41 results about "Chiral amine" patented technology

The invention provides an R-type transaminase mutant and application thereof, and compared with an amino acid sequence of wild-type transaminase as shown in SEQ ID NO.1, the mutant has mutation of a 62nd site, a 152nd site and a 155th site. The mutant has high catalytic activity and excellent stereoselectivity on a heterocyclic ketone substrate, and can be used for efficiently preparing R-configuration heterocyclic chiral amine.

The embodiment of the invention discloses an imine reductase mutant as well as a coding gene and application thereof, and belongs to the technical field of genetic engineering and biosynthesis, and the similarity between the amino acid sequence of the imine reductase mutant and the amino acid sequence of wild type imine reductase is 90%-99.9%. Wherein the amino acid sequence of the wild type imine reductase is as shown in SEQ ID NO. 1. According to the imine reductase mutant provided by the invention, the catalytic activity, optical selectivity and stability of the imine reductase mutant during synthesis of chiral amine compounds can be improved.

Provided are a method for preparing (R)-ketorolac and use thereof. The method includes the following steps: step 1, preparing ketorolac; and step 2, subjecting the ketorolac to resolution to obtain the (R)-ketorolac, the resolution being selected from the group consisting of chiral amine resolution and enzyme resolution.

The invention provides a method for preparing chiral amine by catalyzing asymmetric hydrogenation of aromatic imine through a manganese / chiral ferrocene P, N, N ligand. The manganese precursor and ligand adopted by the method are easy to obtain, the reaction condition is mild, the operation is simple, the target chiral amine compound can be obtained with high yield and high stereoselectivity, and continuous large-scale preparation can be realized. The catalyst system is high in activity, the molar ratio of imine to the catalyst can reach 100000: 1, and the catalyst has a very good industrial application prospect.

The invention discloses an imine reductase mutant and an application of the imine reductase mutant in synthesis of vibeglone. The invention discloses an imine reductase mutant, which is characterized in that on the basis of an imine reductase mutant IR-13-M5, the imine reductase mutant has the following mutations: M203P-F269W-I149G-S241Q-L200T-G268Q, M203P-F269W-I149G-L200T, M203P-F269W-I149G-S241Q-L200T, M203P-F269W-I149G-S241Q-L200T or M203P-F269W-I149G-L200T-G268Q, and the imine reductase mutant has the following mutations: M203P-F269W-I149G The mutant can be used for asymmetric catalytic synthesis of an S-selective chiral amine product vibeglone, the conversion rate reaches 78%, the stereoselectivity reaches up to 99%, and the mutant has a good industrial application prospect.

This invention provides a method for preparing chiral N-tert-butylsulfonamide compounds. The method uses N-tert-butylsulfonylimide as a starting material, employs Mn(CO)₅Br and a chiral PNN ligand as catalysts, and an alcohol as a solvent. A hydrogenation reaction occurs in this homogeneous catalytic system, yielding axially chiral diaryl nitrophenol compounds in high yield (99%) and with high ee values ​​(>99%). This reaction has the advantages of high efficiency, mild conditions, and environmental friendliness. The obtained chiral N-tert-butylsulfonamide can be deprotected with a sulfonyl protecting group to obtain the corresponding chiral primary amine.

The invention discloses a circular polarization organic laser material and a preparation method and application thereof, and the preparation method of the circular polarization organic laser material comprises the following steps: taking chiral amine, rare earth chloride and hydrochloric acid as raw materials, placing the raw materials in a solvent, and heating for reaction to obtain a precursor solution; after drying the precursor solution, dissolving again to obtain a transparent solution; and putting the open container filled with the transparent solution into a closed container filled with an anti-solvent, and growing the zero-dimensional perovskite structure luminescent material A4BX7 single crystal by utilizing the diffusion of the anti-solvent. The chiral ligand is introduced into the hybrid perovskite, a chiral environment is successfully introduced into an inorganic perovskite system, chiral transfer is realized, and the prepared circular polarization organic laser material has good circular polarization organic laser properties and high fluorescence quantum yield.

