84 results about "Cinacalcet Hydrochloride" patented technology

Processes for preparing cinacalcet are provided.

The invention discloses an oral solid rapid release preparation of cinacalcet hydrochloride. The oral solid rapid release preparation comprises cinacalcet hydrochloride and medicinal auxiliary materials, wherein the average particle diameter of cinacalcet hydrochloride is 5-15 mum; the cinacalcet hydrochloride is needlelike crystalized fine particles; the medicinal auxiliary materials include a filling agent, a bonding agent, a disintegrating agent and a lubricating agent; and the preparation is in the form of a tablet. The oral solid rapid release preparation has the beneficial effects that: the average particle diameter of cinacalcet hydrochloride is defined, so that the dissolution rate and dissolution amount of cinacalcet are increased, a preparation process is simple and safe, the quality is controllable, and cost is low; and the oral solid rapid release preparation is suitable for industrial production.

The invention discloses a process for preparing Cinacalcet hydrochloride tablets or capsules and belongs to the technical field of medicinal preparations. The preparation process comprises performing dry-process granulation according to one formula; and tabletting or filling capsules by using three dosages according to a ratio. The in-vitro release of the Cinacalcet hydrochloride is characterized in that: 40 to 80 percent of Cinacalcet hydrochloride is released within 5 to 10 minutes; 80 to 90 percent of the Cinacalcet hydrochloride is released within 15 to 20 minutes; and 90 to 100 percent of Cinacalcet hydrochloride is released within 30 to 45 minutes. In the process, the procedures are simple and safety, the quality is controllable, the cost is low, and the production period is short. The process is suitable for large-scale industrial production.

Provided is amorphous cinacalcet hydrochloride, processes for the preparation thereof, and pharmaceutical compositions therewith.

The invention discloses a novel preparation method of cinacalcet hydrochloride, belonging to the technical filed of preparation of cinacalcet hydrochloride and comprising the steps of: firstly, with 1-acetonaphthone (II) as a raw material, introducing a chiral reagent, and reducing with sodium borohydride to obtain a compound (III); secondly, dissolving the compound (III) into a proper solvent, and reacting with 3-propiolic halide to obtain a compound (IV); thirdly, adding a proper catalyst into the obtained compound (IV) in a solvent at a certain temperature, and carrying out a coupling reaction with meta-chlorobenzotrifluoride to generate a compound (V); and fourthly, reducing the obtained compound (V) with a proper reducing agent and acidizing with hydrochloric acid to obtain the cinacalcet hydrochloride (I). The cinacalcet hydrochloride is synthesized chirally, and has the advantages of special reaction course, good selectivity, high yield, less reaction steps, safe and simple operation and little environment pollution. The raw material used in the reaction course is easy to obtain, has lower production cost and high optical purity, and is suitable for industrialized production.

The invention provides a cinacalcet hydrochloride preparation method which comprises the following steps: (A) by taking trifluoromethylcinnamic acid as a raw material and palladium on carbon as a catalyst, performing hydrogenation reduction to obtain m-trifluoromethylbenzoic acid; (B) performing condensation reaction on the m-trifluoromethylbenzoic acid and R-(1) naphthylethylamine, thus obtaining (R)-N-(1-(naphthalen-1-yl)ethyl)-3-(trifluoromethyl)phenyl)propanamide; (C) performing catalytic reduction on the (R)-N-(1-(naphthalen-1-yl)ethyl)-3-(trifluoromethyl)phenyl)propanamide to obtain cinacalcet; and (D) reacting the cinacalcet and hydrochloric acid to obtain cinacalcet hydrochloride. The method has the advantages of thorough reaction, high yield, no pollution in the reaction process and the like.

The invention discloses a preparation method of cinacalcet hydrochloride as Formula (I) shown. The preparation method comprises the following steps: 3-(trifluoromethyl) cinnamic acid as shown in Formula (I) serving as a raw material has reduction reaction with sodium borohydride under the catalysis of bismuth trichloride so as to obtain 3-(3-trifluoromethyl benzene)-propionic acid as shown in Formula (III); 3-(3-trifluoromethyl benzene)-propionic acid directly has condensation reaction with R-1-naphthylethylamine (compound V) to obtain a compound (VI); and the compound (VI) has reduction reaction with sodium borohydride in the presence of tetrahydrofuran solution of iodine so as to obtain a hydrochloride used for preparing cinacalcet hydrochloride. Compared with conventional technique, the method disclosed by the invention is safe, environment-friendly, convenient to operate, low in cost, and high in yield of the product, and is suitable for industrial production; and the method has high practical production value.

The present invention discloses a cinacalcet hydrochloride preparation method, which comprises: 1, adopting 3-(trifluoromethyl) phenyl propionaldehyde and R-1-(1-naphthyl)ethylamine as raw materials, and carrying out a condensation reduction reaction in a mixing reaction solvent in the presence of sodium triacetoxyborohydride, 2, extracting the reaction product with water, a salt or an alkali aqueous solution to obtain a cinacalcet base organic phase solution, and 3, carrying out acidification salification on the obtained cinacalcet base organic phase solution with hydrochloric acid to obtain the cinacalcet hydrochloride, wherein one of components in the mixing reaction solvent is water. According to the present invention, the water-containing mixing solvent is adopted as the reaction medium, such that technical defects of solvent use during the sodium triacetoxyborohydride use process are overcome, the harsh condition that the reaction solvent requires a water-free treatment is avoided while reaction selectivity is increased, types of produced impurities and impurity content are substantially reduced, cost is reduced, and environment pollution is reduced.

