85 results about "Brivaracetam" patented technology

The imine reductase mutant provided by the invention can catalyze asymmetric reductive amination of ethyl 3-formylhexanoate and (S)-2-aminobutanamide to synthesize brivaracetam, two chiral centers of brivaracetam are constructed in one step, and the problems of poor environmental protection property, low atom utilization rate, long route and the like in the existing industrial synthesis route are solved. Wide application prospects are realized.

The invention discloses ketene reductase and a method for preparing a brivaracetam intermediate by using the ketene reductase. The ketene reductase has at least a difference of an amino acid residue W117 or a homologous site thereof relative to an amino acid sequence as shown in SEQ ID NO: 1, SEQ ID NO: 3 or SEQ ID NO: 5 or an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence as shown in SEQ ID NO: 1, SEQ ID NO: 3 or SEQ ID NO: 5, and the position 117 refers to an amino acid residue number in SEQ ID NO: 1. Compared with a wild type, the single mutant or the combined mutant of ketene reductase from different sources has good enantioselectivity and relatively high conversion rate when the brivaracetam intermediate (R)-4-propyl-dihydrofuran-2-ketone is produced, and a good strategy is provided for industrial production of (R)-4-propyl-dihydrofuran-2-ketone.

The invention belongs to the technical field of biocatalysts, and discloses an alkene reductase mutant and application of the alkene reductase mutant in catalytic preparation of a brivaracetam synthesis intermediate. The amino acid sequence of the alkene reductase mutant is as shown in SEQ ID NO.1, a compound enzyme composed of the mutant, carbonyl reductase K1 and glucose dehydrogenase can take a compound 5-hydroxy-4-n-propyl-2-furanone as a substrate, double bonds are reduced, hydroxyl is removed, a compound (R)-4-propyl dihydrofuran-2 (3H)-ketone is obtained, and the compound (R)-4-propyl dihydrofuran-2 (3H)-ketone can be used for preparing the alkene reductase. The ee value of the (R)-4-propyl dihydrofuran-2 (3H)-ketone obtained through catalysis reaches 93.0%, the (R)-4-propyl dihydrofuran-2 (3H)-ketone with the ee value larger than 99.8% can be further obtained through diastereoisomer crystallization, and the method can be used for efficient and green preparation of the brivaracetam key intermediate (R)-4-propyl dihydrofuran-2 (3H)-ketone.

The present invention designs a method for preparing a key intermediate of synthetic boceprevir, namely a chiral pyrrolidone derivative, through catalytic hydrogenation. Specifically, it involves the use of substrate chiral induction by adjusting and modifying the substituents of the substrate to achieve the asymmetric catalytic hydrogenation of dihydropyrrolidone by a metal catalyst. The advantages of the present invention are that the process route is simple and feasible, the yield is high, the cost is low, and it is easy to industrialize production, etc.

The present invention relates to a modified release tablet formulation comprises brivaracetam and at least one pharmaceutically acceptable excipient wherein the amount of brivaracetam is 20.0% to 55.0% by weight in the total composition and at least one matrix agent. Furthermore, the tablet is also obtained by using an effective process which is simple, rapid, cost effective, time-saving and industrially convenient process.

The invention discloses a nitrilase mutant and application of the nitrilase mutant in synthesis of a brivaracetam chiral intermediate, and provides an efficient (R)-3-cyanohexanoic acid nitrilase synthesis process by constructing the nitrilase mutant with improved catalytic activity and stereoselectivity. The requirement of industrially synthesizing the brivaracetam key chiral intermediate is met, and a foundation is laid for industrial production of brivaracetam synthesized by a chemical-enzyme method.

The present invention relates to a modified release tablet formulation comprises brivaracetam and at least one pharmaceutically acceptable excipient wherein the amount of brivaracetam is 20.0% to 55.0% by weight in the total composition and at least one matrix agent. Furthermore, the tablet is also obtained by using an effective process which is simple, rapid, cost effective, time-saving and industrially convenient process.

