Dec. 2003
Journal of Electronic Science and Technology of China
Vol.1 No.1
An Improved Method of Synthesis for
N- (3-acetyphenyl) Acetamide
LI Yuanxun
TANG Xianzhong
HE Wei
(Department of Microelectronic and Solid-state Electronics, UESTC Chengdu 610054 China)
Abstract 3-acetaminoacephenone is synthesized from acetophenone by nitrating, reducing and
acetylating through an improved method. The designed route is reasonable and the new procedure is
simple. The overall yield is 43.1%, which is about 15% higher than literature reported, and the structure
of the product is identified by IR, 1HNMR, MS and elemental analysis.
Key words 3-acetaminoacephenone; nitration; reduction; acetylation; synthesis
3-acetaminoacephenone has been widely founded
applications in the microelectronics and drug industry
[1,2]
.It is an important intermediate for synthesis of
Zaleplon-a novel sedative-hypnotic drug and
photosensitive polyimides which is used as a
～
photoresist in the manufacture of integrated circuits[3
5]
. Hence, It is regarded as a compound of potentially
commercial value. A lot of chemists have focused
much research on how to synthesize it easier. In the
literature, many essays have reported synthetic routes
and succeeded in preparing the product [6,7]. However,
descriptions of the synthetic methods and procedure
are complex and it’s hard to separate and pure
intermediates that bring operations difficulties. Another
obvious disadvantage is that the total yield rate is too
low, about 30%. Here we overcome majorities of
difficulties in the precious work and develop a simple,
dependable and convenient way to synthesize it.
1
Theory of Synthesis
This article adopts the route as following:
O
CH33
O
CH
CH33
HNO33
HNO
H22SO
SO44
H
O
Sn/HCl
Sn/HCL
CH
CH33
NH
NH22
CHCOCH
NHCOCH33
Synthesis of 3-acetaminoacephenone
In Fig.1, acetophenone is nitrified by HNO3/
H2SO4 at the temperature of −8ºC. Thus
3-nitroacephenone
is
prepared.
Then
Received 2003-03-19
2
Experiment
2.1
Materials and Instruments
The 1H-NMR spectrum is operated at 400 MHz
by using a JEOL JNM-EX 400 WB spectrometer. The
infrared spectrum is recorded on a 200SXV Fourier
transform spectrometer. The elemental analysis is
performed on Italian CARIO ERBA1106 instrument
and melting points of each substance are determined
on XRC-1 apparatus. All reagents and solvents are
obtained from commercial sources and used as
received.
2.2
CH
CH33COCL
COCl
C6H
H6
C
6 6
NO
NO22
Fig.1
O
CH
CH33
3-aminoacetoph-enone is synthesized by using
reductant Sn/HCl. After this, the target product N(3-acetyphenyl) acetamide will be prepared by
acetylating. There are two differences from other
chemists have done before. One is in the procedure of
preparation of 3-aminoacetophenone. The reducing
agent is Sn, not Fe. The other is in the procedure of
preparation of 3-acetaminoacephenone.The acetylating
agent is CH3COCl, not acetic acid or acetic anhydride.
These changes have done much good to operators.
Preparation of 3-nitroacephenone
Weigh 12 g of acetophenone into 250 ml flask,
which immerse in an ice-salt bath and drop 30 ml
concentrated sulfuric acid in with strong stirring. The
cold acids mixture of 8.1 ml nitric acid and 12 ml
concentrated sulfuric acid is added dropwise keeping
the temperature below 0ºC. After this, stirrings are
needed for about 30 min. Then pour the contents of
flask into mixture of ice and water. A yellow product is
collected by filtration. A final recrystallization from
alcohol will give 9.1 g of 3-nitroacephenone[8,9]. Yield
55%. m.p75～76℃,Lit. m.p75～76℃ [10].
