One-pot synthesis of DL-2-Amino-2-thiazoline-4-carboxylic acid

Article abstract of DOI:10.1081/SCC-120017133

DL-2-Amino-2-thiazoline-4-carboxylic acid was prepared in one-pot reaction from 2,3-dichloropropionic acid. Not only the procedure was simplified, but also the yield was increased from less than 63% recorded to 93%.

Full text of DOI:10.1081/SCC-120017133

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One-Pot Synthesis of dl-2-Amino-2-thiazoline-4-
carboxylic Acid
Richeng Xuan a , Weixiao Hu a & Zhongyu Yang a
a Institute of Pharmaceutical Engineering , Zhejiang University of Technology , Hangzhou,
P.R. China
Published online: 21 Aug 2006.
To cite this article: Richeng Xuan , Weixiao Hu & Zhongyu Yang (2003) One-Pot Synthesis of dl-2-Amino-2-thiazoline-4-
carboxylic Acid, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 33:7, 1109-1112, DOI: 10.1081/SCC-120017133
To link to this article: http://dx.doi.org/10.1081/SCC-120017133
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 7, pp. 1109–1112, 2003
One-Pot Synthesis of
DL-2-Amino-2-thiazoline-4-carboxylic Acid
*
Richeng Xuan, Weixiao Hu,and Zhongyu Yang
Institute of Pharmaceutical Engineering,
Zhejiang University of Technology,
Hangzhou, P.R. China
ABSTRACT
DL-2-Amino-2-thiazoline-4-carboxylic acid was prepared in one-pot
reaction from 2,3-dichloropropionic acid. Not only the procedure
was simplified, but also the yield was increased from less than 63%
recorded to 93%.
Key Words: Synthesis; DL-2-Amino-2-thiazoline-4-carboxylic Acid.
*Correspondence: Richeng Xuan, Institute of Pharmaceutical Engineering,
Zhejiang University of Technology, Hangzhou-310014, P.R. China; E-mail:
xuanrch@mail.hz.zj.cn.
1109
DOI: 10.1081/SCC-120017133
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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1110
Xuan,Hu,and Yang
DL-2-Amino-2-thiazoline-4-carboxylic acid is an intermediate for pre-
paring L-cysteine,[1–12] which is widely used in cosmetics, drugs and food
industries.
There are three methods of chemical synthesis to prepare DL-2-
[12]
amino-2-thiazoline-4-carboxylic acid.[12,13] Thefirst mtehod
is using
HCl salt of thiourea and 2-chloroacrylic acid to isothiuronium salt
with 90% yield, and converting the salt to target acid with 70%
yield. The second method[12] is using HCl salt of thiourea and
methyl 2-chloroacrylate to get isothiuronium salt with 85% yield,
and then converting it to the target acid with 30% yield. The third
method[12,13] is using thiourea and methyl 2-chloroacrylate to prepare
target acid with 70% yield. Among the three methods, the third
method has the highest yield, but it is the most complex one. The
second method has the lowest yield overall, just about 25%. Though
the first method only has relatively lower overall yield of 63% to the
third method of 70%, the procedure is relatively simple, and using 2-
chloroacrylic acid instead of methyl 2-chloroacrylate. So the first
method was chosen in our experiment to prepare DL-2-amino-2-thiazo-
line-4-carboxylic acid and it should comprise three steps to prepare
thecompound from 2,3-dichloropropionic acid (Sch. 1). Bceausethe
yields of step 2 and 3 are 90% and 70% respectively,[12] thehighset
yield overall from 2,3-dichloropropionic acid should be not more
than 63%.
During thecourseof preparing DL-2-amino-2-thiazoline-4-carboxylic
acid, it was noticed that all three reactions carry out in water solution but
with different concentration of base or acid, so it was possible to synthe-
size the compound in one-pot without isolation any intermediates.
Usually, one-pot synthesis has some advantages, such as the procedure
can be simplified, the yield might be increased, and the bulk of waste
water should be reduced.
Scheme 1.

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DL-2-Amino-2-thiazoline-4-carboxylic Acid
1111
In fact, the experiment showed it was successful. In one-pot, the title
compound was got with 93% yield from 2,3-dichloropropionic acid, its
purity was 99.0%, and the bulk of waste water was decreased obviously.
EXPERIMENT
IR spectrum was recorded on Nicolet 5DX spectrometer in KBr disk.
1HNMR and 13CNMR were recorded on VANCE DMX500, the
chemical shifts were reported in parts per million (ppm) downfield
from tetramethylsilane. CHN analysis was obtained by using Carlo
Erba elemental analyzer. Melting point determination was performed
on XRC-1 melting-point apparatus. Shimadzu LC-10A was used in
quantitative analysis. All chemicals are commercial reagents.
2,3-Dichloropropionic acid (114.4 g, 0.8 mol) was placed in a 2 L
three-necked flask equipped with a mechanical stirrer and a thermometer.
Thesolution of sodium hydroxide(64.0 g, 1.6 mol) in water (800 mL) was
slowly added with stirring. The mixture was stirred for 5 h at 30–35ꢀC,
clear yellow solution was got. To the former solution was added thiourea
(60.8 g, 0.8 mol)/concentrated hydrochloric acid (204 mL, 2.44 mol) solu-
tion, and was stirred for 3 h at 80–85ꢀC. Let the solution cool to room
temperature, then solid sodium carbonate (127.2 g, 1.2 mol) was added
slowly. After complete addition, the mixture solution was heated and
stirred for 3 h at 40–45ꢀC, then its temperature rose to 70ꢀC and kept
it for 1 h. The pH of solution was regulated to about 2 with concentrated
hydrochloric acid, and the solution was cooled to room temperature
again. The reaction product was filtered by suction. Crystalline precipi-
tate was washed with ethanol/water (50:50, v/v) two times, then it was
dried. Finally, crystalline product (109 g) was obtained in 93% yield,
M.p.: 204–208ꢀC (205–210ꢀC[12]), purity 99.0% (by HPLC). Calcd. for
C4H6N2O2S: C, 32.87; H, 4.14; N, 19.16; found: C, 33.29; H, 3.78;
N, 19.42. Principal bands in theIR-spectrum (KBr, cm À1): 2940, 1610,
1400, 1300, 800, 700, as same as in the spectrum of Sadtler 21291K.
1H-NMR (D2O): ꢀ 4.92 (1H, q, C4), 4.70 (H, s, HDO), 4.08 (1H, q, C5),
3.88 (1H, q, C5). 13C-NMR (D2O): ꢀ 174.70, 173.50, 63.46, 34.24.
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Xuan,Hu,and Yang
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Received in Japan February 17, 2002