34 results about "Sacubitril" patented technology

The application relates to application of a transaminase mutant in synthesis of a key chiral intermediate D-4,4'-diphenylalanine of sacubitril valsartan sodium salt (LCZ696), and belongs to the technical field of biocatalytic synthesis.The mutant is a quadruple mutant of the amino acid sequence shown in SEQ ID NO:1, the amino acid sequence of the transaminase mutant is shown in SEQ ID NO:3, and the corresponding amino acid sequence is shown in SEQ ID NO:4.Compared with a wild-type transaminase parent, the unit enzyme activity is increased by about 30 times under the condition of ensuring the chiral purity of a product, the transaminase has very high stereoselectivity and conversion rate, the industrial production cost of sacubitril and LCZ696 can be further reduced, and the transaminase has good industrial application value.

The invention belongs to the field of drug synthesis, and particularly relates to a method for preparing a sacubitril intermediate, which is characterized in that an intermediate compound 3 and an organic ammonium salt are used as raw materials and react in the presence of an iridium catalyst and a ligand to generate the sacubitril intermediate. According to the method, the yield and the chiral purity are high, the e.e value is as high as 99.7%, the reaction conditions are mild, and dangerous raw materials such as hydrogen and sodium borohydride are avoided.

The invention provides a preparation method of a sacubitril valsartan key intermediate, which comprises the following steps of: reacting (R)-1-(1-([1, 1 '-biphenyl]-4-yl)-3-chloropropane-2-yl) pyrrolidine-2, 5-diketone and trialkyl phosphite under the action of a catalyst to generate a Witting-Horner reagent, then reacting with ethyl pyruvate under an alkaline condition to generate a double-bond product, and reacting with ethyl pyruvate under an alkaline condition to generate the sacubitril valsartan key intermediate. Hydrolyzing the double bond product to generate (R, E)-5-((1, 1 '-biphenyl)-4-yl)-4-amino-2-methyl-2-ethyl pentenoate; the preparation method comprises the following steps: firstly, taking 4-methyl-2-pentenoic acid as a raw material, then protecting the 4-methyl-2-pentenoic acid through BOC anhydride under the action of an acid-binding agent, and finally hydrolyzing under an alkaline condition to obtain (R, E)-5-([1, 1 '-biphenyl]-4-yl)-4-((t-butyloxycarboryl) amino)-2-methyl-2-pentenoic acid. The preparation method has the advantages of simple process steps, convenient operation, easily available raw materials, and easy industrial production.

A sacubitril intermediate, a preparation method therefor, and use thereof. A key intermediate N-Boc amino alcohol represented by formula (10) or formula (10-a) can be efficiently prepared. The intermediate can be used to prepare a neutral endopeptidase (NEP) inhibitor or a prodrug thereof, particularly a NEP inhibitor comprising a skeleton of γ-amino-δ-biphenyl-α-methylalkanoic acid or ester, such as sacubitril. Also provided are intermediates for preparing formula (10) or formula (10-a). Raw materials of the process route are cheap, the operation is simple and convenient, the production cost is low, and the method is suitable for industrial production

The invention discloses a pharmaceutical composition containing propranolol and a neutral endo-peptidase inhibitor, the pharmaceutical composition comprises propranolol and a neutral endo-peptidase inhibitor, and the propranolol and the neutral endo-peptidase inhibitor are combined and connected through a non-covalent bond. According to the invention, sacubitril and propranolol are combined into a dual-effect salt, so that the two active pharmaceutical ingredients are synchronously released, the drug effect is favorably improved, the synergistic effect is favorably generated in the treatment process, the side effect of propranolol is effectively reduced, and the clinical use values of sacubitril and propranolol are potentially improved; on the premise of ensuring the antihypertensive effect, the occurrence probability of side effects is effectively reduced, and the medication safety is improved.

The present disclosure relates to co-crystals of sacubitril (or a salt of sacubitril, in particular an alkaline earth metal salt or alkali metal salt) and melsartan (or a salt of melsartan, in particular an alkaline earth metal salt or alkali metal salt) and methods of preparation thereof, pharmaceutical compositions containing the co-crystals and uses of the co-crystals, in particular for the treatment of cardiovascular system diseases.

The present invention relates to methods and pharmaceutical compositions for treating heart failure in a pediatric human patient comprising administration to said patient of a therapeutically effective amount or a prophylactically effective amount of a combination of a therapeutic agent blocking the angiotensin receptor and a therapeutic agent inhibiting the NEP enzyme, in particular of a combination of sacubitril and valsartan in a pharmaceutically acceptable form and in a 1:1 molar ratio.

