公开(公告)号：US11554355B2

公开(公告)日：2023-01-17

申请号：US17467060

申请日：2021-09-03

Applicant: Fudan University

Inventor： Fener Chen ,  Meifen Jiang ,  Dang Cheng ,  Minjie Liu ,  Huashan Huang

IPC: B01J19/00 ,  C07D239/42

Abstract: 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.

公开(公告)号：US12194428B2

公开(公告)日：2025-01-14

申请号：US17467377

申请日：2021-09-06

Applicant: Fudan University

Inventor： Fener Chen ,  Dang Cheng ,  Minjie Liu ,  Huashan Huang ,  Meifen Jiang ,  Jiaqi Wang

IPC: B01F35/00 ,  B01F33/30 ,  B01F35/53

Abstract: 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.

公开(公告)号：US11834425B2

公开(公告)日：2023-12-05

申请号：US18166478

申请日：2023-02-09

Applicant: Fudan University

Inventor： Fener Chen ,  Meifen Jiang ,  Minjie Liu ,  Yingqi Xia ,  Weijian Li

IPC: C07D279/06

CPC classification number: C07D279/06

Abstract: A full continuous-flow preparation method of vitamin B1 includes: (S1) feeding 3-chloro-4-oxopentyl acetate, 2-methyl-4-amino-5-(aminomethyl) pyrimidine and carbon disulfide to a first continuous-flow reactor for addition; (S2) allowing the reaction mixture to flow into a first continuous filtration and reaction device to collect a filter cake; subjecting the filter cake and hydrochloric acid solution to cyclization; transporting the reaction mixture and an aqueous inorganic base solution to a micromixer and a second continuous-flow reactor for hydrolysis to obtain thiothiamine; (S3) transporting the thiothiamine to a third continuous-flow reactor with hydrogen peroxide for oxidation to obtain thiamine sulfate; and (S4) allowing the thiamine sulfate to enter a second continuous filtration and reaction device for filtration to collect a filter cake; and subjecting the filter cake to reaction with organic hydrochloric acid solution followed by filtration and drying to obtain vitamin B1.

公开(公告)号：US11708363B2

公开(公告)日：2023-07-25

申请号：US17488276

申请日：2021-09-28

Applicant: Fudan University

Inventor： Fener Chen ,  Dang Cheng ,  Minjie Liu ,  Zedu Huang ,  Yuan Tao ,  Jiaqi Wang

IPC: C07D417/12

CPC classification number: C07D417/12

Abstract: Disclosed herein relates to organic synthesis, and more particularly to a method for preparing a key intermediate for the synthesis of statins. The key intermediate is 2-[(4R,6S)-6-[(benzo[d]thiazol-2-ylthio)methyl]-2,2-disubstituted-1,3-dioxan-4-yl] acetate of formula (I):




where R1 is a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a monosubstituted or polysubstituted aryl group, or monosubstituted or polysubstituted aralkyl group; R2 is hydrogen, or monosubstituted or polysubstituted C1-C3 alkyl group, or halogen; and R3 and R4 are each independently a C1-C5 alkyl group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkenyl group, a C1-C3 alkoxy group, a C6-C10 aryl group, or C7-C12 aralkyl group. In the method, a halomethyl compound and a thiol reagent are subjected to nucleophilic substitution in an organic solvent to synthesize a thioether, which then undergoes ketal exchange reaction with a carbonyl compound (V) in the presence of an organic acid to obtain a target product.

公开(公告)号：US11618727B2

公开(公告)日：2023-04-04

申请号：US17384747

申请日：2021-07-24

Applicant: Fudan University

Inventor： Fener Chen ,  Meifen Jiang ,  Minjie Liu ,  Dang Cheng ,  Chao Yu ,  Huashan Huang

IPC: C07C67/31 ,  B01J19/00

Abstract: 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 α-acetyl-α-chloro-γ-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.

