
c Department of Pharmaceutical and Biological
Engineering , School of Chemical Engineering,
Sichuan University , Chengdu, China
Published online: 04 Sep 2009.
To cite this article: Xin-Feng Luo , Ling He , Hai-Bin Yin , Hu Zheng , Di
Bei , Jin-Jin Deng & Wen-Cai Huang (2009) Efficient Acylation and One-Pot
Synthesis of Dehydroandrographolide Succinate on a Large Scale Assisted with
Microwave Radiation, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 39:19, 3444-3452, DOI:
10.1080/00397910902777987

To link to this article: http://dx.doi.org/10.1080/00397910902777987
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Synthetic Communications1, 39: 3444–3452, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902777987
Efficient Acylation and One-Pot Synthesis
of Dehydroandrographolide Succinate on a Large
Scale Assisted with Microwave Radiation
Xin-Feng Luo,1 Ling He,1 Hai-Bin Yin,2 Hu Zheng,1 Di Bei,1
Jin-Jin Deng,2 and Wen-Cai Huang3
1Department of Medicinal Chemistry and Key Laboratory of
Drug-Targeting of Education Ministry of China, West China School of
Pharmacy, Sichuan University, Chengdu, Sichuan, China
2Guangzhou Yuantong Pharmaceutical Technology Co., Ltd., China
3Department of Pharmaceutical and Biological Engineering, School of
Chemical Engineering, Sichuan University, Chengdu, China
Abstract: A rapid and convenient method for acylation and large-scale synthesis
of dehydroandrographolide succinate has been developed under microwave
irradiation. It is a one-pot condensation and is compatible with dehydration
and rearrangement of double bond in mild reaction conditions with good yield,
high purity (up to 99.8%), time-savings, few pollutants and low cost. In addition,
a number of acylation derivatives were synthesized under microwave irradiation.
Keywords: Acylation, andrographolide, dehydroandrographolide succinate, large
scale synthesis, microwave irradiation
Potassium sodium dehydroandroandrographolide succinate was synthe-
sized via esterification, dehydration, salification, and purification of the
andrographolide, that is, the extraction of Acanthaceae Plant-Herba
Andrographitis. It is widely used[1–16] for treatment of viral pneumonia,
pneumonia of children, upper respiratory tract infection, acute bronchitis,
Received October 26, 2008.
Address correspondence to Wen-Cai Huang, Department of Pharmaceutical
and Biological Engineering, School of Chemical Engineering, Sichuan University,
Chengdu 610065, China. E-mail: lhe2001@sina.com
3444

Large-Scale Microwave Radiation
3445
chronic bronchitis, gastrointestinal infection, acute bacillary dysentery,
infection of biliary tract, urinary tract infection, febrile syndrome of
lung cancer, pure cyto-rashes, and other infections. It has few side
effects and generates no anaphylactic response or drug-resistant phe-
nomenon so that those patients who are supersensitive to antibiotics
could use it as an effective cure. Considering its advantages, the State
Administration of Traditional Chinese Medicine approved it as funda-
mental traditional Chinese medicine for use in hospital emergency
departments nationwide.
The key intermediate of potassium sodium dehydroandroandrogra-
pholide succinate–dehydroandrographolide succinate has been explored.[17]
The challenges of synthesis remain: first, the original procedure for dehy-
droandrographolide succinate was complicated and required a vacuum
condition (520–620 mm Hg) with a boiling water bath.[15] This makes it dif-
ficult to control the reaction conditions; especially the vacuum discourages
industrialized manufacture. Second, this method results in low purity[18]
and formation of by-products because of the long time to heat the reaction
to 70–80ꢀC. Moreover, the high temperature resinifies the product. And
third, yield was poor. Therefore, there is a need to develop an efficient
procedure for the large-scale preparation of dehydroandrographolide suc-
cinate. It is advantageous for us to use microwave irradiation to save mate-
rials and time and obtain good yields at the same time. However, for
industrial application, these synthetic methods (assisted with microwave
irradiation) are limited because they require a uniform system without
stirring.
It is very well known that microwave irradiation can shorten the
reaction time of many organic reactions from hours or days to minutes
or even seconds. Microwave irradiation has been well recognized as a
convenient method to promote rapid reactions[19] with much less energy.
Simultaneously, microwave irradiation under milder reaction conditions
using less toxic reagents and solvents offers a further advantage and
additional convenience in organic synthesis. Undoubtedly, it is more
Scheme 1. Synthesis of dehydroandrographolide succinate.

