A new practical synthesis of ethyl (R)-(-)-4-Cyano-3-hydroxybutyrate from (S)-3-chloro-1,2-propanediol

Article abstract of DOI:10.2174/157017812802139654

A practical chemical synthesis of ethyl (R)-(-)-4-Cyano-3- hydroxybutyrate((R)-CNHB) has been accomplished from (S)-3-chloro-1,2- propanediol, which is a main by-product originating from (S,S)-Salen Co(III) catalyzed by hydrolytic kinetic resolution (HKR) of epichlorohydrin. The new synthetic approach demonstrated an efficient utilization of organic by-product for the asymmetric synthesis of the intermediate of atorvastatin.

Full text of DOI:10.2174/157017812802139654

520
Letters in Organic Chemistry, 2012, 9, 520-521
A New Practical Synthesis of Ethyl (R)-(-)-4-Cyano-3-hydroxybutyrate
From (S)-3-chloro-1,2-propanediol
Chengjun Jianga,* and Huabin Hongb
aSchool of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou 310023, P.
R. China
bZhejiang Neo-Dankong Pharmaceutical Co., Ltd., Taizhou 318000, P. R. China
Received December 06, 2011: Revised May 02, 2012: Accepted May 20, 2012
Abstract: A practical chemical synthesis of ethyl (R)-(-)-4-Cyano-3-hydroxybutyrate((R)-CNHB) has been accomplished
from (S)-3-chloro-1,2-propanediol, which is a main by-product originating from (S,S)-Salen Co(III) catalyzed by
hydrolytic kinetic resolution (HKR) of epichlorohydrin. The new synthetic approach demonstrated an efficient utilization
of organic by-product for the asymmetric synthesis of the intermediate of atorvastatin.
Keywords: Atorvastatin, epichlorohydrin, by-product, (R)-(-)-4-Cyano-3-hydroxybutyrate.
INTRODUCTION
discharged (S)-3-chloro-1,2-propanediol will cause serious
environmental issues [10]. This process embodies a low
atom-economy and is not good for environmental protection.
In this letter, we investigate a new synthetic method of (R)-
CNHB from (S)-3-chloro-1,2-propanediol.
Atorvastatin, e.g., LIPTORTM is used as a selective and
competitive inhibitor for the enzyme 3-hydroxy-3-
methylglutaryl-coenzyme(HMG-CoA) reductase, the rate-
limiting enzyme that converts 3-hydroxy-3-methylglutaryl-
coenzyme to mevalonate kinase, a precursor of sterols such
as cholesterol [1]. (R)-CNHB is a key intermediate in the
synthesis of atorvastatin. The increasing requirement led to
the development of different procedures for the synthesis of
(R)-CNHB. Several approaches have been reported for the
synthesis of (R)-CNHB including asymmetric syntheses [2,
3], natural chiral resource oriented synthesis [4] and
biocatalytic process [5-8], but only a few of them are
practical.
RESULTS AND DISCUSSION
As outlined in Scheme 2, we describe an efficient and
novel method for the synthesis of (R)-CNHB. The feature of
this approach resides in the use of (S)-3-chloro-1,2-
propanediol 3 as a chiral starting material and employing the
cyclic sulfite 4 as a key intermediate. The ready availability
and the high enantiopurity of by-product (S)-3-chloro-1,2-
OH
O
O
(S, S)-Salen Co(ꢀ )-OAc
Cl
Cl
Cl
OH
+
2
3
1
(R)- epichlorohydrin
(S)-3-Chloro-1,2-propanediol
racemic epichlorohydrin
by-product
Scheme 1. Hydrolytic kinetic resolution of epichlorohydrin.
propanediol allow us to complete the asymmetric synthesis
of (R)-CNHB.
The conventional synthesis of (R)-CNHB starts from (S)-
epichlorohydrin [9] which can be prepared at a large scale by
Salen Co(III) catalyzed hydrolytic kinetic resolution of
epichlorohydrin. In industry, however, a large amount of by-
product (S)-3-chloro-1,2-propanediol 3 was produced for the
production of (R)-epichlorohydrin (Scheme 1), and the
After reacted (S)-3-chloro-1,2-propanediol with thionyl
chloride for 2 h in CH2Cl2, 3 could be easily converted to
cyclic sulfite 4 in 94% yield, which was a key intermediate.
We performed a regioselective ring-opening cyanation
reaction of 4 with an aqueous solution of sodium cyanide at
25°C for 8h, subsequently treated with 20% H2SO4 to afford
(S)-4-chloro-3-hydroxybutyronitrile 5 in a yield of 85%,
[ꢀ]D20= -11º (c=neat), 1H-NMR(CDCl3) ꢁ(ppm): 4.21(m,1H),
3.66(d,2H), 3.03(s,1H)ꢀ2.73(m, 2H); GC-MS calcd. For
C4H6ClNO m/z119.5, found 119.3. It was then treated with
*Address correspondence to this author at the School of Biological and
Chemical Engineering, Zhejiang University of Science and Technology,
Hangzhou 310023, P.
R.
China;
Tel:
+008657185070370;
Fax: +008657185070370; E-mail: jcj312@163.com
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