Preparation of 3-aminoacetophenone
Weigh 1.0 g of 3-nitroacetophenone and 1.0 g of
granulated tin into a 25 ml round bottom flask. Then
pour 10 ml the dilute acid solution (2.5 ml
concentrated hydrochloric acid with 7.5 ml water) into
the flask through the condenser, stir and heat the
reaction mixture until it begins to reflux. Then it will
take about 30 min to dissolve the tin (a small amount
of undissolved tin will do no harm). Cool the reaction
solution in ice for a few minutes. Add the aqueous
solution of NaOH (2.0 g of sodium hydroxide to 6 ml
of water) to the reaction solution to precipitate the
product. Stir the pale yellow slurry magnetically to
ensure thorough mixing and cool the pale yellow
suspension in ice. Then Collect the precipitate by
suction filtration and wash with ice-cold water. The
desired product totals 0.76 g, yield 86%, m.p93～
94ºC,Lit. m.p95℃[11].
2.4
benzene ring. The existence of concentrated sulfuric
acid can help accelerating and completing nitration
reaction. The proportion of nitric acid in total volume
P affects the yield of product. Fig.2 shows the
relationship between temperature and yield. We can
draw a conclusion that the higher activity of nitration,
the lower yield of the product will be. But if the
temperature is too low, the rate of nitration will be
slowed down too much. So here we control the
temperature at −8℃. The yield has increased to 55%,
which is 13% higher than the literature reported. Fig.3
shows the relationship between yield and proportion of
nitric acid in total volume. We control the proportion at
0.675.
55
50
40
-10
3
Results and Discussion
3.1
Synthesis of 3-nitroacephenone
Nitration Reaction of acetophenone using
HNO3/H2SO4 is an electrophilic substitution reaction to
-5
0
0
T/T/(℃)
( C)
Preparation of N- (3-acetyphenyl) Acetamide
Weigh 7.0 g 3-aminoacetophenone and pour 30
ml benzene and 10 ml (Et) 3N into flask. Reflux until it
solves. Then drop 5.4 ml CH3COCl and reflux for 0.5
h. When the mixture cools down a little, place
charcoalactivated in for 10 min. The product is got
though suction filtration. A final recrystallization from
alcohol and water can give 8.4 g of N- (3-acetylphenyl)
acetamide, yield 91% m.p127～128ºC, Lit. m.p127～
128ºC [12]. IR: v=3 356, 3 114, 3 062, 3 004, 1 704, 1
677, 1 546, 1 481, 1 435, 1 419, 1 357, 798, 697
cm-1.1HNMR(CDCl3): δ=2.22(s,3H), 2.63(s,3H,COCH 3), 7.43(t,1H), 7.58(br,1H), 7.68(d,1H), 7.92(d,1H),
8.0(d,1H) ppm. Anal. Calcd for C10H11NO2: C,
67.80;H, 6.21;N, 7.91. Found: C, 67.53; H, 6.23; N,
7.84.
45
Fig.2
Relationship between yield and temperature in
nitration reaction
70
60
Yield/ (%)
Y/(％)
2.3
91
LI Yuanxun et al: An Improved Method of Synthesis for N- (3-acetyphenyl) Acetamide
Y/(％)
Yield/
(%)
No.1
50
40
0.4
0.5
0.6
0.7
Proportion P
of nitric acid
Fig.3
3.2
Relationship between yield and proportion of nitric acid
in total volume
Synthesis of 3-aminoacetophenone
It is well known that the reducing reaction of
3-nitroacephenone use Fe/HCl as the reductive agent
[13]
. In such procedures, we find separation and
purification of the mixture is complex andbrings
operators too much trouble. The reason is that the
substances are muddy. Here we change Fe/HCl to
Sn/HCl. This avoids these difficulties. The improved
92
Journal of Electronic Science and Technology of China
method is proved effective and the procedure has been
simplified in great degree. And the yield of product is
also high enough.