The application discloses a method for synthesizing chiral 1,3-disubstituted tetrahydroisoquinoline by using a chemical enzyme cascade system and belongs to the technical field of bioengineering. The application establishes a method for preparing chiral 1,3-disubstituted tetrahydroisoquinoline by using an enzyme cascade catalysis. Simple non-chiral ketone is used as a raw material, a transaminase obtained through screening is used to generate a chiral amine, a B-N cyclization reaction is used to obtain a chiral imine, and finally, an imine reductase is used to generate 1,3-disubstituted tetrahydroisoquinoline. The method has a high yield, can be close to 100%, has excellent diastereoselectivity and enantioselectivity, the de value and the ee value are close to 99%, and has good application value and prospect.

The invention provides an omariglitazone intermediate, a preparation method thereof and a method for preparing an omariglitazone key intermediate, and relates to the technical field of organic chemistry. The omarignelone intermediate provided by the invention has a structure as shown in a formula VIII; the omariglitazone intermediate is easy to obtain and can be conveniently prepared by taking benzaldehyde as a starting raw material, a chiral chromatographic column does not need to be used for preparation of the omariglitazone intermediate, a key chiral center of the omariglitazone intermediate is constructed by catalyzing a cheap chiral amine catalyst through an asymmetric Knoevenagel-Michael addition reaction, and the preparation method is simple and convenient. According to the omariglitazone intermediate, industrial production of the omariglitazone key intermediate (the structure as shown in the formula I) is easy to realize, and the production cost is reduced. The invention provides a method for preparing an omariglone key intermediate (a structure shown in a formula I), the omariglone key intermediate can be prepared from the omariglone intermediate through a nitro reduction reaction, a Jappp-Klingemann reaction and an indole synthesis reaction, and the method is suitable for industrial production. A formula VIII and a formula I are shown in the description.

The application relates to a chiral triazole-oxazoline compound and a preparation method and application thereof, and belongs to the technical field of organic synthesis. The chiral triazole-oxazoline compound has the structural formula: the preparation method comprises the steps of click reaction, triazole N2 substitution reaction, Suzuki coupling, triazole ester hydrolysis, amidation with a chiral amine alcohol and dehydration condensation. After a chiral triazole-oxazoline compound and a palladium salt compound are added to generate a catalyst in situ, asymmetric addition of aryl boronic acid on a carbon-carbon double bond of a prochiral organic compound is carried out to prepare a chiral organic compound. The application has the advantages of low raw material cost, few synthesis steps, low experiment site requirement, relatively mild reaction conditions and simple operation for preparing the novel triazole-oxazoline compound.

The invention discloses a method for preparing a chiral amine compound through asymmetric hydrogenation of ruthenium catalyzed imine. The chiral ruthenium catalyst is a chiral metal ruthenium complex prepared by reacting metal ruthenium salt with a chiral phosphine-phosphoramidite ester ligand and chiral diamine in a solvent and carrying out column chromatography. Compared with other chiral amine synthesis methods, the method provided by the invention has the characteristics of cheap catalyst, easy preparation of chiral ligand, mild reaction conditions, simple operation, high yield and enantioselectivity and the like, and can be applied to large-scale preparation of chiral amine compounds. The method is also suitable for synthesis of the key intermediate of the herbicide (S)-metolachlor, the yield can reach 92%, the enantioselectivity can reach 90%, and the method has good industrial application prospects.

The invention provides a biosynthesis method of an esdoxaban tosylate chiral intermediate. According to the preparation method, 3-cyclohexene-1-carboxylic acid methyl ester is taken as a starting raw material, and a target intermediate is finally obtained through carboxylesterase resolution, hydrolysis, hydroxylation, dehydrogenation oxidation, transamination reaction, amidation and Boc2O reaction in sequence. According to the method, high-selectivity carboxylesterase is used for realizing chiral resolution; p450 oxidase with excellent regioselectivity and stereoselectivity is utilized to realize specific hydroxylation of a C-H bond under a mild condition, and a traditional process depending on a highly toxic chemical oxidant is overturned; then, clean oxidation is realized through alcohol dehydrogenase, and a way is laid for subsequent reaction; most importantly, the transaminase is adopted to directly construct the chiral amine, so that the use of a high-risk reagent sodium azide is thoroughly avoided, and major potential safety hazards are eliminated from the source; and finally, green amidation is realized by virtue of lipase, and an acyl chloride method for generating corrosive wastewater is replaced.

