http://www.chemistrymag.org/cji/2004/06c088ne.htm |
Dec. 1,
2004 Vol.6 No.12 P.88 Copyright |
(College of Pharmacy, Hebei University, Baoding 071002; #Nantong Memtech Electronics Industry, Jiangsu Province, Nantong 226003)
Received Aug. 29, 2004; Supported by the National Science Pre-research Foundation of Hebei University, China (No.2003Q04)
Abstract
A high-yielding and efficient synthesis of cis-1,3-dibenzyl-tetrahydro-2H-furo[3,4-d]imidazol-2,4,6-trione is described. Compared with the conventional methods, the method has the characteristics such as simple operations, high yields, short reaction time, mild conditions and minimal environment impact. The effects of different factors on this condensation reaction have been discussed.Keywords microwave irradiation, condensation reaction, cis-1,3-dibenzyl-tetrahydro-2H-furo[3,4-d]imidazol-2,4,6-trione£¬acetic anhydride
1 INTRODUCTION
d-Biotin, a member of the Vitamin B complex group, was separated by Kögl in
1935[1]. It has received considerable attention as an important vitamin for
human nutrition and animal health[2-4]. Since the first total synthesis of d-biotin
was accomplished about 55 years ago, a number of synthetic methods have been developed [5].
Among them, the Sternbach process, developed by the Goldberg and Sternbach at Hoffmann -La
Roche in 1949, utilizing cis-1,3-dibenzyl-tetrahydro-2H-furo [3,4-d]imidazol-2,4,6-trione
3 (for short, trione) as a key intermediate has been one of the most
reliable approaches so far developed [6]. But the patents [6] of
Goldberg M. W. and Sternbach L. H had not reported the yields and the reaction conditions
of synthesizing trione. Chen and co-workers had recently developed a method [7],
in which trione was synthesized without catalyst via stirring the mixture of (4S,
5R)-cis-1,3-dibenzyl-5-methoxycarbonyl-2-oxo-imidazoline-4-carboxylic acid
(for short, carboxylic acid) and acetic anhydride for 8 h (90% yields). After
adding H3PO4 into the reaction system, the reaction time was reduced
to 3 h and gained 85% yields. Because a number of steps (12 steps from trione to d-Biotin)
were needed for the overall synthesis of d-biotin, it is more important to improve
the yield and the quality in the synthetic processing of trione. Microwave
irradiation can enhance many organic condensation reactions [8-9], but in the
synthesis of trione it has not been reported. Herein we report an efficient method
for the synthesis of trione based on the condensation reaction under microwave
irradiation. The results show microwave irradiation can enhance this condensation reaction
to a great extent.(Scheme 1). Compared with the others work in which anhydrides are
synthesized under microwave irradiation [10,11], the method shows us a more
simple way in this field.
scheme 1
2 EXPERIMENTAL
2.1 Apparatus and reagents
Melting points are measured with micro-melting point apparatus without corrected. IR
spectra (KBr) were obtained on a Perkin-Elmer 983G spectrometer. 1H NMR spectra
were determined on a Bruker AC -80 spectrometer using CDCl3 as solvent and
tetramethylsilane (TMS) as internal reference. Mass spectra were determined on a VG7070E
spectrometer (EI, 70ev). Microwave oven (WD750, 750W, 2450Mhz) is from Galanz Electric
Limited Company of Shunde, and Infrared spectrophotometer (FTS-40) is from BIO-RAD of
America. The products were characterized by 1H NMR spectra and their melting
points were compared with the literature values. All reagents used were analytical grade.
2.2 General procedure
In a 50 ml toper bottle, 1.40 g of carboxylic acid (3.95 mmol ,1) and 2.019
g acetic anhydride (19.75 mmol , 2) were mixed well and then put into the microwave
oven. After being irradiated continuously for 6 mins, the mixture was taken out
immediately and white crystal formed. After being added with 30 ml de-ionzed water, the
mixture was filtered under the reduced pressure and washed with de-ionzed water three
times. The white crystal was dried in oven (110oC) for 3h
and the product trione (3) was obtained. The experiment showed that the best
yield attained could be 99.5% and its m.p. was 236-237oC, which
was consistent with the reported value[7]. Meanwhile, the 1HNMR and
infrared spectrum of the product obtained was just the same as reported in the paper [7].
