公开(公告)号：US20200055811A1

公开(公告)日：2020-02-20

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 ,  C07C227/06 ,  C07C227/16

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：US20230192595A1

公开(公告)日：2023-06-22

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-indo1-2-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：US20220089524A1

公开(公告)日：2022-03-24

申请号：US17103520

申请日：2020-11-24

Applicant: Fudan University

Inventor： Fener CHEN ,  Dang CHENG ,  Meifen JIANG ,  Minjie LIU ,  Huashan HUANG ,  Lulu WANG

IPC: C07C253/20 ,  B01J19/00

Abstract: 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.

公开(公告)号：US20210394148A1

公开(公告)日：2021-12-23

申请号：US17467041

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 ,  B01J25/02

Abstract: 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.

公开(公告)号：US20210394141A1

公开(公告)日：2021-12-23

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: B01F15/00 ,  B01F13/00

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：US20240246820A1

公开(公告)日：2024-07-25

申请号：US18625907

申请日：2024-04-03

Applicant: Fudan University

Inventor： Fener CHEN ,  Minjie LIU ,  Li WAN ,  Yajiao ZHANG ,  Dang CHENG

IPC: C01B21/46 ,  B01D1/00 ,  B01D5/00

CPC classification number: C01B21/46 ,  B01D1/0082 ,  B01D5/006 ,  B01D5/0075

Abstract: A method for on-line continuous recovery of excess nitric acid in nitration reaction is provided. Nitration reaction liquid and nitrogen gas are simultaneously conveyed to a mixer, mixed and transferred to a temperature-controlled corrosion-resistant column for on-line continuous evaporation, where the nitration reaction liquid enters the temperature-controlled corrosion-resistant column from a top end, and the waste gas and excess nitric acid are discharged from a top port of the temperature-controlled corrosion-resistant column, and nitric acid is recovered. The nitric acid-free liquid is discharged from a bottom end of the temperature-controlled corrosion-resistant column by a pump.

公开(公告)号：US20220267253A1

公开(公告)日：2022-08-25

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 ,  B01J19/00

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.

公开(公告)号：US20220090151A1

公开(公告)日：2022-03-24

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

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：US20210394149A1

公开(公告)日：2021-12-23

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：US20210355516A1

公开(公告)日：2021-11-18

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 ,  C12N9/02 ,  C12N1/20 ,  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.