Provided are a co-immobilized enzyme, a preparation method and use thereof. The co-immobilized enzyme includes: an amino resin carrier, a main enzyme, and a coenzyme. The main enzyme and the coenzyme are co-immobilized on the amino resin carrier, herein the main enzyme is covalent-immobilized on the amino resin carrier, and the coenzyme is immobilized on the amino resin carrier by a mode of covalent and/or non-covalent; and the main enzyme is selected from any one of the following enzymes: transaminase, amino acid dehydrogenase, imine reductase, ketoreductase, enoyl reductase, and monooxygenase. The main enzyme and the coenzyme thereof are co-immobilized on the amino resin carrier for co-immobilization, so the activity and the recycling efficiency of the enzyme are improved.
C12N 11/089 - Enzymes or microbial cells immobilised on or in an organic carrier the carrier being a synthetic polymer obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
2.
Method for continuously synthesizing propellane compound
Disclosed is a method for continuously synthesizing a propellane compound. The method includes the following steps: using 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane or a derivative thereof as a raw material to form a ring with a lithium metal agent by a continuous reaction, so as to synthesize the propellane compound. A technical scheme of the present disclosure is applied, and a continuous reaction device is used.
C07C 1/28 - Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from organic compounds containing only halogen atoms as hetero atoms by ring closure
3.
Continuous synthesis method for 1, 1′-bicyclic [1.1.1]pentane-1,3-diethyl ketone compounds
Provided is a continuous synthesis method for 1,1′-bicyclic[1.1.1]pentane-1,3-diethyl ketone compounds. The continuous synthesis method comprises: under the irradiation of a light source, continuously conveying raw material A and raw material B to a continuous reaction device for a continuous photochemical reaction to obtain 1,1′-bicyclic[1.1.1]pentane-1,3-diethyl ketone compounds, and controlling the reaction temperature in the continuous reaction device by a temperature control device during the continuous photochemical reaction. A propellane with substituents, as a reaction raw material, is subjected to the above photochemical reaction in the continuous reaction device to reduce the probability of its slow decomposition and deterioration under the irradiation, and greatly improve the conversion rate of the reaction material and product yield.
C07C 45/68 - Preparation of compounds having C=O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of C=O groups by change of size of the carbon skeleton by increase in the number of carbon atoms
B01J 19/00 - Chemical, physical or physico-chemical processes in general; Their relevant apparatus
B01J 19/12 - Processes employing the direct application of electric or wave energy, or particle radiation; Apparatus therefor employing electromagnetic waves
4.
IMMOBILIZED ENZYME, AND PREPARATION METHOD THEREFOR AND USE THEREOF
Disclosed are an immobilized enzyme, and a preparation method therefor and the use thereof. Specifically, the preparation method comprises the following steps: using polyethylene glycol to modify a crosslinker to obtain a polyethylene-glycol-modified crosslinker; precipitating a free enzyme; and then adding the polyethylene-glycol-modified crosslinker thereto for cross-linking immobilization to obtain an immobilized enzyme. The enzyme is immobilized by means of using the polyethylene-glycol-modified crosslinker, and upon immobilization, the carrier-free immobilized enzyme has a better stable structure and a stronger mechanical stability.
C12N 11/098 - Enzymes or microbial cells immobilised on or in an organic carrier the carrier being a synthetic polymer formed in the presence of the enzymes or microbial cells
5.
MODIFIED EPOXY RESIN IMMOBILIZED ENZYME, AND PREPARATION METHOD THEREFOR AND USE THEREOF
Disclosed are a modified epoxy resin immobilized enzyme, and a preparation method therefor and the use thereof. Specifically, the preparation method comprises the following steps: modifying epoxy resin, adding polyethyleneimine to the modified epoxy resin for further modification, and then adding an enzyme to be immobilized and glutaraldehyde for immobilization to obtain a modified epoxy resin immobilized enzyme. The epoxy resin is modified, and the polyethyleneimine is added to the modified epoxy resin for further modification; aldehyde groups in the resin and amino groups in the polyethyleneimine are covalently bonded to various enzymes, and then the bifunctional reagent glutaraldehyde is used for activation; in this way, space resin arms are increased to form a network structure, and the enzymes can be more easily bonded by covalent bonding, and the enzyme load can also be improved due to reduced space inhibition.
C12N 11/08 - Enzymes or microbial cells immobilised on or in an organic carrier the carrier being a synthetic polymer
C12N 11/089 - Enzymes or microbial cells immobilised on or in an organic carrier the carrier being a synthetic polymer obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
6.
IMMOBILIZED ENZYME, PREPARATION METHOD THEREFOR, AND APPLICATION THEREOF
Provided is an immobilized enzyme, a preparation method therefor, and an application thereof. The immobilized enzyme comprises an enzyme and an amino resin carrier for immobilizing the enzyme. The enzyme is selected from one of the following enzymes: transaminase, ketoreductase, monooxygenase, ammonia-lyase, alkene reductase, imine reductase, dehydrogenase, and nitrilase. The amino resin carrier is modified with a cross-linking agent treated with a polymer. By means of modifying the amino resin carrier with the cross-linking agent treated with the polymer, the enzyme immobilized on the amino resin carrier can easily form a cross-linking network, such that the immobilization effect of the enzyme is stable, thereby increasing the effectiveness of recycling the enzyme.