Highly Efficient One Step Synthesis of Primary Amines
Letters in Organic Chemistry, 2012, Vol. 9, No. 7
521
O
S
OH
O
OH
1) NaCN
O
SO2Cl2
Cl
O
CN
Cl
OH
Cl
Cl
2) 20% H2SO4
3
4
5
OH
O
OH
NC
EtOH, HCl
NaCN
O
O
7
6
Scheme 2. Synthesis of Ethyl (R)-(-)-4-Cyano-3-hydroxybutyrate from (S)-3-chloro-1,2-propanediol.
hydrochloric acid in ethanol, the reaction processes were
traced by GC (UPELCOWAX-10ꢀ5m*0.10mm*0.10μm),
after the reaction, the mixture was extracted with CH2Cl2,
the organic layer was washed with water and dried over
magnesium sulfate, the solvent was evaporated, and the
residue was distilled to afford ethyl (S)-(-)-4-chloro-3-
hydroxybutyrate 6 as a colorless liquid (93-95 ºC, 5 mmHg)
with the yield of 93%ꢁ [ꢀ]D20= -14.5 ºꢀc=neatꢂ, 1H-NMR
(CDCl3) ꢁ(ppm): 4.38~4.50(m,1H), 4.17(q, 2H), 3.69-
3.85(m,2H), 3.17(s,1H) ꢁ 2.54~2.76(m, 2H), 1.28(t,3H);
GC-MS calcd. For C6H11ClO3 m/z166.1, found 166.0.
Province of the People’s Republic of China (NO.
2011R09028-10).
CONFLICT OF INTEREST
Declared none.
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Ethyl (S)-(-)-4-chloro-3-hydroxybutyrate was dissolved
in DMF, an aqueous solution of sodium cyanide was added
thereto, followed by stirring at 50ºC for 3h to give a
conversion of 100%, the reaction mixture was extracted with
ethyl acetate, the solvent was evaporated, and the residue
was distillated at reduced pressure to give (R)-CNHB as a
colorless liquid with the yield of 70%, [ꢀ]D20= -5º (c=neat)
Optical Purity:98% ee, (PTA-5,30m*25mm*1.0μm). 1H-
NMR(CDCl3) (ppm): 4.34(m,1H), 4.20(q,2H), 3.42(s,1H),
2.63(s ,4H),1.29(t,3H), GC-MS calcd. For C7H11NO3 m/z
151.1, found 151.2.
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In summary, we report a new asymmetric synthetic
method for (R)-CNHB utilizing
a chiral propanediol
precursor with the total yield of 52% by four steps, each step
through distillation or simple extraction, and without column
chromatography. Additionally, the new synthetic route also
demonstrated a potential utilization of organic by-product in
the synthesis of intermediate of atorvastatin.
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ACKNOWLEDGEMENT
[9]
The authors are grateful for the financial support from
the Science and Technology Department of Zhejiang
[10]