The present application provides an amine dehydrogenase, which is obtained by mutating an amino acid dehydrogenase as shown in SEQ ID NO. 1, and the mutation comprises at least one mutation in the amino acids at positions 293, 69, 115 and 262 of SEQ ID NO. 1. The present application also provides the use of the amine dehydrogenase in preparing chiral amines. By means of protein engineering, the present application modifies the amino acid dehydrogenase catalyzing amino acid substrates into an amine dehydrogenase (AmDH) with ketone and aldehyde as substrates. The amine dehydrogenase of the present application has high reductive amination activity, and can be applied in the process of catalyzing transamination of hydroxy ketone and prochiral ketone compounds to prepare chiral amines, including but not limited to 3-hydroxy-D-tyrosine. The high catalytic activity, high yield and 99%+ stereoselectivity meet the requirements, and the present application has the advantages of green and efficient, low cost and high optical purity of products, and is one of the most ideal reactions for the synthesis of chiral amines.

This invention discloses an R-type transaminase mutant and its applications, relating to the field of biocatalysis technology. The amino acid sequence of the R-type transaminase of this invention is shown in SEQ ID NO.7, the nucleotide sequence of the encoding gene is shown in SEQ ID NO.1, and the amino acid sequences of the R-type transaminase mutant are shown in SEQ ID NO.2-SEQ ID NO.6. This invention also provides the application of the R-type transaminase mutant in the asymmetric synthesis of chiral amine compounds. The R-type transaminase of this invention has a maximum sequence similarity of only about 80% with existing R-type transaminases. It provides a method for the enzymatic synthesis of chiral intermediates, with simple reaction steps, mild reaction conditions, and a single-step reaction to reduce and amination 1-naphthyl acetone to a high optical purity (…). R )-1-(1-naphthyl)-ethylamine, with a conversion rate of over 90% and an ee value (enantiomer excess) greater than 99%.

This invention belongs to the field of medicinal chemistry, specifically relating to a method for synthesizing ivcarboxylate. The specific technical solution includes: a method for synthesizing ivcarboxylate, comprising: reductive amination of a chiral amine with a benzyl-protected nitrogen atom with a pyrrolidone, followed by catalytic hydrogenation to remove the protecting group, thereby obtaining ivcarboxylate. The preparation method provided by this invention has a short synthetic route, relatively mild preparation conditions, and great application potential.

The present disclosure provides engineered transaminase polypeptides for the production of amines, polynucleotides encoding the engineered transaminases, host cells capable of expressing the engineered transaminases, and methods of using the engineered transaminases to prepare compounds useful in the production of active pharmaceutical agents.

The present application provides a kind of thermostable transaminase or its mutant and its application in preparing chiral amine compound.The amino acid sequence of the thermostable transaminase is selected from any one of the following:(1) the amino acid sequence shown as SEQ ID NO:1;(2) the amino acid sequence shown as SEQ ID NO:1 is derived by substitution, deletion or addition of one or more amino acids and has transaminase activity;(3) the amino acid sequence shown as SEQ ID NO:1 has at least 95% identity and has transaminase activity.The present application also improves the catalytic activity and stability of the transaminase from thermophilic microorganism by modification, thereby improving the catalytic efficiency and being suitable for the preparation process of chiral amine.

The invention discloses a preparation method of a tovorafenib chiral amine intermediate, and belongs to the technical field of medical intermediates. The preparation method comprises the following steps: by taking D-alanine as a raw material, carrying out Boc protection and amidation to obtain N-Boc-D-alaninamide, then carrying out thiocyclization to obtain a chiral aminothiazole ring, and finally, sequentially carrying out hydrolysis, amidation and deprotection to obtain the tovorafenib chiral amine intermediate. The process is green and environment-friendly, D-alanine is adopted as a chiral raw material, a chiral amine group is directly introduced, an expensive metal catalyst and a chiral ligand do not need to be adopted, the chiral amine protecting group is easy to remove, and the core competitiveness of the product is enhanced.