C12N 11/02 - Enzymes or microbial cells immobilised on or in an organic carrier
C12P 19/40 - Nucleosides having a condensed ring system containing a six-membered ring having two nitrogen atoms in the same ring, e.g. purine nucleosides
7.
CO-IMMOBILIZED ENZYME, PREPARATION METHOD THEREFOR AND APPLICATION THEREOF
Provided are a co-immobilized enzyme, a preparation method therefor and an application thereof. The co-immobilized enzyme comprises: an amino resin carrier, a main enzyme, and a coenzyme. The main enzyme and the coenzyme are co-immobilized on the amino resin carrier, the main enzyme being covalently immobilized on the amino resin carrier, and the coenzyme being immobilized on the amino resin carrier by a covalent and/or non-covalent means; and the main enzyme is selected from any one of the following enzymes: transaminase, amino acid dehydrogenase, imine reductase, ketoreductase, alkene reductase, and monooxygenase. A main enzyme and a coenzyme thereof are co-immobilized on an amino resin carrier for co-immobilization, improving the activity and the recycling efficiency of the enzymes.
Provided are a proline hydroxylase and uses thereof. The proline hydroxylase comprises having the amino acid sequence of SEQ ID NO: 2 with the exception of a mutation of one or more amino acids; wherein the mutation of one or more amino acids must comprises E27K, and the mutation of one or more amino acids selected from the group consisting of: H14R, L16N, T25R, F26L, E27K, D30S, S33N, E34N, E34G, E34L, E34S, E34D, Y35W, Y35K, S37W, S37F, S37E, S37N, S37T, S37C, W40F, K41E, D54G, H55Q, S57L, I58T, I58Y, I58A, I58R, I58V, I58S, I58C, K86P, T91A, F95Y, C97Y, I98V, K106V, K106T, K106Q, F111S, K112E, K112R, S154A, K162E, L166M, I118F, I118V, I118R, H119R, H119F, I120V, K123D, K123N, K123Q, K123S, K123I, K123T, T130N, D134G, V135K, N165H, D173G, K209R, I223V and S225A, and having proline hydroxylase activity.
The present invention provides a continuous synthesis-purification integrated device and a continuous reaction system containing the same. The continuous synthesis-purification integrated device comprises: a reaction section, a purification section and a temperature control unit, wherein the reaction section is provided with a feed inlet, a first gas phase connection port and a first liquid phase connection port; the purification section is provided with a liquid supplement port, a second gas phase connection port and a product outlet, the second gas phase connection port is communicated with the first liquid phase connection port, and the gas phase material in the purification section is discharged through the first gas phase connection port, and the liquid supplement added through the liquid supplement port comprises a impurity removal agent; and the temperature control unit is used for controlling the temperature of the continuous synthesis-purification integrated device. When the continuous synthesis-purification integrated device is used, not only the raw material conversion rate and the product yield can be improved, but also the product purity can be increased, the reaction route can be shortened, and the number of devices, reaction time, floor area, labor intensity and energy consumption and the like can be reduced.
C07B 41/02 - Formation or introduction of functional groups containing oxygen of hydroxy or O-metal groups
C07B 63/00 - Purification; Separation specially adapted for the purpose of recovering organic compounds; Stabilisation; Use of additives
C07C 37/055 - Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis by substitution of a group bound to the ring by oxygen, e.g. ether group
C07C 37/74 - Separation; Purification; Stabilisation; Use of additives by physical treatment by distillation
C07C 37/78 - Separation; Purification; Stabilisation; Use of additives by physical treatment by distillation by azeotropic distillation
A method for the continuous synthesis of propellane compounds, comprising the following steps: using 1,1-dibromo-2,2-chloromethyl cyclopropane or a derivative thereof as a raw material, preparing propellane compounds by means of continuous reaction and ring fusion with a metal lithium reagent. The present method uses a continuous reaction device, continuous feeding, continuous reaction, continuous transfer, and continuous quenching, and the post-treatment can even obtain a separation yield of more than 90%, implementing highly efficient preparation of propellanes. In addition, the present method shortens the reaction time, solving the problem of products in scaled-up production being unstable in alkaline conditions and deteriorating with long reaction times, greatly reducing the risk of using lithium reagent in the reaction, and being more conducive to scaled-up production.
C07C 1/28 - Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from organic compounds containing only halogen atoms as hetero atoms by ring closure
C07C 13/605 - Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with three condensed rings with a bridged ring system
11.