公开(公告)号：US11555008B2

公开(公告)日：2023-01-17

申请号：US17123098

申请日：2020-12-15

Applicant: Fudan University

Inventor： Fener Chen ,  Dang Cheng ,  Minjie Liu ,  Meifen Jiang ,  Zedu Huang ,  Zexu Wang ,  Jiaqi Wang

IPC: B01J19/00 ,  C07C227/04 ,  C07C229/22

Abstract: A method for preparing L-carnitine using a micro-reaction system. (R)-4-halo-3-hydroxybutyrate was subjected to quaternization and hydrolysis in an aqueous trimethylamine solution in the presence of an inorganic base in a micro-channel reactor to produce the L-carnitine.

公开(公告)号：US10526622B2

公开(公告)日：2020-01-07

申请号：US15871039

申请日：2018-01-14

Applicant: FUDAN UNIVERSITY

Inventor： Fener Chen ,  Zedu Huang ,  Ge Meng ,  Minjie Liu ,  Zhining Li ,  Zexu Wang ,  Haihui Peng ,  Fangjun Xiong ,  Yan Wu ,  Yuan Tao

IPC: C12P7/62 ,  C07C69/732 ,  C12N9/04 ,  C07C67/28 ,  G01N30/02

Abstract: The present disclosure relates to the technical field of biochemical engineering and particularly discloses a preparation method for (R)-3-hydroxyl-5-hexenoate. In the method of the present disclosure, the (R)-3-hydroxyl-5-hexenoate is prepared by catalytic reduction of 3-carbonyl-5-hexenoate by ketoreductase with 3-carbonyl-5-hexenoate as the substrate. The amino acid sequence of ketoreductase is shown in SEQ ID NO.1. In the present disclosure, the (R)-3-hydroxyl-5-hexenoate having a very high chiral purity is obtained by asymmetric reduction by ketoreductase as the biocatalyst. The present disclosure has the advantages of easy operation, mild reaction conditions, high reaction yield and good practical industrial application value.

公开(公告)号：US12281348B2

公开(公告)日：2025-04-22

申请号：US17516894

申请日：2021-11-02

Applicant: Fudan University

Inventor： Fener Chen ,  Dang Cheng ,  Zedu Huang ,  Minjie Liu ,  Huashan Huang ,  Meifen Jiang ,  Lulu Wang

IPC: C12M1/00 ,  C12M1/02 ,  C12M1/34 ,  C12M1/36 ,  C12P7/625

Abstract: 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.

公开(公告)号：US11913055B2

公开(公告)日：2024-02-27

申请号：US17504858

申请日：2021-10-19

Applicant: Fudan University

Inventor： Fener Chen ,  Dang Cheng ,  Zedu Huang ,  Chen Hu ,  Meifen Jiang ,  Minjie Liu ,  Huashan Huang

IPC: C12P7/42 ,  C12P7/62 ,  C12N9/04 ,  C12M3/06 ,  C12N11/084 ,  C12N11/089 ,  C12M1/40 ,  C12M1/00

CPC classification number: C12P7/62 ,  C12M21/18 ,  C12M23/16 ,  C12M29/00 ,  C12N11/084 ,  C12N11/089 ,  C12Y101/0108 ,  C12Y101/01184

Abstract: 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.

公开(公告)号：US11827581B2

公开(公告)日：2023-11-28

申请号：US17741112

申请日：2022-05-10

Applicant: Fudan University

Inventor： Fener Chen ,  Minjie Liu ,  Meifen Jiang ,  Dang Cheng ,  Chao Yu ,  Huashan Huang

IPC: C07C227/12 ,  C07C227/08 ,  B01J19/00

CPC classification number: C07C227/12 ,  B01J19/0093 ,  C07C227/08 ,  B01J2219/0086 ,  B01J2219/00867 ,  B01J2219/00889 ,  C07C227/08 ,  C07C229/22

Abstract: 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.