The invention relates to the technical field of medicines, in particular to a briracetam oral solution and a preparation method thereof. According to the present invention, by adjusting the formula and the preparation process of the oral solution of the briracetam, the stability of the briracetam is effectively improved, the antibacterial effect is effectively improved without adding the preservative, the taste of the oral solution is adjusted, and the medication compatibility of children patients is improved.

The invention discloses a synthesis method of (R)-4-propyl pyrrolidine-2-ketone, which comprises the following steps: step S1, reacting (R)-3-(chloromethyl) hexanoyl chloride with ammonia gas, and carrying out post-treatment to obtain (R)-3-(chloromethyl) hexanamide; and S2, carrying out an intramolecular ring closing reaction on the (R)-3-(chloromethyl) hexanamide under an alkaline condition, and carrying out post-treatment to obtain the (R)-4-propyl pyrrolidine-2-ketone. The high-purity target product prepared by the method can be used as a standard substance for quality research of the briracetam; and the synthesis route is simple, the process is simple, the cost is low, and the operation is safe.

The invention relates to the field of catalysts, and provides a preparation method of a palladium carbon catalyst for brivaracetam intermediate synthesis, and the preparation method comprises the following steps: dispersing pretreated active carbon in an impregnation liquid I, stirring for 8-16 hours, filtering, washing, and roasting to obtain a catalyst precursor I; the impregnation liquid I is a palladium salt acetone solution with palladium ion concentration of 4-8wt%; dispersing the catalyst precursor I in the steeping liquor II, stirring at normal temperature for 1-5 hours, filtering, washing and roasting to obtain a catalyst precursor II; the impregnation liquid II is a mixture of a fumaric acid-acrylic acid copolymer and a palladium salt aqueous solution with the palladium ion concentration of 10-20wt%; and reducing the catalyst precursor II to obtain the palladium carbon catalyst. The first impregnation adopts a low-concentration palladium salt acetone solution for long-time impregnation; the second-time impregnation adopts a high-concentration palladium salt aqueous solution and a fumaric acid-acrylic acid copolymer for normal-temperature short-time impregnation; the obtained palladium-carbon catalyst has high activity and good stability when being used for brivaracetam intermediate synthesis.

The invention discloses a brivaracetam intermediate and a preparation method thereof, and belongs to the field of pharmacy. The preparation method has the advantages of mild reaction, simple operation, low cost, high yield, high purity, short reaction route, easily available raw materials and excellent technical effect.

The present invention relates to a dual-release tri-layer tablet for brivaracetam, which is composed of three layers: an immediate-release layer, a barrier layer, and a sustained-release layer, wherein the barrier layer is drug-free and located in the center, and at least 75% of the area of ​​each of the immediate-release layer and sustained-release layer is covered by the barrier layer, and the sustained-release material in the barrier layer comprises a wax-like sustained-release material. The tablet has the following properties: after administration of the tablet, the drug substance dissolves at a rate of 25% or more within 30 minutes, 30-65% within 2 hours, 65% or more within 6 hours, and 80% or more but less than 100% within 14 hours, when measured by the paddle method at a rotation speed of 50 rpm in test solutions of pH 1.2, pH 4.5, pH 6.8, or water; and the tablet also shows zero-order release 30 minutes after administration, thereby significantly improving the release profile of the drug brivaracetam, enhancing compliance and safety, and optimizing the therapeutic effect of the drug. The present invention also relates to a dual-release tri-layer tablet for brivaracetam, and a method for preparing the same, which belong to the pharmaceutical technology.

The present application discloses a method for preparing a brivaracetam solution and the brivaracetam solution thereof, belonging to the field of medical technology. The method for preparing the brivaracetam solution comprises the following steps: (1) preparing solution 1: mixing a mixture including sodium carboxymethylcellulose and glycerol with purified water and stirring to obtain solution 1; (2) preparing solution 2: mixing purified water, methylparaben, sodium malate, malic acid, sucralose, crystalline sorbitol solution, brivaracetam, and glycerol and stirring to obtain an intermediate solution, mixing the intermediate solution with essence and stirring to obtain solution 2; (3) mixing solution 1, solution 2 and purified water, stirring, and filtering to obtain a brivaracetam solution. The method improves the clarity of the solution by controlling the order and temperature of addition of each auxiliary material, and the obtained brivaracetam solution has good stability and is free of precipitation and degradation impurities.