CONTINUOUS SYNTHESIS METHOD FOR 1,1'-BICYCLO[1.1.1]PENTANE-1,3-DIETHYL KETONE ORGANIC MATTER
A continuous synthesis method for 1,1'-bicyclo[1.1.1]pentane-1,3-diethyl ketone organic matter. The continuous synthesis method comprises: under the irradiation of a light source, continuously transporting raw material A and raw material B to a continuous reaction device for a continuous photochemical reaction to obtain 1,1'-bicyclo[1.1.1]pentane-1,3 -diethyl ketone organic matter, and using a temperature control device to control the reaction temperature in the continuous reaction device. Using a propellane that has a substituent group as a reaction raw material and carrying out the described photochemical reaction in the continuous reaction device may reduce the probability of the slow decomposition and deterioration thereof under illumination, and greatly increase the conversion rate of reaction raw materials and the product yield.
C07C 45/68 - Preparation of compounds having C=O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of C=O groups by change of size of the carbon skeleton by increase in the number of carbon atoms
C07C 49/323 - Saturated compounds containing keto groups bound to rings polycyclic having keto groups bound to condensed ring systems
C07C 49/35 - Saturated compounds containing keto groups bound to rings containing ether groups, groups, groups, or groups
12.
CONTINUOUS SYNTHESIS METHOD FOR SUBSTITUTED BENZOATE ORGANIC MATTER
The present invention provides a continuous synthesis method for a substituted benzoate organic matter. The continuous synthesis method comprises: in the presence of a catalyst and an organic solvent, continuously feeding an organic matter as represented by formula (I) and oxygen into a continuous reaction device for continuous oxidation reaction to obtain a substituted benzoate organic matter, and performing continuous discharge, wherein the substituted benzoate organic matter has a structure as represented by formula (II). Oxygen is a green reagent, and is cheap and easy to obtain; the present invention would not produce a large amount of waste gas, waste water, and waste residues after the completion of reaction, and the system is easy to handle. The use of continuous reaction operation can reduce the risk of solvent flash evaporation explosion due to high concentration oxygen in batch reactions. Under the same oxidation conditions, the use of a continuous preparation process can reduce the escape of oxygen, greatly increase the utilization of oxygen, simplify the operation, and improve the reaction safety and the yield of substituted benzoate organic matters.
C07C 51/245 - Preparation of carboxylic acids or their salts, halides, or anhydrides by oxidation with molecular oxygen of oxygen-containing groups to carboxyl groups of keto groups or secondary alcohol groups
C07C 63/68 - Compounds having carboxyl groups bound to carbon atoms of six-membered aromatic rings containing halogen
C07C 201/12 - Preparation of nitro compounds by reactions not involving the formation of nitro groups
C07C 205/58 - Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by halogen atoms
C07C 205/59 - Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
13.
CONTINUOUS SYNTHESIS METHOD FOR 1,1'-BICYCLO[1.1.1]PENTANE-1,3-DIETHYL KETONE COMPOUNDS
A continuous synthesis method for 1,1'-bicyclo[1.1.1]pentane-1,3-diethyl ketone organic matter. The continuous synthesis method comprises: under the irradiation of a light source, continuously transporting raw material A and raw material B to a continuous reaction device for a continuous photochemical reaction to obtain 1,1'-bicyclo[1.1.1]pentane-1,3 -diethyl ketone organic matter, and using a temperature control device to control the reaction temperature in the continuous reaction device. Using a propellane that has a substituent group as a reaction raw material and carrying out the described photochemical reaction in the continuous reaction device may reduce the probability of the slow decomposition and deterioration thereof under illumination, and greatly increase the conversion rate of reaction raw materials and the product yield.
C07C 45/68 - Preparation of compounds having C=O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of C=O groups by change of size of the carbon skeleton by increase in the number of carbon atoms
C07C 49/323 - Saturated compounds containing keto groups bound to rings polycyclic having keto groups bound to condensed ring systems
C07C 49/35 - Saturated compounds containing keto groups bound to rings containing ether groups, groups, groups, or groups
14.
METHOD FOR CONTINUOUS SYNTHESIS OF SUBSTITUTED BENZOIC-ACID ORGANIC SUBSTANCE
The present invention provides a method for the continuous synthesis of a substituted benzoic-acid organic substance. The continuous synthesis method comprises: in the presence of catalyst and organic solvent, the organic matter represented by formula (I) and oxygen are continuously inputted to a continuous reaction apparatus for continuous oxidation reaction to obtain a substituted benzoic-acid organic substance, which is discharged continuously, the substituted benzoic-acid organic substance having the structure represented by formula (II). Oxygen is a green reagent and is inexpensive and readily available; a large amount of wastewater, waste gas, and solid waste is not generated after the reaction, and the system is easy to handle. The use of a continuous reaction operation can reduce the risk of flash distillation and explosion of solvent due to a high concentration of oxygen in a batch reaction. Under the same oxidation conditions, the continuous preparation process can reduce the escape of oxygen, greatly increasing the oxygen utilization rate and also simplifying the operation, improving the safety of the reaction and the yield of the substituted benzoic-acid organic substance.