3.3
Synthesis of N- (3-acetyphenyl) Acetamide
This reaction is a traditional Friedel-Crafts
reaction. A lot of essays have reported how to acetylate
it [14]. But many of the methods use expensive starting
materials and need too much time. The yield of the
product is also not satisfactory. We know only under
conditions of existence of Lewis acid, the benzene ring
will be acetylated. According to this, in our
experiments, we adopt the solvent of benzene because
of the differences of the solubility in benzene between
the starting material 3-aminoacetophenone and the
product 3-acetaminoacephenone. Adding (Et) 3N is
important. From parallel experiments, we find the rate
of the reaction increases with (Et) 3N and the yield is
also enhanced. Time has been reduced from 90 min～
30 min, while the yield increases from 78%～90%.
Different acetylating agents also influence the reaction.
Using CH3COCl or acetic anhydride has almost the
same effect on the yield, which is better than acetic
acid.
Vol.1
Medicinal Chemistry. 2001, 11(6): 353-355(in Chinese)
[4] Tang Xianzhong, Yang Bangcao, Wang Zhengyi, et al. Study
of photosensitive polyimides used in MCM[J]. Mixed
Microelectronics
Technology,
1999,
11(1):
10-17(in
Chinese)
[5] Tang Xianzhong, Yang Bangcao, He Wei. Synthetic study of
photosensitive diamidogen[J]. Journal of University of
Electronic Science And Technology of China, 2002, 29(3):
256-259(in Chinese)
[6] Huang Xuefeng, Li Yuyan, You Qidong. Synthesis of
zaleplon[J]. China Pharmacist, 2002, 5(5): 265-266(in
Chinese)
[7] Ren Jinzhi, Wang Zhaohui. Synthesis of sedative-hypnotic
zaleplon[J]. Journal of China Pharmaceutical University,
2000, 31(6): 474-476(in Chinese)
[8] Icke R N, Redemann C E. Organic Synthesis[M]. New York:
John Wiley & Sons, 1965. 644
[9] Corson B B, Hazen R K. Organic Synthesis[M]. New York:
John Wiley, 1943. 434-438
[10] Nanjing
University.
Organic
Synthesis[M].
Beijing:
Science Press. 1964. 296-299(in Chinese)
[11] Novak L, Protiva M. Mephenhydramine derivatives
substituted in the p- and m- position[J]. Chem Communs,
1959:3 966-3 977
4
Conclusions
N- (3-acetyphenyl) acetamide has been synthesized,
and the relative procedure been developed. We discuss
several factors that affect the reactions in details. The
overall yield arrives 43.1%, which is about 15% higher
than the literature reported and the operations are
convenient.
[12] Nelson J L, Samuel N B. Synthesis of aminoacetophenones
and aminopropiophenones [J]. J.Org.Chem, 1946,11(4):
405-418
[13] Bredereck H, Simchen G. Darstellung and eigenschaften
der amidacetale and aminalester. [J]. Chem. Ber, 1968,
101(1): 41
[14] Wen Ruan. Reaction of Drug Synthesis [M]. Beijing:
Chemical Industry Press. 1988. 144(in Chinese)
References
[1] Feng K, Tsushima M, Matsumoto T, et al. Synthesis and
Brief Introduction to Author(s)
LI Yuanxun( 李 元 勋 )was born in 1979. He is now
properties of novel photosensitive polyimides containing
chalcone moiety in the main chain[J]. J.Polym.Sci, 1998, 36:
685-693
pursuing M.S. degree in UESTC. His research interests include:
synthesis of organic electronic materials. Email: li626@163.
com
[2] Shen Jingshan, Li Jianfeng, Li Fei, et al. Synthesis of
TANG Xianzhong(唐先忠)was born in 1963. He is now
zaleplon[J]. Chinese Journal of Pharmaceuticals, 2002, 33(7):
an Associate Professor. His research interests include: synthesis
313-314(in Chinese)
of organic functional materials. Email: txzuestc@163.com
[3] Zheng Lianyou, Wang Songqing, Li Bingchao, et al.
HE Wei(何为)was born in 1957. He is now a Professor in
Improvement on the synthetic technology of zaleplon as a
UESTC. His research interests include: electrochemistry. Email:
new sedative and hypnotic drug[J]. Chinese Journal of
heweiz@uestc.edu.cn