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Appl Biochem Biotechnol (2012) 168:22972308
DOI 10.1007/s12010-012-9938-7
Received: 4 July 2012 /Accepted: 5 October 2012 /
Published online: 16 October 2012# Springer Science+Business Media New York 2012
Abstract (S) -3-Chloro-1-(2-thienyl)-1-propanol was synthesized by the asymmetric reduction of 3-chloro-1-(2-thienyl)propanone with liquid-core immobilized Candida pseudotropicalis 104. The optimum time was 28 h for the re-cultivation of immobilized cells. The optimum film solvent for the liquid-core capsule was 0.3 % chitosan (Mw 1.0105). Conversion decreased with the increase of the liquid-core capsule diameter and with the addition of more substrates at the same reduction time. The immobilized cells show good reduction ability in a potassium phosphate buffer (pH6.6~7.2). The material outside the spread speed of immobilized cells was not restricted when the shaking speed was higher than 160 r/min. Liquid-core immobilized cells can be reused 11 times. Compared with the batch reduction, the continuous reduction of 3-chloro-1-(2-thienyl)propanone in the membrane reactor with liquid-core immobilized cells as catalyst can relieve the inhibition from a high-concentration substrate. Conversion and enantiometric excess of (S)-3-chloro-1-(2-thienyl)-1-propanol reached 100 % and >99 % in a continuous reduction of 12 g/L 3-chloro-1-(2-thienyl)propa-none for 10 days.
Keywords (S)-3-Chloro-1-(2-thienyl)-1-propanol . Immobilized cells . Liquid-core capsule . Candida pseudotropicalis 104
Introduction
(S)-Duloxetine [(S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-1-propanamine] is not only a potent new antidepressant but also a norepinephrine reuptake inhibitor and a new drug for treating urinary stress incontinence. (S)-Duloxetine can inhibit serotonin reuptake in rat
O. Zhimin (*)
Pharmaceuticals College, Zhejiang University of Technology, Hang Zhou, Zhejiang 310014, China e-mail: [email protected]
S. Xingyuan : S. Hanbing : B. Hongxia (*)
The Third Affiliated Hospital of Qiqihar Medical College, Qiqihar, Heilongjiang 161000, China e-mail: [email protected]
Synthesis of Duloxetine Intermediate (S)-3-Chloro-1-(2-thienyl)-1-propanolwith Liquid-Core Immobilized Candida pseudotropicalis 104
Ou Zhimin & Sun Xingyuan & Shi Hanbing & Bi Hongxia
2298 Appl Biochem Biotechnol (2012) 168:22972308
synaptosomes two times more potently than (R)-enantiomer [1, 2]. (S)-3-Chloro-1-(2-thienyl)-1-propanol is a key chiral building block for the synthesis of (S)-duloxetine and can be obtained by the asymmetric reduction of 3-chloro-1-(2-thienyl)propanone using the chemical or biotransformation method (Fig. 1) [3].
Reaction conditions of biotransformation are mild and environmentally friendly compared with the chemical method [46]. The asymmetric reduction of 3-chloro-1-(2-thienyl)-propanone with a microorganism as the catalyst was recognized as an effective method because conversion can theoretically reach 100 % and...