C07C 51/245 - Preparation of carboxylic acids or their salts, halides, or anhydrides by oxidation with molecular oxygen of oxygen-containing groups to carboxyl groups of keto groups or secondary alcohol groups
C07C 63/68 - Compounds having carboxyl groups bound to carbon atoms of six-membered aromatic rings containing halogen
C07C 201/12 - Preparation of nitro compounds by reactions not involving the formation of nitro groups
C07C 205/58 - Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by halogen atoms
C07C 205/59 - Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
A ketoreductase mutant and use thereof are provided. The amino acid sequence of the ketoreductase mutant is an amino acid sequence obtained by mutation of the amino acid sequence shown in SEQ ID NO: 1, wherein the mutation at least comprises one of the following mutation sites: position 6, position 94, position 96, position 117, position 144, position 156, position 193, position 205, position 224, position 176, position 85 and position 108; alternatively, the amino acid sequence of the ketoreductase mutant has a mutation site in a mutated amino acid sequence and an amino acid sequence having 80% or more homology with the mutated amino acid sequence.
Provided are a proline hydroxylase and uses thereof. The proline hydroxylase comprises (a) a protein having the amino acid sequence as shown in SEQ ID NO: 2; (b) a protein having an amino acid sequence of SEQ HD NO: 2 with a mutation of one or more amino acids and having a proline hydroxylase activity; or (c) a protein retaining the mutation of one or more amino acids as in (b), and having the proline hydroxylase activity and having at least 78% homology with the amino acid sequence of the protein in (b). Protein having the amino acid sequence as shown in SEQ HD NO: 2 and mutants obtained by genetically engineering have higher catalytic specificity or significantly increased catalytic activity when compared to proline hydroxylases in prior art.
Provided are a ketoreductase mutant and an application thereof. The amino acid sequence of the ketoreductase mutant is an amino acid sequence obtained by mutating the amino acid sequence shown in SEQ ID NO: 1, and the mutation comprises at least one of the following mutation sites: position 6, position 94, position 96, position 117, position 144, position 156, position 193, position 205, position 224, position 176, position 85 and position 108; alternatively, the amino acid sequence of the ketoreductase mutant has a mutation site in a mutated amino acid sequence and an amino acid sequence having 80% or more homology with the mutated amino acid sequence. The ketoreductase mutants have high stability, especially the resistance to acetone and isopropanol such that when the mutants are used in the preparation of a chiral hydroxyl heterocyclic substance, the components of the reaction system are simplified, costs are lowered, and the prepared chiral alcohol has an ee value of as high as 99.8%.
C07D 401/14 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Provided are a proline hydroxylase and an application thereof. The proline hydroxylase includes (a) a protein having the amino acid sequence as shown in SEQ ID NO: 2; (b) a protein in which the amino acid sequence as shown in SEQ ID NO: 2 has gone through mutations of one or more amino acids and which has proline hydroxylase activity; or (c) a protein which retains the mutations of one or more amino acids as in (b), which has having has proline hydroxylase activity and which has at least 78% homology with the amino acid sequence of the protein in (b). Proteins having the amino acid sequence as shown in SEQ ID NO: 2 and mutants obtained by genetically engineering the same have higher catalytic specificity or significantly increased catalytic activity when compared to existing proline hydroxylases.
A method for manufacturing aryl nitriles represented by formula I. The method for manufacturing the compound represented by formula I comprises: using an aryl compound represented by formula II as a starting material; for the compound represented by formula II, n = 0 or 1, and X1, X2, X3, and X4 are independently selected from N, S, O, or C; Y is OSO2F, OTf, or OTs; R1, R2, R3 and R4 are independently selected from any one of H, an alkyl group, an aryl group, or a halide. Nitrilization of the aryl compound is performed using a catalytic effect provided by a catalyst, a reducing agent, and a ligand to obtain the class of aryl nitrile compounds.
A method for preparing a crizotinib intermediate, the method comprising: (1) synthesizing a compound 1 and a compound 2 into a compound 3 by means of flow chemical reaction; (2) synthesizing the compound 3 obtained in step (1) and a boric acid vinegar compound 4 into a crizotinib intermediate I by means of flow chemical reaction. The preparation method results in a high yield, and can be used to greatly reduce the energy consumption and costs in the preparation process of crizotinib. The method is environmental friendly, safe and highly automated, and is suitable for large industrial production. The reaction route is as shown in (i), wherein Y is a leaving group, z is an amino protective group, and x is selected from F, Cl, Br and l.
C07D 401/14 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
C12P 7/22 - Preparation of oxygen-containing organic compounds containing a hydroxy group aromatic
The application provides a Diketoreductase (DKR) mutant, its nucleotide coding sequence, and an expression cassette, recombinant vector and host cell containing the sequence, as well as a method for application of the mutant to the preparation of 3R,5S-dicarbonyl compound. An ee value of the obtained 3R,5S-dicarbonyl compound is higher than 99%, and a de value is about 90%. The DKR mutant is a key pharmaceutical intermediate, and particularly provides an efficient catalyst for synthesis of a chiral dicarbonyl hexanoic acid chain of a statin drug.
A polymer containing a carboxyl group, a preparation method and an application thereof, a supported catalyst and a preparation method thereof and preparation methods of penem antibiotic intermediate are disclosed. The polymer has high rigidity and hardness, thus the mechanical properties of the polymer is effectively improved. Meanwhile, in the polymer, the carboxyl group is used as a main functional group, and is used as a carrier to prepare, by means of a coordination reaction between the carboxyl group and a heavy metal, a supported metal catalyst which has better connection stability between the metal and the polymer. The above two factors can improve the stability of the supported metal catalyst, such that the catalyst can be recycled without losing the catalytic activity. Meanwhile, loss of a heavy metal active ingredient and production cost can be reduced.