3446
X.-F. Luo et al.
environmentally friendly. The microwave reaction is nonhomogeneous,
especially when the amount of the reactants become larger. Therefore,
for large-scale applications, it is interesting to develop more convenient
methods with respect to environmental and economic considerations.
Recently, in our research, process development of industrial production
prompted us to exploit the application of microwave irradiation in the
large-scale synthesis of dehydroandrographolide succinate and a series
of acylation derivatives for synthesis of potentially pharmacologically
active compounds.
RESULTS AND DISCUSSION
As compared with traditional methods, the microwave irradiation
method has several advantages such as using less starting material, less
toxic reagents and solvents, less complicated equipment, mild conditions,
simple workflow, easy preparation of procedures, and good yields and
purity. The microwave-heated reactions were faster than traditional reac-
tions, and their rate enhancement was more than one order of magnitude
better. In this synthesis, process development of industrial production
prompted us to exploit the application of microwave irradiation in the
acylation to go with dehydration and rearrangement of double bond as
shown in Table 1.
Reaction conditions were investigated under microwave irradiation
and traditional heating. Table 1 shows that only compound 3 was formed
rapidly under microwave irradiation in good yield, but the condensation
by conventional refluxing under identical conditions gave lesser yields
(42%) in more than 2 h. The results reveal that microwave irradiation
has evident advantages of good yields and short reaction time over tradi-
tional heating mode.
Table 1. Comparison of reactivity between the traditional method and
microwave irradiation
Succinic
anhydride Na2SO3 Pyridine Reaction Yield Purity
Androgra-
pholide (mol)
Method
(mol)
(g)
(ml)
time
(%)
41.7 94–98
91.6 99.8
(%)
Traditional
method
0.03
0.03
0.115
0.8
12.5
2–4 h
Microwave
irradiation
0.094
0.3
4–5
2 min

Large-Scale Microwave Radiation
3447
Table 2. Optimization of reaction time
Andrographolide
(mol)
Succinic anhydride
(mol)
Reaction time
(min)
Purity
(%)
Entry
1
2
3
4
5
0.03
0.03
0.03
0.03
0.03
0.094
0.094
0.094
0.094
0.094
1.5
2
2.5
3
95.7
99.8
95.3
90.4
84.6
4
The reaction mixture should be comminuted completely. The
reaction time for heating the mixture should be strictly controlled; other-
wise the purity of the product will be less than before see Table 2.
When the amount of the reactants become greater, the reaction is
nonhomogenous, but we still can get good yields and pure products by
microwaving for 2 min every 1 min for the total microwave radiation time
of 4 to 5 min.
Subsequently, we applied several substrates to try to demonstrate the
prolongation of substrates for the synthesis of medicine in the future. The
substrates could give their corresponding product in good yields (Table 3,
entries 1–5).
The effect of substrates was examined. The results of Table 3 show
that we have found the products of acylation. We can also see the steric
effect from Table 3 (entry 6). This effect led to an acylation reaction
handicap. The reaction rates were deccelerated when there were ortho-
tertiary butyl groups present. We have not found the product of diacyla-
tion to be formed under identical conditions.
EXPERIMENTAL
Equipment and Reagents
The reactions were carried out in a MCL-II microwave reactor. Silica-gel
F254 plates were used for thin-layer chromatography (TLC), and spots
were examined under ultraviolet (UV) light at 254 nm and developed
by an iodine vapor. Flash chromatography was performed on silica-gel,
and H NMR spectra were recorded on a Varian Mercury 400-MHz spec-
trometer. The mass spectra (ESI) were recorded on a Bruker Daltonics
Data analysis 3.2 mass spectrometer.