The application discloses a chiral ligand S , S p t A practical synthesis method of Bu-FOXAP is disclosed. By improving the synthesis process in the literature, the production operation is more simple. Compared with the column chromatography purification method used in each step in the literature, the new process does not need column chromatography purification, the product can be purified by beating or recrystallization, the purity of the final product can reach more than 97.0 %, the ee value is greater than 99.0 %, the d.r. value is greater than 20:1, the purification is simple and the cost is greatly reduced. The chiral ligand prepared by the new process can be used as a catalyst for asymmetric hydrogenation reaction after in-situ complexing with ruthenium metal, and can be used for catalytic synthesis of a key intermediate of a best-selling drug, sacubitril / valsartan.​

This invention provides a method for preparing a sacubitril intermediate, relating to the field of pharmaceutical synthesis technology. Using (2R)-4-nitro-2-methyl-butyrate ethyl ester and 4-bromomethylbiphenyl as initial raw materials, the method involves condensation reaction, hydrogenation reduction reaction, acidification, amino protection reaction with BOC anhydride, hydrolysis, salt formation and resolution reaction with R(+)-α-methylbenzylamine, and acidification to liberate the sacubitril intermediate. The preparation method provided by this invention is simple, easy to operate, has a high yield of the target product (36.5% overall yield in Example 1), high purity, low raw material cost, low production cost, and generates minimal waste, making it suitable for industrial production.

The invention relates to a preparation method of sacubitril, which comprises the following steps: (1) reacting (S)-1-([1, 1 '-biphenyl]-4-yl)-3-chloropropane-2-ol with succinimide under the condition of triphenylphosphine and DEAD (Diethylaminoethyl Adenine) to obtain (R)-1-(1-([1, 1'-biphenyl]-4-yl)-3-chloropropane-2-yl) pyrrolidine-2, 5-diketone; (2) adding water and an alkaline reagent into the product in the step (1) to obtain (R)-4-(([1, 1 '-biphenyl]-4-yl)-3-hydroxypropyl-2-yl)-amino-4-oxobutyric acid; (3) carrying out oxidation and wittig reaction on the product obtained in the step (2) to prepare (4R)-5-[1, 1 '-biphenyl]-4-yl-4-[(3-carboxyl-1-oxopropyl) amino]-2-methyl-2-pentenoic acid-1-ethyl ester; (4) performing palladium-carbon catalytic reaction on the product obtained in the step (3) for alkali adjustment to prepare a sacubitril sodium salt aqueous solution; and (5) performing free extraction on the sacubitril sodium salt, concentrating, adding acetone and isopropanol to prepare a mixed solution, and reacting with valsartan and sodium hydroxide to prepare the sacubitril valsartan sodium. The method is simple and convenient to operate, can obtain the product with high purity and high yield, and is suitable for industrial production.

The invention discloses a detection method of sacubitril valsartan sodium tablet isomer impurities, and belongs to the technical field of pharmaceutical analysis. According to the method, sacubitril enantiomer and diastereoisomer impurities and valsartan optical isomer impurities in sacubitril and valsartan sodium tablets are detected by adopting HPLC (High Performance Liquid Chromatography), and under chromatographic conditions, a chromatographic column is a polysaccharide derivative reverse-phase coating type chiral chromatographic column, and the surface of silica gel is coated with cellulose-tri (4-methyl benzoate); a mobile phase is composed of a mobile phase A and a mobile phase B, the mobile phase A comprises water, acetonitrile and trifluoroacetic acid, and the volume ratio of the water to the acetonitrile to the trifluoroacetic acid is (790-810): (190-210): (0.9-1.1); a mobile phase B: methanol-acetonitrile, wherein the volume ratio of methanol to acetonitrile is (500-600): (500-400); a gradient elution mode is adopted. The method uses a reversed-phase system, is simple and convenient to operate, and can effectively realize separation and detection of sacubitril, valsartan and various isomer impurities, thereby realizing the purpose of controlling the quality of sacubitril and valsartan sodium tablets.

The invention discloses a Sacubitril-based compound as well as a pharmaceutically acceptable salt, an ester, a solvate, a pharmaceutical composition and a preparation method of the Sacubitril-based compound and the pharmaceutically acceptable salt, the ester, the solvate, the pharmaceutical composition and the preparation method of the Sacubitril-based compound. The sacubitril-based compound is a monoester compound or a monoamide compound, which can be obtained by reacting sacubitril with panoxadiol or 1, 3-diaminoadamantane. The pharmaceutically acceptable salts, esters, solvates, and pharmaceutical compositions include a sacubitril-based compound. All the components can be used for treating cardiovascular diseases including heart failure and hyperlipidemia.

The present invention relates to a pharmaceutical compound formulation that contains sacubitril-valsartan and an SGLT-2 inhibitor as active ingredients, thereby having a synergistic effect in the treatment of heart failure, while minimizing the effects of drug dissolution between each drug to ensure bioequivalence, suppressing the generation of related substances, and exhibiting excellent stability of the active ingredients.