B01J 31/06 - Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing polymers
C07D 477/06 - Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
C08F 12/32 - Monomers containing only one unsaturated aliphatic radical containing two or more rings
C08F 12/34 - Monomers containing two or more unsaturated aliphatic radicals
C08F 212/14 - Monomers containing only one unsaturated aliphatic radical containing one ring substituted by hetero atoms or groups containing hetero atoms
B01J 23/46 - Ruthenium, rhodium, osmium or iridium
B01J 31/28 - Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups of the platinum group metals, iron group metals or copper
C08J 9/00 - Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof
C08J 9/14 - Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof using blowing gases generated by a previously added blowing agent by a physical blowing agent organic
A transaminase and a use thereof are provided. The transaminase has the amino acid sequences as shown in SEQ ID NO: 2 or 4, or has at least 80% identity to the amino acid sequences as shown in SEQ ID NO: 2 or 4, or has amino acid sequences which are obtained by the substitution, deletion or addition of one or more amino acids and have an the activity of an omega-transaminase with high stereoselective R-configuration catalytic activity, wherein the high stereoselective refers to the content of one of the stereoisomers being at least about 1.1 times that of the other.
The present invention provides a process for preparing nilotinib. The preparation method comprises the steps of: performing a carbonylation and amination reaction with respect to compound A and 3-(4-methyl-1H- imidazol-1-yl)-5-(trifluoromethyl) aniline to obtain an aminated product; and performing an R group deprotection treatment on the aminated product to obtain nilotinib. Compound A has a structure shown in formula I, wherein in formula I, the R group is selected from benzyl, -COCF3, -CHO or -CO2R', and the R' group is a C1-C10 alkyl group, a C1-C3 alkoxy group, or a C7-C19 aralkyl group. The preparation method has a short synthesis route, mild reaction conditions, and uses special materials, thereby improving nilotinib yield while reducing process costs.
C07D 401/14 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
26.
DOUBLE-CARBONYL REDUCTASE MUTANT AND APPLICATION THEREOF
A double-carbonyl reductase mutant and application thereof. An amino acid sequence of the double-carbonyl reductase mutant is the mutant amino acid sequence coded by SEQ ID NO:9, the mutant amino acid sequence has at least two mutation sites: NO:94, NO:151, NO:231, NO:236 and NO:251, and the I mutation of NO:94 is V, A or G; the V mutation of NO:151 is Q, N or S; the F mutation of NO:231 is W, Y or P; the I mutation of NO:236 is L, V or A; the Q mutation of NO:251 is H, R or K; or the amino acid sequence of the double-carbonyl reductase mutant has the mutation sites in the mutant amino acid sequence, and has greater than 90% homology with the mutant amino acid sequence. The enzymatic activity of the double-carbonyl reductase mutant having the mutation sites is improved substantially.
Disclosed are a double-carbonyl reductase, a coding gene of same, and an application thereof. The double-carbonyl reductase is provided with one of the following amino acid sequences: 1) the amino acid sequence of SEQ NO. 1; or, 2) an amino acid sequence having a function of stereoselectively reducing formula (I) into formula (II) and derived from SEQ NO. 1 by means of substitution and/or deletion and/or addition of one or multiple amino acids in the amino acid sequence of SEQ NO. 1, where the amino acid sequence derived from SEQ NO. 1 and SEQ NO. 1 have a sequence similarity of 80% or more, R1 is selected from an aryl, an alkyl, a cycloalkyl, an alkyl-substituted aryl, a halogen-substituted aryl, an aralkyl heterocyclyl, a cyclic heteroalkyl or a cyclic heteroalkyl, and R2 is selected from an alkyl, a cycloalkyl, a haloalkyl or a halocycloalkyl. Employment of the double-carbonyl reductase of the present invention allows for one-step reduction of a dione substrate to prepare 3R,5S-dihydroxy compounds of a single optical purity.
Provided are a double-carbonyl reductase, a coding gene of same, and an application thereof. The double-carbonyl reductase is provided with one of the following amino acid sequences: 1) the amino acid sequence of SEQ ID NO: 1; and, 2) an amino acid sequence having a function for stereoselectively reducing formula (I) into formula (II) and derived from SEQ ID NO: 1 by means of substitution and/or deletion and/or addition of one or multiple amino acids in the amino acid sequence of SEQ ID NO: 1, where the amino acid sequence derived from SEQ ID NO: 1 and SEQ ID NO: 1 have a sequence similarity of 80% or more, R1 is selected from an aryl, an alkyl, a cycloalkyl, an alkyl-substituted aryl, a halogen-substituted aryl, an aralkyl heterocyclyl, a cyclic heteroalkyl or a cyclic heteroalkyl, and R2 is selected from an alkyl, a cycloalkyl, a haloalkyl or a halocycloalkyl. Also provided is a use of the double-carbonyl reductase for reducing a dione substrate to prepare 3R,5S-dihydroxy compounds of a single optical purity.