3448

3449

3450
X.-F. Luo et al.
Preparative Procedure
Synthesis of Dehydroandrographolide Succinate
Andrographolide (10.0 g, 28.5 mmol) and 0.3 g of sodium sulfite were
comminuted under infrared (IR) light, and then 9.41 g of succinic anhy-
dride (94.1 mmol) were added and comminuted. The resulting mixture
was transfered to the 50-ml, round-bottom flask. Five ml of pyridine were
added to the mixture and heated to boiling under microwave irradiation
for 1.8 min, and then the mixture was poured into 300 ml water while stir-
ring intensely. The mixture was filtered and the white solid was washed
with water to give 14.67 g dehydroandrographolide succinate (white acer-
ous solid), mp 135–137ꢀC (lit.[20] 137.6–139.2ꢀC), yield 91.6%, purity
1
99.8%. H NMR (CDCl3, 400 MHz) d (ppm): 7.17 (m, 1H), 6.95–6.86
(m, 1H), 6.13 (d, 1H), 4.82 (d, J ¼ 1.2, 2H), 4.80 (s, 1H), 4.64 (t, 1H),
4.56 (s, 1H), 4.39–4.17 (dd, J1 ¼ 78.4, J2 ¼ 12, 2H), 2.77–2.56 (m, 7H),
2.48 (d, J ¼ 2, 1H), 2.47 (d, J ¼ 12, 1H), 2.34 (d, J ¼ 10, 1H), 2.05 (dt,
J ¼ 4.8, 1H), 1.85–1.82 (dd, J1 ¼ 1.2, J2 ¼ 11, 1H), 1.67 (m, 2H), 1.55
(m, 2H), 1.34–1.30 (dd, J1 ¼ 2, J2 ¼ 12, 1H), 1.22 (m, 1H), 1.01 (s, 3H),
0.87 (s, 3H). 13C NMR (CDCl3, 100 MHz), d (ppm): 177.1, 172.3,
171.9, 148.1, 135.5, 129.1, 124.4, 121.4, 109.3, 80.4, 69.7, 64.9, 61.6,
54.8, 41.6, 38.6, 38.2, 36.6, 29.5, 29.1, 24.1, 23.7, 22.4, 15.2. MS (ESI-)
m=z (%) for C28H35O10(M-H) calcd. 531.22; found 531.3 (100%).
Synthesis of Dehydroandrographolide Succinate on a Large Scale
Andrographolide (250.0 g, 0.71 mol), 240 g of succinic anhydride
(2.4 mol), and 6 g of sodium sulfite were comminuted. The resulting
mixture was transfered to the 1000-ml, round-bottom flask. To the mix-
ture, 100 ml of pyridine (dried) were added and heated to boiling under
microwave irradiation (200–230 mA) for 2 min every 1 min for a total
microwave radiation time of 4 to 5 min, and then the mixture was poured
into 8 L water while stirring intensely. The mixture was filtered, and the
white solid was washed with water to give 342 g dehydroandrographolide
succinate (white solid), mp 136–138ꢀC, yield 90%.
General Method for the Synthesis of Acyl Compounds
The mixture of substrate, anhydride, and pyridine were added and heated
to boiling under microwave irradiation for 3–15 min with a substra-
te=anhydride=pyridine ratio of 1:3:2, and then the mixture was poured

Large-Scale Microwave Radiation
3451
into ice water while stirring intensely. The mixture was filtered, and the
white solid was washed with water to give acylation products.
CONCLUSIONS
In summary, we have developed a rapid, mild, and efficient procedure for
acylation of hydroxyl and amino under microwave irradiation. The method
offers several advantages such as rapid and mild conditions, simple workup,
and good yields (except entry 7 in Table 2) using inexpensive reagents and is
compatible with dehydration and rearrangement of double bond.
ACKNOWLEDGMENTS
This work was financially supported by the industry–academy–research
combination project from the Ministry of Education in Guangdong
Province (No. 2007B090400016). Dehydroandrographolide succinate
was determined by Professor Rou-Bing Chao (Department of Medicinal
Chemistry and Key Laboratory of Drug-Targeting of Education Minis-
try of China, West China School of Pharmacy, Sichuan University).
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