The comparison of protecting methods to the amino group in 2-Aminomethylphenylacetic acid

Article abstract of DOI:10.1007/s11164-013-1069-4

2-Aminomethylphenylacetic acid is an important intermediate of ceforanide, and this article compared two different protecting agents for protecting the amino group in 2-aminomethylphenylacetic acid by BOC (Di-tert butyl dicarbonate) or acetacetic ester, a

Full text of DOI:10.1007/s11164-013-1069-4

Res Chem Intermed
DOI 10.1007/s11164-013-1069-4
The comparison of protecting methods to the amino
group in 2-Aminomethylphenylacetic acid
•
Yougui Zhao Ronggeng Wang Mei Liu
•
Received: 2 January 2013 / Accepted: 22 January 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract 2-Aminomethylphenylacetic acid is an important intermediate of
ceforanide, and this article compared two different protecting agents for protecting
the amino group in 2-aminomethylphenylacetic acid by BOC (Di-tert butyl dicar-
bonate) or acetacetic ester, and compared the deprotection condition. The yield was
higher when BOC was used as protecting agent, but when it was deprotected, it was
more difficult than when acetacetic ester was used as protecting agent.
Keywords 2-Aminomethylphenylacetic acid Á Ceforanide Á Protecting amino
group Á Deprotect of amino group BOC (Di-tert butyl dicarbonate) Á Acetacetic ester
Introduction
Ceforanide is the new cephalosporin developed by the Takeda company [1–4], and
2-Aminomethylphenylacetic acid is an important intermediate of Ceforanide. The
amino group must be protected before the carboxyl can condensate with the amino in
7-ACA, and the protected group must be kept stable when the condensation reaction
occurs, and then it should be easy removed after the condensation reaction is over.
There are many methods for protecting the amino group[5], but BOC [6, 7] and
acetacetic ester [8] are more suitable for protective reagents for 2-aminomethylphe-
nylacetic acid. This article compared two protective agents for protecting the amino
group and for deprotection after reaction (Figs. 1, 2).
Y. Zhao
Hebei Chemical and Pharmaceutical Vocational Technology College, Shijiazhuang, Hebei, China
R. Wang (&)
Hebei University of Science and Technology, Shijiazhuang, China
e-mail: wrg1964@163.com
M. Liu
Hebei Medical University, Shijiazhuang, Hebei, China
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Y. Zhou
HO
O
NH
2
-
O
O
O
O
OH
O
+
+ C(CH
3
NH
O
O
O
OH
Fig. 1 BOC as protective agent
Fig. 2 Acetacetic ester as
protective agent
NH
2
O
O
O
+
O
OH
Experimental
Reaction of BOC protective agent
2-Aminomethylphenylacetic acid (20 g, 0.12 mol), 1,4-dioxane (30 ml), and H2O
(15 ml) were added to a three-necked flask, stirred until dissolved, with the
temperature kept below 0–5 °C, then BOC (32 g, 0.15 mol) was added, with stirring
continued for 10 min, and then was allowed to slowly warm to room temperature,
and kept at this temperature for 3 h. The reaction was monitored by TLC
(methanol:ethanol = 3:1) until the raw material spot disappeared. The mixture was
evaporated in a vacuum to get rid of 1,4-dioxane, extracted with acetic ether, then
citric acid was added to the aqueous phase to pH 2–3, The solid which appeared was
filtered, washed with 20 ml brine, and dried at 60 °C in a vacuum to obtain a white
powder (2-(Boc-aminomethyl)phenylacetic acid); the yield was 88.1 %, m.p.
115–117 °C.
Reaction of acetacetic ester as protective agent
After reaction between sodium (0.60 g, 0.026 mol) and absolute ethanol (50 ml),
the mixture was added drop by drop into another mixture of 2-aminomethylphe-
nylacetic acid (4.27 g, 0.03 mol), acetacetic ester (3.38 g, 0.03 mol) and 42 ml
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The comparison of protecting methods to the amino group
absolute ethanol, and refluxed for 6–7 h. After cooling down to room temperature,
the mixture was suction filtered and the liquid was evaporated to dry. The solid was
recrystallized with absolute ethanol and the production was 6.36 g colorless crystal
needles (sodium 0-(1-ethoxycarbonyl-1-propen-2-ylaminomethyl)phenylacetate);
the yield was 82.3 %, m.p.: 230–232 °C.
Deprotection of BOC 2-Aminomenthylphenylacetic acid
2-(Boc-aminomethyl)phenylacetic acid (2.65 g, 0.01 mol) and trifluoroacetic acid
(TFA) (2.28 g, 0.2 mol) was stirred at room temperature until no further gas was
released. Diethyl ether (20 ml) was added into the clear solution and stirred. After
the solid came out, the mixture was suction filtered. The solid was washed by
diethyl ether and dried in a vacuum. The solid was dissolved in water and 10 %
NaOH was added drop by drop into the solution to get white crystals in an ice bath.
After suction filtration, the crystals were washed with water and dried in a vacuum
to obtain a white solid (2-Aminomethylphenylacetic acid) ,m.p. 180–182 °C, yield
78 %.
Deprotection of acetacetic ester protected 2-amionmethylphenylacetic acid
Sodium 0-(1-ethoxycarbonyl-1-propen-2-ylaminomethyl)phenylacetate (2.99 g,
0.01 mol) was dissolved in water and 4 N HCl was added drop by drop into the
solution to pH = 2.0 in an ice bath. After suction filtration, the solid was washed
with water and dry in a vacuum, to give a white solid (2-aminomethylphenylacetic
acid), m.p. 180–182 °C, yield 79 %.
Result and discussion
The yield is higher when BOC was the protective agent, but the recovery is more
difficult for 1,4-dioxane, because of the high boiling point of 1,4-dioxane and the
more expensive trifluoroacetic acid (TFA) as deprotective agent; sodium ethoxied
had to be used in strict anhydrous condition. Anhydrous ethanol had to be used as
solvent, otherwise the yield was too low. Although the yield is lower when using
acetacetic ester as protective agent, the cheaper inorganic acid or base can be
applied for the deprotected reaction. It is a good choice for us to use acetacetic ester
for protecting the amino group.
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