Disclosed are a double-carbonyl reductase, a coding gene of same, and an application thereof. The double-carbonyl reductase is provided with one of the following amino acid sequences: 1) the amino acid sequence of SEQ NO. 1; and, 2), an amino acid sequence having a function of stereoselectively reducing formula (I) into formula (II) and derived from SEQ NO. 1 by means of substitution and/or deletion and/or addition of one or multiple amino acids in the amino acid sequence of SEQ NO. 1, where the amino acid sequence derived from SEQ NO. 1 and SEQ NO. 1 have a sequence similarity of 80% or more, R1 is selected from an aryl, an alkyl, a cycloalkyl, an alkyl-substituted aryl, a halogen-substituted aryl, an aralkyl heterocyclyl, a cyclic heteroalkyl or a cyclic heteroalkyl, and R2 is selected from an alkyl, a cycloalkyl, a haloalkyl or a halocycloalkyl. Employment of the double-carbonyl reductase of the present invention allows for one-step reduction of a dione substrate to prepare 3R,5S-dihydroxy compounds of a single optical purity.
The present invention relates to a preparation method for a chiral intermediate for use in statins, acquired with chloroacetic acid and benzyl alcohol as starting materials via a series of reactions, namely etherification, condensation, substitution, and asymmetric reduction. The preparation method provided in the present invention has a novel route of synthesis, allows an intermediate compound to be introduced conveniently into the chiral center of a glycol via enzyme reduction, and not only is low in costs, but also is reliable in quality. The route of synthesis provided in the present invention uses raw materials of low costs, has an easy to operate process, and provides a final product of great purity and high yield.
Provided is a double-carbonyl reductase mutant, a nucleotide coding sequence thereof and, comprising the sequence, an expression cassette, a recombinant vector, and a host cell, and a method for using the mutant in preparation of 3R,5S-double carbonyl compounds, where the ee values of the acquired 3R,5S-double-carbonyl compounds are greater than 99%, while the de values of same are approximately 90%. The double-carbonyl reductase mutant is a key pharmaceutical intermediate, and specifically provides a high-efficiency catalyst for synthesis of a chiral dihydroxy hexanoic acid chain of statins.
Provided are an intermediate compound for preparing rosuvastatin calcium and a preparation method of the rosuvastatin calcium. The method comprises: using the foregoing intermediate compound as a raw material, and subjecting the raw material to a step of Wittig reaction, a step of protecting group removal and hydrolysis and a step of calcium salt formation, so as to obtain the rosuvastatin calcium. The product, which is prepared from the intermediate compound, can be substantially enhanced in stereoselectivity and also notably improved in purity and yield; in addition, the method for preparing rosuvastatin calcium from the intermediate compound is simple, convenient and low in cost.
Disclosed is a method for preparing sulfobutyl ether-β-cyclodextrin. The method overcomes shortcomings of the prior art; β-cyclodextrin and 1,4-sulfobutyrolactone are used as raw materials, and a proper amount of organic solvent is introduced into an alkaline aqueous solution, so that the solubility of the 1,4-sulfobutyrolactone is increased, and the synthesis rate of the sulfobutyl ether-β-cyclodextrin is improved. Operations, such as ultrasonic dialysis, active carbon decoloration, freezing and drying, are performed on the obtained product solution, so as to obtain the powder product of sulfobutyl ether-beta-cyclodextrin. The method has a stable process, needs a moderate reaction condition, has good selectivity, and needs simple aftertreatment operations; the obtained product has very high purity and yield, thereby providing a new idea and a method for mass production of sulfobutyl ether-β-cyclodextrin.
POLYMER CONTAINING CARBOXYL GROUP, METHOD FOR PREPARING SAME AND USE THEREOF, METHOD FOR PREPARING SUPPORTED CATALYST AND PENEM ANTIBIOTIC INTERMEDIATES
The present invention discloses a polymer containing a carboxyl group, a method for preparing same and a use thereof, and a method for preparing a supported catalyst and a penem antibiotic intermediate. The polymer is made by polymerizing three monomers with different structures. The carboxyl group-containing polymer is a crosslinked polymer, and the polymer chain contains a large number of phenyl rings, and which can improve the rigidity and hardness of the polymer, thus effectively improving the mechanical properties of the polymer. Meanwhile, in the polymer, the carboxyl groups are used as the main functional groups, and are used as a carrier to prepare a supported metal catalyst, by means of a coordination reaction between the carboxyl groups and heavy metals, which has a better connection stability between the metal and the polymer. The above two factors can improve the stability of the supported metal catalyst, such that the catalyst can be recycled without the loss of the catalytic activity. Meanwhile, they are also able to reduce the loss of the heavy metals active ingredients and reduce production costs.
C08F 220/12 - Esters of monohydric alcohols or phenols
C08F 220/64 - Acids; Metal salts or ammonium salts thereof
C07D 477/06 - Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
B01J 31/06 - Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing polymers
35.
