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：US11802299B2

公开(公告)日：2023-10-31

申请号：US17545963

申请日：2021-12-08

Applicant: Fudan University

Inventor： Fener Chen ,  Yuan Tao ,  Zedu Huang ,  Dang Cheng ,  Ge Meng

IPC: C12P13/00

CPC classification number: C12P13/001 ,  C12Y101/01184

Abstract: An enzyme-catalyzed method of synthesizing (2S,3R)-2-substituted aminomethyl-3-hydroxybutyrate, including: preparing engineered bacteria containing a carbonyl reductase SsCR-encoding gene; preparing a resting cell suspension of the engineered bacteria; preparing a culture containing carbonyl reductase; and mixing the culture containing carbonyl reductase with substrate 2-substituted aminomethyl-3-one butyrate, glucose dehydrogenase, a cosolvent, glucose and a cofactor followed by asymmetric carbonyl reduction to obtain (2S,3R)-2-substituted aminomethyl-3-hydroxybutyrate. The amino acid sequence of the carbonyl reductase is shown in SEQ ID NO.1.

公开(公告)号：US11441163B2

公开(公告)日：2022-09-13

申请号：US17038081

申请日：2020-09-30

Applicant: Fudan University

Inventor： Fener Chen ,  Kejie Zhu ,  Zedu Huang ,  Dang Cheng ,  Jiaqi Wang ,  Yuan Tao

IPC: C12P17/04 ,  C12N1/20 ,  C12N9/02 ,  C12N15/70

Abstract: An enzyme-catalyzed synthesis of (1S,5R)-bicyclolactone. A first genetically-engineered bacterium containing Baeyer-Villiger monooxygenase gene and a second genetically-engineered bacterium containing glucose dehydrogenase gene are constructed and then suspended with culture medium to prepare a first suspension and a second suspension, respectively. The first and second suspensions are centrifuged to respectively produce a first supernatant containing Baeyer-Villiger monooxygenase and a second supernatant containing glucose dehydrogenase, which are mixed. The mixed supernatant is then mixed with a raceme of a substituted bicyclo[3.2.0]-hept-2-en-6-one, a solvent, a hydrogen donor and a cofactor to perform an asymmetric Baeyer-Villiger oxidation to produce the (1S,5R)-bicyclolactone, where an amino acid sequence of the Baeyer-Villiger monooxygenase is shown in SEQ ID NO:1.

公开(公告)号：US11834388B2

公开(公告)日：2023-12-05

申请号：US18172865

申请日：2023-02-22

Applicant: Fudan University

Inventor： Fener Chen ,  Dang Cheng ,  Lulu Wang ,  Ge Meng ,  Yingtang Ning

IPC: C07C227/18 ,  C07C227/40

CPC classification number: C07C227/18 ,  C07C227/40

Abstract: This application relates to pharmaceutical engineering, and more particularly to a continuous-flow preparation method of diclofenac sodium. The continuous-flow preparation method includes: subjecting aniline and chloroacetic acid to amidation to obtain 2-chloro-N-phenylacetamide (3); subjecting 2-chloro-N-phenylacetamide (3) and 2,6-dichlorophenol to continuous condensation to obtain N-(2,6-dichlorophenyl)-2-hydroxy-N-phenylacetamide (5); subjecting N-(2,6-dichlorophenyl)-2-hydroxy-N-phenylacetamide (5) and thionyl chloride to chlorination to obtain N-(2,6-dichlorophenyl)-2-chloro-N-phenylacetamide (6); subjecting N-(2,6-dichlorophenyl)-2-chloro-N-phenylacetamide (6) to Friedel-Crafts alkylation in the presence of aluminum chloride to obtain 1-(2,6-dichlorophenyl)-1,3-dihydro-2H-indol-2-one (7); and subjecting 1-(2,6-dichlorophenyl)-1,3-dihydro-2H-indol-2-one (7) to hydrolysis to obtain the diclofenac sodium.

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：US10662145B2

公开(公告)日：2020-05-26

申请号：US16288031

申请日：2019-02-27

Applicant: FUDAN UNIVERSITY

Inventor： Fener Chen ,  Lingdong Wang ,  Ge Meng ,  Zedu Huang ,  Dang Cheng ,  Haihui Peng ,  Guanfeng Liang

IPC: C07C227/18 ,  C07C201/08 ,  C07C227/16 ,  C07C227/06

Abstract: The invention relates to the chemical synthesis of pharmaceutical API, and specifically to a method of synthesizing diclofenac sodium, which is a kind of nonsteroidal anti-inflammatory drug for relieving pain. The method includes: nitrating phenylacetate to prepare o-nitrophenylacetate (2); hydrogenating o-nitrophenylacetate (2) to prepare o-aminophenylacetate (3); amidating an amino group of o-aminophenylacetate (3) to obtain 2-(2-benzoylaminophenyl) acetate (4); 2-(2-benzoylaminophenyl) acetate (4) reacting with thionyl chloride to prepare a chloroimine intermediate, and then condensing the intermediate of chloroimine with 2,6-dichlorophenol using an inorganic base to prepare (E)-methyl-2-(2-((2,6-dichlorophenoxy)(phenyl)methyleneamino) phenyl ester (5); subjecting (E)-methyl-2-(2-((2,6-dichlorophenoxy)(phenyl)methyleneamino) phenyl ester (5) to Chapman rearrangement to afford methyl 2-(2-(N-(2,6-dichlorophenyl)benzoylamino)phenyl) ester (6); and hydrolyzing methyl 2-(2-(N-(2,6-dichlorophenyl)benzoylamino)phenyl) ester (6) to provide the target compound as of diclofenac sodium API. The overall yield is up to 67% based on methyl phenylacetate.

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：US11299451B2

公开(公告)日：2022-04-12

申请号：US16953317

申请日：2020-11-19

Applicant: Fudan University

Inventor： Fener Chen ,  Dang Cheng ,  Zedu Huang ,  Zhining Li ,  Meifen Jiang ,  Yuan Tao

IPC: C07C209/62 ,  C07C17/013 ,  C07C29/38

Abstract: A method for synthesizing 2-(1-cyclohexenyl)ethylamine. Cyclohexanone (II) is reacted with a Grignard reagent in a first organic solvent to produce 1-vinylcyclohexanol (III), which is then subjected to chlorination and rearrangement reaction with a chlorinating reagent in a second organic solvent in the presence of an organic base to synthesize (2-chloroethylmethylene)cyclolxane (IV). Then (2-chloroethylmethylene)cyclohexane (IV) and urotropine are subjected to quaternization in a third organic solvent to synthesize N-cyclohexylidene ethyl urotropine hydrochloride (V). Finally, the N-cyclohexylidene ethyl urotropine hydrochloride (V) undergoes hydrolysis and rearrangement reaction in a solvent in the presence of an inorganic mineral acid to synthesize 2-(1-cyclohexenyl)ethylamine (I).