Disclosed in the present invention are a 5-substituted indoline chiral amine compound I, a preparation method therefor, and a preparation method for silodosin. Silodosin is prepared from an indoline derivative and a (R)-2-aminopropanol derivative as starting materials by steps of converting the (R)-2-aminopropanol derivative into an aziridine derivative; halogenating the indoline derivative to obtain a compound of formula III, then forming a Grignard reagent from same, and in the presence of a Cu(I) catalyst, reacting same with the (R)-2-aziridine derivative to obtain the 5-substituted indoline chiral amine I; and performing a formylation reaction, an oximation reaction, a dehydration reaction, an N-alkylation reaction, deprotection of hydroxyl, deprotection of amino, and a hydrolysis reaction to obtain silodosin. The present invention uses an efficient chiral source introduction mode, wherein the 5-substituted indoline chiral amine is prepared by converting D-alanine into a chiral aziridine derivative and reacting same with an indoline moiety, thereby omitting an optical resolution step, such that the obtained compound has a high ee value and the yield is improved.

The application provides an improved engineered transaminase polypeptide which can asymmetrically prepare a chiral amine compound with extremely high stereoselectivity, in particular, more effectively catalyzes the generation of an intermediate of sacubitril, has higher activity and stability, and has application value for the industrialization of sacubitril.

The invention relates to a method for preparing (R)-4-((1-(2-cyanoacetyl) piperidine-3-yl) amino)-1H-pyrrolo [2, 3-b] pyridine-5-ethyl formate (compound 1). The process involves the addition of an ethyl formate group, the displacement of the halogen with a chiral amine, the deprotection of the chiral cyclic amine, and the subsequent coupling reaction with cyanoacetic acid. The displacement may be performed in an autoclave at elevated pressure.

An imine reductase mutant and the use thereof in the preparation of a tofacitinib chiral amine building block. By means of an enzymatically coupled coenzyme regeneration system, the imine reductase mutant can efficiently catalyze racemic 1-benzyl-4-methylpiperidin-3-one as a substrate to undergo dynamic kinetic resolution and asymmetric reductive amination, so as to accurately synthesize a tofacitinib chiral amine building block (3R,4R)-1-benzyl-N-4-dimethylpiperidin-3-amine. Compared with conventional resolution methods, the technology has the significant advantages of simple operation, mild reaction conditions, environmental friendliness, high product yield, low cost, etc., and exhibits excellent application prospects in the synthesis of tofacitinib chiral amine intermediates.

Provided in the present application is a synthesis method for a chiral amine. The synthesis method for a chiral amine provided in the present application comprises: subjecting a carbonyl substrate and an amino donor to a reductive amination reaction under the catalysis of a catalyst to obtain a chiral amine, wherein the catalyst is an imine reductase or a reductive aminase. In the present application, using the imine reductase or the reductive aminase as a catalyst for chiral amine synthesis enables the synthesis of a chiral amine from a non-keto-acid ketone compound substrate and an amino donor under mild reaction conditions. Said method not only has a wide substrate range, but is also simple and economical to operate, and can directly synthesize a variety of chiral amine compounds, making it suitable for industrial production.

A process is described for preparing the compound of formula (S)-3 for optical enzymatic or chiral amine resolution of compounds of formula 4 wherein R is a cyano, carboxy or C1-C6 alkoxy carbonyl group and P is a protecting group of the hydroxy group.

This invention discloses a chiral amination synthesis process for a pharmaceutical intermediate, comprising two steps: First, hydroxylamine hydrochloride and compound I are mixed in a 40-50 wt% aqueous ethanol solution, and an alkaline reagent is added to adjust the pH to 4-6. The mixture is then heated under reflux to generate an oxime ether compound II. Second, compound II is dissolved in THF or toluene, and a chiral spiroboroate catalyst derived from diphenylvaline is added. A BH3·THF reducing agent is then slowly added dropwise at room temperature to perform an asymmetric reduction to obtain a chiral primary amine compound III. The advantages of this invention are: the reaction route avoids high-risk reagents and harsh conditions, significantly improving process safety; and through process route optimization, efficient asymmetric reduction is achieved, resulting in a product with high chiral purity. The reaction route of this invention features mild reaction conditions, simple operation, and is easy to scale up industrially. The overall route is concise, with short steps and high yield, making it suitable for large-scale industrial production.