OMEGA-TRANSAMINASE OF R CONFIGURATION AND USE THEREOF
Provided is an omega-transaminase of R-configuration. The omega-transaminase of R-configuration has the amino acid sequences as shown in SEQ ID NO: 2, or has at least 80% identity to the amino acid sequences as shown in SEQ ID NO: 2, or has the amino acid sequences of proteins which have substituted, deleted or added one or more amino acids and have omega-transaminase activity of a high stereoselectivity R-configuration catalytic activity; and does not have the amino acid sequences encoded by the nucleotide sequence as shown in SEQ ID NO: 4. The high stereoselectivity refers to the content of one of the stereoisomers being at least about 1.1 times that of the other. Also provided is a use of omega-transaminase, which can be useful for highly efficient synthesis of a chiral amine of R-configuration with a relatively high chiral purity, and is therefore suitable for the industrial production of the chiral amines.
Provided is a transaminase and a use thereof. The transaminase has the amino acid sequences as shown in SEQ ID NO: 2 or 4, or has at least 80% identity to the amino acid sequences as shown in SEQ ID NO: 2 or 4, or has amino acid sequences which are obtained by the substitution, deletion or addition of one or more amino acids and have an omega-transaminase activity of a high stereoselectivity R-configuration catalytic activity wherein the high stereoselectivity refers to the content of one of the stereoisomers being at least about 1.1 times that of the other. The transaminase can synthesize a chiral amine of R-configuration with a relatively high chiral purity, and is therefore suitable for the industrial use of the synthesis of chiral amines.
The present invention relates to a method for preparing a penem antibiotic intermediate. The method comprises the following steps: step 1: preparing an intermediate compound by means of a Mannich reaction; and step 2: converting the intermediate compound into a penem antibiotic intermediate. The method shortens the reaction period, reduces the cost, and reduces environmental pollution, and reaction materials are easily obtained; and the selectivity and the yield of the method are remarkably improved in comparison with the prior art.
C07D 205/08 - Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
38.
METHOD FOR PREPARING CARBAPENEM INTERMEDIATE β-METHYL-ADC-8
A method for preparing a carbapenem intermediate β-methyl-ADC-8, comprising: (1) a reaction of 2-haloacrylate compounds with N-substituted-4-acyloxyazetidinone under the effect of a metal, or a Mannich reaction of a propionate compound with N-substituted-4-acyloxyazetidinone to obtain an α and β racemic mixture of a compound A; (2) an ozonization reaction of the α and β racemic mixture of the compound A to obtain an α and β racemic mixture of a compound B; and (3) a selective hydrolytic reaction in the presence of an additive by controlling the pH value of the reaction system to obtain β-methyl-ADC-8. The general structural formula of the compound A is formula (A), and the structural formula of the compound B is formula (B).
C07F 7/18 - Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
C07D 205/08 - Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
39.
PREPARATION METHOD FOR INTERMEDIATE 4AA OF IMIPENEM DRUGS
Disclosed is a preparation method for an intermediate 4AA of imipenem drugs. The preparation method comprises: making 4-substituted aniline into an intermediate (A); performing epoxidation on L-threonine to produce (2R, 3R)-epoxy butyric acid; enabling the (2R, 3R)-epoxy butyric acid and the intermediate (A) to undergo a coupling reaction, and obtaining an intermediate (B); enabling the intermediate (B) to undergo a cyclization reaction, and obtaining an intermediate (C); enabling the intermediate (C) to undergo a hydroxyl protection reaction, and obtaining an intermediate (D); enabling the intermediate (D) to be oxidized to form an acetoxy group, and enabling an oxidized product to undergo an ozonation reaction, wherein G is H, F, Cl, Br, a methoxy group, oxethyl or an amino group; X is Cl, Br or I; and R is H, straight chain alkyl of C1-C6, cyclopropyl, isopropyl, tert-butyl, a phenyl group, p-chlorophenyl, o-chlorophenyl, p-bromophenyl, o-bromophenyl, p-methoxyphenyl, o-methoxyphenyl or m-methoxyphenyl. According to the preparation method, raw materials are cheap and easy to obtain, reaction conditions are mild, the conversion rate and the yield rate are high, and the preparation method is suitable for industrial production.
Disclosed in the present invention is a continuous production method of 2-MeTHF (2-methyltetrahydrofuran). The method comprises the following steps: inputting gasified furfural and hydrogen into a first reaction area and conducting primary catalytic hydrogenation reaction; inputting gas output by the first reaction area into a second reaction area and conducting secondary catalytic hydrogenation reaction; and condensing gas output by the second reaction area to obtain the 2-MeTHF; the first reaction area is filled with catalyst for reducing aldehyde groups and the second reaction area is filled with catalyst for aromatic saturated hydrogenation. By using low-toxicity, low-cost and easy-to-obtain catalyst to produce high-purity 2-MeTHF through gas-phase continuous reaction under low pressure or low ambient temperature, the traditional technology having the disadvantages of high pressure, great investment and great risk is changed, and the use of high-toxicity precious metals can be reduced. The production technology is simple, the investment is small, the risk is small, the furfural treatment capacity per unit time is large, the yield is high, the purity of the obtained crude product is high and the impurities are easy to separate.
