US 12,281,348 B2
Method for the continuous flow synthesis of (R)-4-halo-3-hydroxy-butyrate
Fener Chen, Shanghai (CN); Dang Cheng, Shanghai (CN); Zedu Huang, Shanghai (CN); Minjie Liu, Shanghai (CN); Huashan Huang, Shanghai (CN); Meifen Jiang, Shanghai (CN); and Lulu Wang, Shanghai (CN)
Assigned to Fudan University, Shanghai (CN)
Filed by Fudan University, Shanghai (CN)
Filed on Nov. 2, 2021, as Appl. No. 17/516,894.
Claims priority of application No. 202011235128.8 (CN), filed on Nov. 8, 2020.
Prior Publication US 2022/0056489 A1, Feb. 24, 2022
Int. Cl. C12M 1/00 (2006.01); C12M 1/02 (2006.01); C12M 1/34 (2006.01); C12M 1/36 (2006.01); C12P 7/625 (2022.01)
CPC C12P 7/625 (2013.01) [C12M 23/58 (2013.01); C12M 27/00 (2013.01); C12M 29/00 (2013.01); C12M 41/12 (2013.01); C12M 41/26 (2013.01); C12M 41/48 (2013.01); C12Y 101/01184 (2013.01)] 10 Claims
OG exemplary drawing
 
1. A method for the continuous flow synthesis of (R)-4-halo-3-hydroxy-butyrate using a micro-reaction system, wherein the micro-reaction system comprises a micro-mixer and N micro-reaction units, and N is a positive integer selected from 1-20; each of the N micro-reaction units comprises a micro-channel reactor and a pH regulator that are sequentially connected with each other; an outlet of the micro-mixer is connected with an inlet of a micro-channel reactor in the first micro-reaction unit adjacent to the micro-mixer, and an outlet of the micro-channel reactor in the first micro-reaction unit is connected with a first inlet of a pH regulator in the first micro-reaction unit; a second inlet of the pH regulator in the first micro-reaction unit is configured to allow a pH adjusting agent to be pumped in; an outlet of the pH regulator in the first micro-reaction unit is connected with an inlet of a micro-channel reactor in the next micro-reaction unit so the N micro-reaction units are successively connected in series, and the micro-channel reactors and pH regulators are connected alternately; wherein the micro-reaction system further comprises a pH regulating system consisting of a pH meter, a computer, at least N pumps for transporting the pH adjusting agent and a tank for storing the pH adjusting agent; the pH meter comprises a main body and at least N pH-measuring probes; the pH-measuring probes are separately fixed in each pH regulator in order to measure the pH of the reaction mixture in each pH regulator; the main body of the pH meter is simultaneously connected to all the pH-measuring probes and the computer; the computer is connected to all the pumps that transport the pH adjusting agent; the pumps that transport the pH adjusting agent are simultaneously connected to the pH adjusting agent storing tank and the pH regulators; the computer is configured to monitor the pH of the reaction mixture flowing into each pH regulator, and calculate and control the corresponding flow rate of the pH adjusting agent that is being pumped into each pH regulator in real time by using a software, thereby accurately adjusting the pH of the reaction mixture in all the pH regulators;
the method comprising:
(1) pumping a substrate solution containing ethyl chloroacetoacetate and a biocatalyst solution into the micro-mixer to mix the two solutions to obtain a reaction mixture; and
(2) allowing the reaction mixture to flow out of the micro-mixer to enter the N micro-reaction units connected in series; subjecting the reaction mixture to biocatalytic asymmetric reduction reaction; allowing the reaction mixture to flow out of the micro-reaction system through a back pressure valve to enter a receiving flask; and subjecting the reaction mixture to separation and purification to obtain the target product (R)-4-halo-3-hydroxy-butyrate;
wherein the (R)-4-halo-3-hydroxy-butyrate is shown in formula (I), and the ethyl chloroacetoacetate is shown in formula (II); and the biocatalytic asymmetric reduction reaction is shown in the following reaction scheme:

OG Complex Work Unit Chemistry
wherein R is linear C1-C8 alkyl, branched C1-C8 alkyl, C3-C8 cycloalkyl, monosubstituted aryl, polysubstituted aryl, monosubstituted aralkyl, or polysubstituted aralkyl.