Disclosed is a method for enzymatic synthesis of a brivaracetam chiral intermediate, i.e., a method for synthesizing a brivaracetam chiral intermediate (R)-3-cyanohexanoic acid by catalyzing the hydrolysis of 3-cyanohexanitile using an enzyme with nitile hydrolysis activity, and the enzyme with nitrile hydrolysis activity is obtained by carrying out a single mutation or a double mutation on an amino acid at position 140 or an amino acid at position 175 in an amino acid sequence as set forth in SEQ ID NO.2. Compared with a wild type, the nitrilase mutant of the present invention has the activity increased by 10 times, an ee value increased to 300 or more from 39, a substrate conversion rate of 45%, and a product ee which can reach 98.5%, and the yield of (R)-3-aminomethyl-hexanoic acid by catalytic hydrogenation synthesis using (R)-3-cyanohexanoic acid reaches 85% or more. The present invention features a short synthesis route, mild reaction conditions, and high atom economy, and can be applied to the industrial synthesis of the brivaracetam intermediate.

The invention relates to the field of drug synthesis, and provides a brivaracetam intermediate preparation method, which comprises: carrying out catalytic hydrogenation on a raw material (R)-2-oxo-4-(propyl-1-alkenyl) pyrrolidine-3-carboxylate to obtain an intermediate product (R)-2-oxo-4-propyl pyrrolidine-3-carboxylate, and carrying out decarboxylation to obtain a product (R)-4-propyl pyrrolidine-2-ketone; the catalytic hydrogenation catalyst is obtained by impregnating active carbon with a palladium salt solution twice, the palladium concentration is higher and the impregnation time is shorter in comparison with the post-impregnation and the pre-impregnation, and the impregnation liquid of the post-impregnation also contains a fumaric acid-acrylic acid-vinyl chloride copolymer; the pressure of catalytic hydrogenation is divided into two stages, the pressure of the first stage is 0.1-0.3 Mpa, and the pressure of the second stage is 0.6-1 Mpa. According to the present invention, with the catalytic hydrogenation catalyst, the yield of the (R)-2-oxo-4-propyl pyrrolidine-3-carboxylic ester is increased, and the preparation of the brivaracetam intermediate (R)-4-propyl pyrrolidine-2-ketone is easily achieved.

The present disclosure relates to a preparation method of brivaracetam or a pharmaceutically acceptable salt thereof, which has short reaction time, good yield and high purity, and is suitable for industrial production.

The present invention provides a scalable synthesis of enantiomerically pure brivaracetam, and related derivatives.

The key intermediate of brivaracetam was synthesized by the ruthenium-catalyzed asymmetric hydrogenation of unsaturated cyclobutanone esters, which features high yield, high ee value, mild reaction conditions, low catalyst dosage, and can be scaled up to gram scale, showing great potential application value.

A brivaracetam pharmaceutical composition contains an active pharmaceutical ingredient, a matrix forming agent, and a swelling agent. It has a sustained release effect and has a more flat release curve compared with a common gel skeleton sustained-release preparation, and thus achieves the purposes of reducing the release rate of the medicament, controlling the in vivo effective dosage of the medicament, stabilizing the blood concentration, reducing toxic and side effects and reducing the times of daily administration.

The present disclosure relates to transdermal drug delivery compositions for delivering brivaracetam, and uses, processes, methods of preparation and delivery thereof. The present disclosure also relates to iontophoresis drug delivery devices and systems, and methods of treatment comprising such compositions.

The present application relates to a kind of high stability's bexontan solution, with 0.1-10% bexontan, 20-50% high molecular material and buffer solution in bexontan solution with mass volume percentage, wherein, the high molecular material is selected from any one or combination of polymethyl methacrylate, cyclodextrin, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, the buffer solution is selected from any one of citric acid buffer solution, phosphate buffer solution, malic acid buffer solution, succinic acid buffer solution, tartaric acid buffer solution, lactic acid buffer solution, acetic acid buffer solution, bexontan solution pH4-7.5.The bexontan solution of the present application significantly delays the diffusion of drug bitter taste in oral cavity and realizes taste masking, and has excellent stability, more optimal cost, quality controllable, good taste and the like advantages.