C07D 307/06 - Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
41.
SYNTHESIS METHOD FOR L-HETEROCYCLIC AMINO ACID AND PHARMACEUTICAL COMPOSITION HAVING SAID ACID
A synthesis method for L-heterocyclic amino acid and a pharmaceutical composition thereof are provided. The method comprises: step a.) preparing heterocyclic keto acid, wherein the heterocycle of the heterocyclic keto acid is selected from a five-membered heterocycle, a six-membered heterocycle, a seven-membered heterocycle, an alkyl-substituted five-membered heterocycle, an alkyl-substituted six-membered heterocycle, and an alkyl-substituted seven-membered heterocycle; step b.) mixing the heterocyclic keto acid with ammonium formate, phenylalanine dehydrogenase, formate dehydrogenase and coenzyme NAD+ to generate L-heterocyclic amino acid, wherein the phenylalanine dehydrogenase amino acid sequence is SEQ ID No. 1. The synthesis method allows for a high conversion rate of raw materials and high chiral selectivity.
C12N 15/63 - Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
A61K 31/381 - Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
A61K 31/444 - Non-condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. amrinone
A61K 31/4409 - Non-condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
A61K 31/4402 - Non-condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
A61K 31/4406 - Non-condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
The present invention provides a synthesis method for L-cyclic alkyl amino acid and a pharmaceutical composition having said acid. Said synthesis method comprises: step a.) preparing a cyclic alkyl keto acid or cyclic alkyl keto acid salt having structural formula (I) or structural formula (II), and step b.) mixing cyclic alkyl keto acid or cyclic alkyl keto acid salt with ammonium formate, leucine dehydrogenase, formate dehydrogenase and coenzyme NAD+, and carrying out a reductive amination reaction to generate L-cyclic alkyl amino acid, wherein in structural formula (I), n1≥1, m1≥0, and M1 is H or a monovalent cation, and in structural formula (II), n2≥0, m2≥0, M2 is H or a monovalent cation, and the leucine dehydrogenase amino acid sequence is SEQ ID No. 1. Using a specific leucine dehydrogenase with formate dehydrogenase and coenzyme NAD+ to enable a reductive amination reaction of cyclic alkyl keto acid so as to generate L-cyclic alkyl amino acid allows for a high conversion rate of raw materials and high chiral selectivity.
C12P 17/06 - Oxygen as only ring hetero atoms containing a six-membered hetero ring, e.g. fluorescein
A61K 31/351 - Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
A61K 31/195 - Carboxylic acids, e.g. valproic acid having an amino group
43.
METHOD FOR SYNTHESIZING SAPROPTERIN DIHYDROCHLORIDE
Disclosed is a method for synthesizing sapropterin dihydrochloride. The present invention reduces a synthesis route of the sapropterin dihydrochloride, and resolves a racemate intermediate or an intermediage having a low antimer isomerism value by using a chiral resolving reagent, thereby obtaining an intermediate having a high antimer isomerism value. Raw materials are cheap and readily available, and the cost is significantly reduced, hence providing an effective scheme for mass industrial production of the sapropterin dihydrochloride.
C07D 475/04 - Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
44.
METHOD FOR SYNTHESIZING SAPROPTERIN DIHYDROCHLORIDE
Disclosed is a method for synthesizing sapropterin dihydrochloride. The present invention reduces a synthesis route of the sapropterin dihydrochloride, introduces a tetrahydrofuran solution as a catalyst in an asymmetric synthesis manner, a chiral center of the tetrahydrofuran solution using a samarium catalyst, and obtains a target compound having a high antimer isomerism value by means of selective catalysis. The yield is improved, raw materials are cheap and readily available, and the cost is significantly reduced, hence providing an effective scheme for mass industrial production of the sapropterin dihydrochloride.
C07D 475/04 - Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
45.
CONTINUOUS OZONATION REACTION DEVICE AND OPERATING METHOD THEREFOR
A continuous ozonation reaction device comprising a feed inlet (111), a feed distribution unit, one or more single reaction tube(s) (30), a product outlet (171) and gas inlets (131, 173). The first end of the feed distribution unit is connected to the feed inlet (111); the second end of the feed distribution unit is connected to the first end of the one or more single reaction tube(s) (30); the product outlet (171) is connected to the second end of the single reaction tube(s) (30), and the gas inlets (131, 173) convey ozone to the single reaction tube(s) (30). Also provided is an operating method of the continuous ozonation reaction device. The continuous ozonation reaction device realizes continuous large-scale production of ozonation reaction on the premise of ensuring safety.
B01J 8/06 - Chemical or physical processes in general, conducted in the presence of fluids and solid particles; Apparatus for such processes with stationary particles, e.g. in fixed beds the solid particles being arranged in tubes
B01J 19/24 - Stationary reactors without moving elements inside
B01J 10/00 - Chemical processes in general for reacting liquid with gaseous media other than in the presence of solid particles; Apparatus specially adapted therefor
C02F 1/78 - Treatment of water, waste water, or sewage by oxidation with ozone
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