3 RESULTS AND DISCUSSION
3.1 Influence of the proportion of reagents to yield
This condensation reaction has been investigated at various mole ratios of carboxylic
acid and Ac2O when the power of microwave irradiation and reaction time
were unchanged. The results were shown in Table 1. The yields were increased with the mole
ratio of reactant up to 1:5 and then leveled off gradually (entry 2 ). Other troubles like
that filtering was not easy and excessive acetic anhydride should be treated, which made
the operation and purification more difficult.
Table 1 Relationship between the proportions of reaction reagents and the yields
Entry |
Molar ratio |
750 |
Time of irradiation |
Average yield |
1 |
1:3 |
100 |
6 |
93.0 |
2 |
1:5 |
100 |
6 |
99.5 |
3 |
1:7 |
100 |
6 |
99.3 |
4 |
1:9 |
100 |
6 |
99.1 |
5 |
1:13 |
100 |
6 |
98.0 |
6 |
1:15 |
100 |
6 |
97.0 |
3.2 Influence of the irradiation time to the
product yield
When the other reaction conditions were invariable, the influence of irradiating time on
the yield was investigated in this experiment. As summarized in Table 2, the yields were
increased with longer reaction time before 6 minutes, after it the yields were reduced
because of the increase of side reactions. In order to prevent from producing the
emergence of boiling phenomenon, we installed a self-made reflux device while reacting in
the microwave oven.
Table 2 Relationship between the irradiation times and the yields
Entry |
Molar ratio |
750 |
Time
of irradiation |
Average yield (%) |
1 |
1:5 |
100 |
2 |
86.4 |
2 |
1:5 |
100 |
4 |
97.9 |
3 |
1:5 |
100 |
6 |
99.5 |
4 |
1:5 |
100 |
8 |
99.1 |
5 |
1:5 |
100 |
10 |
98.9 |
3.3 Influence of the irradiation power to
the product yield
When the other reaction conditions were invariable,
the effect of different microwave power on the reaction was shown in Table 3. This may be
due to the fact that the more molecules absorbs microwave energy in short time, the better
the results are as microwave radiation intensity increases. The most excellent yield was
obtained when the irradiation power was 750W (entry 1).
Table 3 Relationship between the irradiation powers and the yields
Entry |
Molar ratio |
Power |
Time of irradiation |
Average yield |
1 |
1:5 |
100 |
6 |
99.5 |
2 |
1:5 |
80 |
6 |
95.5 |
3 |
1:5 |
60 |
6 |
82.6 |
4 |
1:5 |
30 |
6 |
45.6 |
3.4 Influence of the catalyst to the yield
As shown in Table 4 (entries 1-6), 85% H3PO4 played an important
role in the reaction. The rate of reaction increased when H3PO4 as
acidic dehydrating catalyst was added. The yield was low when a little 85% H3PO4
was added. The good yields were obtained when the molar ratio of carboxylic
acid: Ac2O: H3PO4 are up to 1:5:0.67 (entry 4). The
results show that the catalyst H3PO4 can obviously quicken the
reaction process.
Table 4 Influence of the catalyst to the yield
Entry |
Molar ratio |
750(%) |
Time of irradiation (min) |
Average yield (%) |
1 |
1:5:0.13 |
100 |
1 |
80.3 |
2 |
1:5:0.26 |
100 |
1 |
95.5 |
3 |
1:5:0.43 |
100 |
1 |
95.9 |
4 |
1:5:0.67 |
100 |
1 |
99.0 |
5 |
1:5:0.85 |
100 |
1 |
99.0 |
6 |
1:5:1.05 |
100 |
1 |
99.0 |
4 CONCLUSIONS
In the process of synthesis of biotin using the Sternbach's method, many chemical
intermediates in more than ten steps are needed. The final yield of biotin should be
guaranteed by every excellent intermediate ahead. This microwave-assisted method can help
to reach this goal. We have also tried this reaction in the absence of Ac2O,
the result is unsatisfied. Not only the yield was lower than 40%, but also concentrated H3PO4
was needed.
In the paper, cis-1,3-dibenzyl-tetrahydro-2H-furo[3,4-d]imidazol-2,4,6-trione
was successfully synthesized under microwave irradiation and the optimum conditions were
found (carboxylic acid: Ac2O=1:5). The yield could be as high as 99.5%,
and the reaction time was only 6 mins, which was shorter than the shortest time reported
180 mins. All operation cycle took only about 20 min. The method was very easy to operate,
not only energy was greatly saved, but also many reagents were reduced, which brought high
economic value. In addition, pollution could be further reduced.
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