The application provides a saccubatr sodium spherical crystal and a preparation method thereof. The saccubatr sodium spherical crystal has excellent fluidity and filterability, and has no obvious solvent residue. The saccubatr sodium spherical crystal has uniform particle size distribution, is beneficial to improving product quality, is suitable for being made into various preparations, and has a simple and easy preparation process and is suitable for industrialized production.

This invention discloses a compound tablet containing sacubitril / valsartan and rosuvastatin calcium, and its preparation method, belonging to the field of pharmaceutical preparation technology. The technical solution comprises: an active ingredient and pharmaceutical excipients; the active ingredient includes sacubitril / valsartan sodium and rosuvastatin calcium; the pharmaceutical excipients include fillers, binders, disintegrants, stabilizers, glidants, lubricants, and a gastrointestinal film-coating premix; the tablets are prepared using a dry granulation process. This invention solves the problems of poor adherence to single-drug use, asynchronous dissolution, and insufficient stability, achieving a synergistic effect of lowering blood pressure and lipids. Furthermore, the preparation process is simple, efficient, and suitable for industrial production.

The application provides a refining method of a sacubitril valsartan sodium intermediate, and relates to the field of drug intermediate synthesis. The sacubitril valsartan sodium intermediate compound is (2R, 4S)-4-amino-5-(diphenyl-4-yl)-2-methylvalerate ethyl ester hydrochloride. The application also relates to a control method of specific impurities in the refining process of the compound, which comprises the following steps: mixing the sacubitril valsartan sodium intermediate crude product with ethyl acetate or isopropyl acetate, then heating to a reflux state, keeping the reflux state for 1-2 hours, and then performing slow cooling, pressure filtration, vacuum drying and other process procedures to obtain the sacubitril valsartan sodium intermediate (2R, 4S)-4-amino-5-(diphenyl-4-yl)-2-methylvalerate ethyl ester hydrochloride. The sacubitril valsartan sodium intermediate obtained by the refining method has high purity, no solvent residue, mild reaction conditions and is easy to be industrialized.

The application provides a preparation method of a sacubitril intermediate compound III, which comprises the following steps: performing ring opening reaction on a compound of formula IV and a compound of formula V under the action of CuX, and the reaction formula is shown in the following formula: wherein X and X1 are independently selected from Cl, Br and I; the chiral 2-methyl pentanoic acid group is directly introduced into the chiral raw material compound of formula IV, the reaction route is short, time is saved, the purity of the chiral isomer is improved, and the post-treatment operation is simple; and the method has obvious technical advantages compared with the prior art.

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 present invention relates to novel pharmaceutical compositions for the treatment of heart failure in a patient.

The present application relates to a kind of preparation methods of sacubitril valsartan sodium, comprising: (1) the toluene suspension of (2R, 4S) 5- ([1, 1 '-biphenyl] 4-yl) 4-amino-2-methyl pentanoic acid ethyl ester hydrochloride is reacted with succinic anhydride to obtain sacubitril crude product, then acid-base is adjusted to obtain sacubitril free acid, and form sacubitril free acid acetone solution;(2) the sacubitril free acid obtained in (1) is reacted with valsartan, sodium hydroxide in the mixed solution of acetone and isopropyl alcohol, to obtain sacubitril valsartan sodium;Wherein, the acid-base adjustment in step (1) includes sequentially using citric acid aqueous solution to adjust acid, using sodium hydroxide aqueous solution to adjust alkali, using hydrochloric acid to adjust acid;The sodium hydroxide in step (2) is added in the form of sodium hydroxide aqueous solution, and the sodium hydroxide in the sodium hydroxide aqueous solution is 0.05-0.2 mol / mL in molar concentration, can obtain product with high purity and high yield, suitable for industrial production.

This invention relates to a sacubitril / valsartan sodium tablet composition and its preparation method, belonging to the field of pharmaceutical formulation technology. The technical solution of this invention is: a tablet composition containing sacubitril / valsartan sodium, comprising 50 parts of sacubitril / valsartan sodium, 4-16 parts of chitosan, 30-45 parts of microcrystalline cellulose, 3-8 parts of croscarmellose sodium, and 0.7-2 parts of magnesium stearate. This invention provides a stable sacubitril / valsartan sodium tablet and its preparation method. The tablets obtained by the preparation method have advantages such as rapid dissolution, smooth surface, and good stability, solving the sticking and punching problem in the preparation process of sacubitril / valsartan sodium tablets, and are suitable for large-scale industrial production.

