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：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：US11345941B2

公开(公告)日：2022-05-31

申请号：US16805742

申请日：2020-02-29

Applicant: FUDAN UNIVERSITY

Inventor： Fener Chen ,  Zedu Huang ,  Zhining Li ,  Jiaqi Wang

IPC: C12P17/12 ,  C12N9/06 ,  C12P41/00

Abstract: This application relates to biological pharmacy and biochemical engineering, and more particularly to a method of preparing a (S)-1-benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline compound. This method includes: subjecting a 1-benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline raceme as a substrate to selective oxidation in the presence of a monoamine oxidase and the non-selective reduction to prepare the (S)-1-benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline compound, where the monoamine oxidase has an amino acid sequence as shown in SEQ ID NO: 1 or an amino acid sequence having an identity of more than 80% with SEQ ID NO: 1. The kinetic resolution is carried out in the presence of the monoamine oxidase as a catalyst and a reductant, and the resulting product has a high chiral purity.

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：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).

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：US10316012B1

公开(公告)日：2019-06-11

申请号：US16246531

申请日：2019-01-13

Applicant: FUDAN UNIVERSITY

Inventor： Fener Chen ,  Haihui Peng ,  Sha Hu ,  Ge Meng ,  Yan Wu ,  Dang Cheng ,  Zedu Huang ,  Guanfeng Liang

IPC: C07D307/93

Abstract: Disclosed is a method of synthesizing a series of compounds with the structure of (1S, 5R)-lactone. In the method, under the catalysis of a chiral phosphonic acid, substituted bicyclo[3.2.0]-hept-2-en-6-one (II) as a substrate is reacted with hydrogen peroxide for enantioselective Baeyer-Villiger oxidation to produce a chiral lactone (I). This method involves mild reaction conditions, simple operation, quantitatively recyclable catalyst and high reaction selectivity and stereoselectivity, which is suitable for industrial production.

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.