The application discloses an imine reductase mutant, a preparation method and application thereof, and belongs to the field of synthesis and application of chiral amine catalyzed by biological enzymes. A series of advantageous mutants are obtained by a method of directed evolution on the basis of imine reductase ThIRED from Torrubiella hemipterigena. The imine reductase advantageous mutant obtained by the application has high catalytic activity, high selectivity and wide substrate applicability, and has wide application prospects in industrialized production of high-activity imine reductase.

The invention provides a method for catalytically synthesizing a K-Ras inhibitor chiral amine intermediate based on imine reductase, which comprises the following steps: generating an imine intermediate from 1-(2-(bis (4-methoxybenzyl) amino) pyridine-3-yl) ethyl-1-ketone and ethanolamine under the action of lewis acid or a dehydration reagent; and carrying out catalytic reduction on the obtained imine intermediate through imine reductase to obtain the chiral amine compound. In combination with the reaction characteristics of imine reductase, a novel process for synthesizing the chiral amine through reduction of imine under enzyme catalysis is developed, chiral resolution is not needed, and a chiral amine compound with the purity meeting the requirement can be obtained only through recrystallization with an organic solvent; and the safety risk caused by sodium cyanoborohydride strong reducing agents is avoided. The whole process is simple to operate, low in cost, environment-friendly, high in yield, mild in reaction condition and safe in flow, the cost is far lower than that of a metal catalysis route, and the method has outstanding industrial application potential.

The invention relates to the technical field of biology, in particular to the technical field of enzyme engineering, and particularly relates to a transaminase mutant and application thereof. Specifically, the transaminase mutant is mutated on the basis of wild transaminase as shown in SEQ ID NO: 1 through a site-specific mutagenesis method (particularly, the 121st site is mutated into N from E, the 152nd site is mutated into A from Y, the 260th site is mutated into A from V and / or the 324th site is mutated into S from T), so that the amino acid sequence of the transaminase mutant is changed, and the change of the protein structure and function is realized; the transaminase mutant has the advantage that the enzyme activity is greatly improved, the enzyme activity is improved by multiple times compared with that of a transaminase parent, the stability is also greatly improved, and when the transaminase mutant is used for chiral amine production, the cost in chiral amine industrial production is greatly reduced.

The invention discloses an R-type transaminase mutant, a preparation method thereof and an application of the R-type transaminase mutant in chiral amine synthesis. The 128 site, the 144 site and the 257 site of an amino acid sequence of wild-type R-type transaminase (SEQ ID NO.1) derived from Aspergillus terreus NIH2624 are mutated through a site-specific mutagenesis technology; the obtained three mutants (R128W, R128W / Q144R and R128W / E257G) can efficiently catalyze 1-benzyl-3-piperidone to asymmetrically synthesize the high-value chiral amine (R)-3-amino-1-benzylpiperidine, the conversion rates after 4 hours of reaction at 37 DEG C are all higher than 60%, the highest conversion rate is 70.03%, the ee value is greater than 99%, and the conversion rate of wild R-type transaminase (WT) to the substrate before mutation is only 2.99%.

The invention aims to provide a raceme resolution preparation method of L-selenium-methyl selenocysteine, namely, the L-selenium-methyl selenocysteine with optical activity is prepared through convenient and simple resolution of racemic methyl selenocysteine by using a cheap chiral amine resolving agent. The method is carried out according to the following steps: racemic DL-selenium-methyl selenocysteine is used as an initial raw material, resolution is carried out by chiral amine under mild reaction conditions, and the L-methyl selenocysteine is obtained with high yield and high optical activity. The method has the characteristics of high activity, good selectivity, high yield, low toxicity and the like.