公开(公告)号：US20240270696A1

公开(公告)日：2024-08-15

申请号：US18625925

申请日：2024-04-03

Applicant: Fudan University

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

IPC: C07D233/94 ,  B01J19/00

CPC classification number: C07D233/94 ,  B01J19/006 ,  B01J19/0066 ,  B01J19/0093 ,  B01J2219/00033 ,  B01J2219/00768 ,  B01J2219/00783 ,  B01J2219/00864 ,  B01J2219/00867 ,  B01J2219/00889

Abstract: A full continuous synthesis method of metronidazole is provided. An aqueous glyoxal solution, an aqueous acetaldehyde solution and aqueous ammonia are mixed and reacted to produce a 2-methylimidazole-containing reaction mixture, which is mixed with a nitric acid solution and then reacted in the presence of concentrated sulfuric acid to obtain a 2-methyl-5-nitroimidazole-containing reaction mixture. The 2-methyl-5-nitroimidazole-containing reaction mixture is divided by a splitter, such that one part is used to replace concentrated sulfuric acid, and the other part is mixed with formic acid, and undergoes a ring-opening reaction with ethylene oxide to obtain a metronidazole solution. The metronidazole solution is adjusted to pH 2-6 and filtered to obtain a filtrate, which is adjusted to pH 8-14 and filtered to obtain a crude product. The crude product is subjected to decoloring, crystallization, filtration and drying to obtain pure metronidazole with a purity greater than 99.9%.

公开(公告)号：US20220033863A1

公开(公告)日：2022-02-03

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: C12P7/62 ,  C12N11/084 ,  C12M1/40 ,  C12M3/06 ,  C12M1/00 ,  C12N11/089

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：US20210380524A1

公开(公告)日：2021-12-09

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: C07C227/04 ,  B01J19/00

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：US20230234911A1

公开(公告)日：2023-07-27

申请号：US18172414

申请日：2023-02-22

Applicant: Fudan University

Inventor： Fener CHEN ,  Dang CHENG ,  Lulu WANG ,  Ge MENG ,  Yingtang NING ,  Zedu HUANG

IPC: C07C227/18 ,  B01J21/02

CPC classification number: C07C227/18 ,  B01J21/02

Abstract: A method of synthesizing diclofenac sodium, including: subjecting aniline and chloroacetic acid to amidation to obtain 2-chloro-N-phenylacetamide; subjecting 2-chloro-N-phenylacetamide and 2,6-dichlorophenol to condensation reaction to obtain 2-(2,6-dichlorophenoxy)-N-phenylacetamide; subjecting 2-(2,6-dichlorophenoxy)-N-phenylacetamide to Smiles rearrangement in the presence of an inorganic base to obtain N-(2,6-dichlorophenyl)-2-hydroxy-N-phenylacetamide; subjecting N-(2,6-dichlorophenyl)-2-hydroxy-N-phenylacetamide and thionyl chloride to chlorination to obtain N-(2,6-dichlorophenyl)-2-chloro-N-phenylacetamide; subjecting N-(2,6-dichlorophenyl)-2-chloro-N-phenylacetamide to Friedel-Crafts alkylation in the presence of a Lewis acid catalyst to obtain 1-(2,6-dichlorophenyl)-1,3-dihydro-2H-indol-2-one; and subjecting 1-(2,6-dichlorophenyl)-1,3-dihydro-2H-indol-2-one to hydrolysis in the presence of an inorganic base to obtain diclofenac sodium.

公开(公告)号：US20220056489A1

公开(公告)日：2022-02-24

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: C12P7/62 ,  C12M1/02 ,  C12M1/34 ,  C12M1/36 ,  C12M1/00

Abstract: A method for the continuous flow synthesis of (R)-4-halo-3-hydroxy-butyrate using a micro-reaction system. The micro-reaction system includes a micro-mixer, a certain number of micro-reaction units that are successively connected in series, a pH regulating system and a back pressure valve. The micro-reaction unit is composed of a micro-channel reactor and a pH regulator that are sequentially connected with each other. A substrate solution containing halogenated acetoacetate and a biocatalyst solution are simultaneously pumped into the micro-reaction system to enable continuous flow biocatalytic asymmetric reduction reaction of the halogenated acetoacetate to obtain the target product (R)-4-halo-3-hydroxy-butyrate.

公开(公告)号：US20220017508A1

公开(公告)日：2022-01-20

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

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-di substituted-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：US20220002224A1

公开(公告)日：2022-01-06

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 ,  C07C29/38 ,  C07C17/013

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).

公开(公告)号：US20210394150A1

公开(公告)日：2021-12-23

申请号：US17467091

申请日：2021-09-03

Applicant: Fudan University

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

IPC: B01J19/00 ,  C07D239/42 ,  B01J25/02

Abstract: 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.

公开(公告)号：US20230183260A1

公开(公告)日：2023-06-15

申请号：US18166906

申请日：2023-02-09

Applicant: Fudan University

Inventor： Fener CHEN ,  Dang CHENG ,  Jiale WU ,  Meifen JIANG ,  Li WAN ,  Jiaqi WANG

IPC: C07D495/04 ,  B01J19/00

CPC classification number: C07D495/04 ,  B01J19/0093 ,  B01J2219/00867 ,  B01J2219/00033

Abstract: A full continuous-flow preparation method of (+)-biotin, including: subjecting a cyclic anhydride and a chiral biphenyl propylene glycol to asymmetric ring-opening reaction to produce a first intermediate, which undergoes selective reduction with a borohydride and cyclization with an inorganic mineral acid to produce (3aS, 6aR)-lactone; subjecting the (3aS, 6aR)-lactone and a sulfenylating reagent to sulfenylation to produce (3aS, 6aR)-thiolactone, which undergoes Fukuyama coupling with a zinc reagent in the presence of a palladium catalyst and elimination reaction in the presence of an inorganic mineral acid to produce an alkenyl valerate compound; subjecting the alkenyl valerate compound to reduction in the presence of a Pd/C catalyst to produce a valerate ester, which undergoes hydrolysis to produce a valeric acid salt; and subjecting the valeric acid salt to debenzylation in the presence of an inorganic mineral acid to produce the target product (+)-biotin.

公开(公告)号：US20210355070A1

公开(公告)日：2021-11-18

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.