The present invention relates to an oral solution composition comprising brivaracetam and at least one sweetening agent is sodium cyclamate, acesulfame potassium or mixtures thereof. Furthermore, the oral solution composition is also obtained by using an effective process which is simple, rapid, cost effective, time-saving and industrially convenient process.

The present invention relates to an oral solution comprising brivaracetam and at least one pharmaceutically acceptable excipient wherein at least one cellulose derivative excipient is present. Furthermore, the oral solution is also obtained by using an effective process which is simple, rapid, cost effective, time-saving and industrially convenient process.

The present application provides a polymer of a compound shown in formula I, or a copolymer of the compound shown in formula I as a monomer and a monomer containing a carbon-carbon double bond as an adhesive of a gel patch adhesive ointment layer. The gel patch adhesive ointment prepared by the present application has excellent adhesion, good compatibility with the active drug brivaracetam, and good drug release behavior, and has a wide application prospect.

The invention discloses a liquid chromatographic analysis method for isomer impurities in a briracetam intermediate, which comprises the following steps: step 1, mixing a briracetam intermediate (compound 1) sample with a diluent to prepare a sample solution; and 2, detecting the sample solution by using high performance liquid chromatography so as to determine the content of isomer impurities in the sample of the compound 1. According to the method, normal-phase high-performance liquid chromatography is adopted, and normal hexane and isopropanol are used as mobile phases, so that the elution strength is improved, and the separation capacity is improved. By adopting gradient elution, the separation capacity is improved, the peak shape is improved, and the sensitivity is increased.

The invention discloses an imine reductase which is derived from Jianggellauris, Streptomyces aureococcus, Streptomyces alboflavus, Sandaracinus amylolyticus, Phyllobacterium SYSU D60010, Mesorhizobium, Labitorixococcus or a metagenome, the imine reductase is used as a biocatalyst for preparing the anti-epileptic drug brivaracetam and a diastereoisomer of the brivaracetam, the problems that an existing industrial synthesis route is poor in environmental protection property, low in atom utilization rate, long in route and the like are solved, and the imine reductase has a wide application prospect.

To provide therapeutic approaches for treating epileptogenesis associated with a brain insult, e.g., traumatic brain injury (TBI), stroke, or brain infection.SOLUTION: Provided are liquid pharmaceutical compositions including topiramate or a pharmaceutically acceptable salt thereof, meglumine, and a pharmaceutically acceptable excipient, the liquid pharmaceutical compositions optionally further including, e.g., levetiracetam or brivaracetam and / or atorvastatin or a pharmaceutically acceptable salt thereof (e.g., atorvastatin sodium).SELECTED DRAWING: Figure 1

The invention discloses a briracetam orally disintegrating tablet and a preparation method thereof, and belongs to the technical field of biological medicines. The briracetam orally disintegrating tablet is prepared from the following components in parts by mass: 10 to 50 parts of a briracetam cyclodextrin inclusion compound, 10 to 87 parts of a filling agent, 1 to 20 parts of a disintegrating agent, 1 to 10 parts of a lubricating agent and 1 to 10 parts of a flavoring agent. According to the preparation method disclosed by the invention, the defect of poor flowability of the briracetam is effectively improved by a process of firstly preparing the cyclodextrin inclusion compound of the briracetam and then pressing the inclusion compound into the tablet; performance inspection on the tablets shows that the tablets have the characteristic of rapid disintegration accidentally, and the stability is remarkably improved.

The present invention relates to a telescoping process for the preparation of brivaracetam. The process according to the present invention is a cost effective process in that it avoids isolation of intermediates at every step (Formula (I)).

The present invention relates to a film coated tablet comprising brivaracetam at least one pharmaceutically acceptable excipient wherein brivaracetam has a d (0.9) particle size between 100 µm to 300 µm and the amount of disintegrant is 2.0% to 7.0% by weight in the total composition. Furthermore, the tablet is also obtained by using an effective process which is simple, rapid, cost effective, time-saving and industrially convenient process.