Fudan University

Huashan Huang

Fener Chen

Dang Cheng

Minjie Liu

Meifen Jiang

Zedu Huang

Lulu Wang

Chao Yu

Jiaqi Wang

Chen Hu

This application relates to organic synthesis, and more particularly to a method for the continuous flow synthesis of (R)-4-halo-3-hydroxy-butyrate using a micro-reaction system. This application performs an enzymatic asymmetric reduction of a substrate solution containing halogenated acetoacetate and a biocatalyst solution in the micro-reaction system composed of a micro-mixer, a micro-channel reactor, and a pH regulator to obtain the (R)-4-halo-3-hydroxy-butyrate. Compared to the prior art, the reaction time of the method is only a few minutes, the yield of the product (R)-4-halo-3-hydroxy-butyrate is greater than 95%, the reaction process is continuous, the degree of automation is high, the efficiency is high, and the process is simple to operate and easy to be used in industrialized production.

Method for the continuous flow synthesis of (R)-4-halo-3-hydroxy-butyrate

A multi-layered micro-channel mixer includes a base plate and a cover plate. Two inlet fluid reservoirs, two inlet channels, two groups of fluid distribution channel networks, two groups of process fluid channels, an impinging stream mixing chamber, a fluid mixing intensification channel and an outlet buffer reservoir are provided on the base plate. Two fluids are fed into the two inlet fluid reservoirs, respectively. The fluids then flow into the process fluid channels via the inlet channels and the multi-stage fluid distribution channel networks, respectively. Then the two fluid streams ejected from the opposing process fluid channels impinges upon each other in the impinging stream mixing chamber. The mixed fluid is subjected to vortex or secondary flow generated by the baffles or the internals in the impinging stream mixing chamber and fluid mixing intensification channel, and finally the mixed fluid is discharged through the outlet buffer reservoir.

Multi-layered micro-channel mixer and method for mixing fluids

Disclosed herein relates to biopharmaceuticals, and more particularly to a continuous flow method for preparing (R)-3-hydroxy-5-hexenoate. Carbonyl reductase and isopropanol dehydrogenase are co-immobilized onto an inert solid medium simultaneously to prepare a carbonyl reductase/isopropanol dehydrogenase co-immobilized catalyst, which is then filled into a microchannel reactor of the micro reaction system. A solution containing substrate 3-carbonyl-5-hexenoate is subsequently pumped into the microchannel reactor to perform an asymmetric carbonyl reduction reaction to obtain (R)-3-hydroxy-5-hexenoate.

Continuous flow method for preparing (R)-3-hydroxy-5-hexenoate

A full continuous-flow preparation method of L-carnitine, including: mixing chlorine gas and a diketene solution via a first micromixer followed by transportation to a first microchannel reactor for continuous chlorination and esterification reaction to obtain 4-chloroacetoacetate; feeding the 4-chloroacetoacetate and a reductase to a second micromixer and a second microchannel reactor in sequence for continuous catalytic reaction to obtain (R)-4-chloro-3-hydroxybutyrate; simultaneously transporting the (R)-4-chloro-3-hydroxybutyrate and a trimethylamine solution to a third micromixer and a third microchannel reactor for continuous substitution and hydrolysis reaction; and subjecting the reaction mixture to desalination and concentration to obtain the L-carnitine.

Full continuous-flow preparation method of L-carnitine

A method for preparing (dimethylaminomethylene) malononitrile by using a micro reaction system. Cyanoacetamide, N,N-dimethylformamide and a catalyst are mixed to obtain a mixture, and the mixture and phosphorus oxychloride are simultaneously pumped into the micro reaction system that includes a micromixer and a microchannel reactor connected in series for continuous dehydration condensation. After adjusted to a target pH, the crude product is subjected to continuous liquid-liquid extraction with an organic solvent in a centrifugal extraction unit comprising a plurality of annular centrifugal extractors connected in series. The organic phase is collected to obtain the target product (dimethyl aminomethylene) malononitrile.

Method for preparing (dimethylaminomethylene) malononitrile using a micro reaction system

This disclosure relates to organic synthesis, and more particularly to a method for preparing 3-chloro-4-oxopentyl acetate using a fully continuous-flow micro-reaction system. In this method, chlorine and an acetylbutyrolactone-containing liquid are simultaneously transported to a first micro-channel reactor for continuous chlorination to obtain &#x3b1;-acetyl-&#x3b1;-chloro-&#x3b3;-butyrolactone. The reaction mixture is simultaneously transported to a micro-mixer and a second micro-channel reactor together with a mixed solution of glacial acetic acid, hydrochloric acid and water, and the continuous acylation is carried out to obtain 3-chloro-4-oxopentyl acetate. After quenched with a quenching agent, the reaction mixture was subjected to extraction and separation to obtain the 3-chloro-4-oxopentyl acetate.

Method for preparing 3-chloro-4-oxopentyl acetate using fully continuous-flow micro-reaction system

A full continuous flow preparation method of 2-methyl-4-amino-5-aminomethylpyrimidine. A mixed solution of cyanoacetamide, N,N-dimethylformamide and a catalyst is mixed with phosphorus oxychloride in a first micro-mixer, and then the reaction mixture undergoes continuous flow reaction in a microchannel reactor to obtain (dimethylaminomethylene) malononitrile. The reaction mixture is subjected to continuous quenching, extraction and separation, and the organic phase is concentrated, mixed with a methanol solution, and then reacted with an organic base to obtain 2-methyl-4-amino-5-cyanopyrimidine. After the mixed liquid is continuously filtered, the filter cake is dissolved in methanol, mixed with hydrogen in a second micro-mixer, and then transported to a fixed-bed reactor for hydrogenation reaction. The products are concentrated, dried and purified to obtain the desired 2-methyl-4-amino-5-aminomethylpyrimidine.

Full continuous flow preparation method of 2-methyl-4-amino-5-aminomethylpyrimidine

Disclosed herein relates to pharmaceutical engineering, and more particularly to a micro reaction system and a method for preparing 2-methyl-4-amino-5-cyanopyrimidine using the same. An acetamidine hydrochloride solution and an (dimethylaminomethylene)malononitrile solution are separately pumped into the micro reaction system including a micromixer and an agitating microchannel reactor in communication at the same time for a continuous condensation-cyclization reaction to obtain 2-methyl-4-amino-5-cyanopyrimidine.

Micro reaction system and method for preparing 2-methyl-4-amino-5-cyanopyrimidine using same

A micro-reaction system and a method for preparing 2-methyl-4-amino-5-aminomethyl pyrimidine. A Raney nickel catalyst is modified with formalin, and the modified Raney nickel catalyst is filled into a micro-channel reactor of the micro-reaction system. A substrate solution containing 2-methyl-4-amino-5-cyanopyrimidine and a base and hydrogen are transported to the micro-mixer and the micro-channel reactor in sequence for continuous catalytic hydrogenation to obtain 2-methyl-4-amino-5-aminomethyl pyrimidine.

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Shanghai, China

Huashan Huang