The invention provides a sacubitril-valsartan sodium indapamide sustained-release tablet and a preparation method thereof, the sacubitril-valsartan sodium indapamide sustained-release tablet is of a double-layer tablet structure and comprises a first indapamide sustained-release layer and a second sacubitril-valsartan sodium quick-release layer, and the sacubitril-valsartan sodium indapamide sustained-release tablet can be prepared by adjusting the type and dosage of sustained-release materials in the indapamide sustained-release layer. According to the type and dosage of the disintegrating agent and the dosage of the adhesive in the sacubitril valsartan sodium quick release layer, the process of the double-layer tablet is stable, the release behavior of the double-layer tablet is similar to that of a single preparation, and the consistency of the curative effect of the medicine is ensured.

The present invention discloses high-purity oral solid dosage forms comprising sacubitril, valsartan, its complex or pharmaceutically acceptable salts thereof, and an SGLT-2 inhibitor or pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable excipients, wherein the active ingredients are in a single-compartment form, without physical separation between them, distributed uniformly and homogeneously.

The invention discloses a sacubitril intermediate synthetic transaminase mutant with high conversion rate and application thereof, and belongs to the technical field of enzyme engineering. Transaminase from aspergillus terreus is used as a starting sequence, mutation sites are screened through a novel enzyme modification technology, a series of mutants capable of improving amino transfer and sacubitril intermediate synthesis are found, heterologous expression verification is carried out after the mutants are introduced into genetic engineering escherichia coli, and the mutants can be used for improving the amino transfer and the sacubitril intermediate synthesis. Compared with a wild enzyme before mutation, when the obtained mutant enzyme is used as a catalyst to prepare a sacubitril intermediate, the substrate conversion rate is at least improved by 416.67%, the product generation rate is at least improved by 500%, and the mutant enzyme has very wide application prospects in industrial production.

The present invention comprises sacubitril or pharmaceutically acceptable salts thereof in crystalline form, valsartan or pharmaceutically acceptable salts thereof in amorphous form and a disintegrant, wherein the disintegrant is comprised only in the internal phase.

This invention belongs to the field of pharmaceutical synthesis, specifically relating to a method for preparing sacubitril intermediates. The method uses intermediate compound 3 and an organic ammonium salt as raw materials, reacting them in the presence of an iridium catalyst and ligand to generate the sacubitril intermediate. This invention achieves high yield and chiral purity, with an ee value as high as 99.7%, and utilizes mild reaction conditions, avoiding the use of hazardous raw materials such as hydrogen and sodium borohydride.

The invention provides a sacubitril sodium spherical crystal and a preparation method thereof, the sacubitril sodium spherical crystal has excellent flowability and filterability, and has no obvious solvent residue; and the spherical crystal of sacubitril sodium has uniform particle size distribution, is beneficial to improving the product quality, is suitable for being prepared into various preparations, is simple and feasible in preparation process and is suitable for industrial production.

The utility model discloses a tablet press for sacubitril valsartan sodium tablet production, and relates to the technical field of tablet presses, the tablet press comprises a box body and a mounting bin fixed at the top of the box body and communicated with the box body, two symmetrically arranged cranks are rotatably connected in the mounting bin, a movable rod located in the box body is rotatably connected between the two cranks, and the movable rod is located in the box body. An inclined rod is rotationally connected to the bottom of the movable rod, the two ends of the inclined rod are meshed with an adjusting rod and a stamping rod respectively, an upper die is fixed to the bottom of the stamping rod, a gear is meshed with the side, away from the inclined rod, of the stamping rod, and a fixed rack fixed in the box body is meshed with the other side of the gear; and the top of the adjusting rod is rotationally connected with a screw rod. The height of the adjusting rod in the vertical direction is adjusted by rotating the screw rod, the swing amplitude of the movable rod and the inclined rod is adjusted, the moving amplitude of the stamping rod and the upper die at the bottom of the stamping rod in the vertical direction is adjusted, and the tabletting thickness of sacubitril valsartan sodium tablets is adjusted.

The present invention relates to a pharmaceutical combination preparation which has a synergistic effect in the treatment of heart failure by including sacubitril-valsartan and an SGLT-2 inhibitor together as active ingredients, while ensuring bioequivalence between drugs because the influence of one drug on the elution of another drug is minimized. In addition, the generation of impurities in the pharmaceutical combination preparation is inhibited, and thus the stability of the active ingredient is also very excellent.

The present disclosure relates to co-crystals of sacubitril (or a salt of sacubitril, in particular an alkaline earth metal salt or alkali metal salt) and azilsartan (or a salt of azilsartan, in particular an alkaline earth metal salt or alkali metal salt) and methods of preparation thereof, pharmaceutical compositions containing the co-crystals and uses of the co-crystals, in particular for the treatment of cardiovascular system diseases.