Processes for preparing cinacalcet are provided.

The invention relates to cinacalcet hydrochloride, new polymorphic crystalline forms of cinacalcet hydrochloride, amorphous cinacalcet hydrochloride and synthetic processes for their preparation.

The invention relates to a cinacalcet hydrochloride containing pharmaceutical composition and a preparation method thereof. The composition contains cinacalcet hydrochloride, a specific surfactant, and other pharmaceutically acceptable excipients such as a filling agent, a disintegrating agent, an adhesive, and a lubricant. In a wet granulation film coating process adopted in the invention, by simplifying auxiliary materials in a preparation formulation, the safety of medication usage is improved, the production process is simplified, the production cycle is shortened, the production cost is reduced, prepared cinacalcet hydrochloride tablets are good in appearance, and the dissolution effect of the tablets is significantly improved.

The invention discloses an immediate release cinacalcet hydrochloride preparation and a preparation method thereof. The immediate release cinacalcet hydrochloride preparation comprises a tablet core and a coating material, wherein the tablet core is prepared from the following ingredients in percentage by weight: 10%-50% of cinacalcet hydrochloride, 27%-54% of pregelatinized starch, 13%-26% of microcrystalline celluloses, 1%-5% of polyvinylpyrrolidone, 1%-10% of crosslinked polyvinylpyrrolidone, 0.05%-2% of colloidal silicon dioxide and 0.05%-2% of magnesium stearate. The immediate release cinacalcet hydrochloride preparation disclosed by the invention is very good in dissolving-out speed, the dissolution rate of the preparation in 0.05mol / L hydrochloric acid is measured at the temperature of 37 DEG C by adopting a USP2 (united states pharmacopoeia) device, and over 85% of the dissolution rate can be achieved at rotation speeds of 75rpm and 50rpm only within 15min, therefore, the preparation can be suitable for patients with weak gastric motility such as children, middle and aged men and the like, and the population taking the preparation of the product is enlarged.

The invention relates to a preparation method of high-purity cinacalcet hydrochloride. The method comprises the following steps: using R(+)-1-naphthylethanamine and (3-(3-trifluoromethyl) phenyl)-1-bromopropane as starting materials, taking acetonitrile as a solvent, reacting under the action of alkali to get cinacalcet, acidifying a reaction solution in water with hydrochloric acid to get a cinacalcet hydrochloride crude product, and recrystallizing the crude product with ethyl acetate to get the high-purity cinacalcet hydrochloride. The method is simple to operate and suitable for industrialization.

The invention relates to cinacalcet hydrochloride, new polymorphic crystalline forms of cinacalcet hydrochloride, amorphous cinacalcet hydrochloride and synthetic processes for their preparation.

The invention provides processes for the preparation of cinacalcet hydrochloride crystalline Form I.

The invention provides a synthetic method of cinacalcet hydrochloride intermediate compound meta-trifluoro methyl phenylpropyl bromine and cinacalcet hydrochloride. According to the synthetic method, synthetic technology of intermediate compound meta-trifluoro methyl phenylpropyl bromine is optimized, so that yield and purity of meta-trifluoro methyl phenylpropyl bromine and cinacalcet hydrochloride are improved significantly, product quality is ensured, raw material utilization ratio is increased, and product cost is reduced effectively.

The invention discloses a preparation technology of a Cinacalcet hydrochloride solid dispersion tablet, and belongs to the technical field of preparation of medicinal preparations. The technology is characterized in that the Cinacalcet hydrochloride solid dispersion tablet is prepared through a solid dispersion process and a powder direct tabletting process. The in vitro dissolution rate of Cinacalcet hydrochloride is characterized by 40-80% at 5-10min, 80-90% at 15-20min and 90-100% at 30-45min. The technology has the advantages of simple process, safety, controllable quality, low cost, short production cycle, and suitableness for large-scale industrial production.

The invention discloses a preparation method of m-trifluoromethyl phenylpropionic acid, which is prepared through catalytic hydrogenation of m-trifluoromethyl cinnamic acid. The catalytic hydrogenation is carried out in the presence of a strong-alkali and weak-acid salt, molar ratio of the strong-alkali and weak-acid salt to the m-trifluoromethyl cinnamic acid being 0.2:1-0.9:1. The strong-alkaliand weak-acid salt preferably is Na2CO3 or K2CO3. In the catalytic hydrogenation of m-trifluoromethyl cinnamic acid, the Na2CO3 or K2CO3 is added according to certain molar ratio, so that generation of benzene ring reduction impurities A, B and C and defluorination impurity D is prevented effectively at the same time, thereby producing the m-trifluoromethyl phenylpropionic acid at high purity, further synthesizing high-purity cinacalcet hydrochloride.

The invention provides a cinacalcet hydrochloride film-coated tablet composition and a preparation method thereof. The cinacalcet hydrochloride film-coated tablet comprises cinacalcet hydrochloride, polacrilin potassium, microcrystalline cellulose, silicon dioxide, magnesium stearate and a film coating. The cinacalcet hydrochloride film-coated tablet has the advantages of simple process, low cost and good digestion.

The invention discloses a synthesis method of cinacalcet hydrochloride and an intermediate thereof. The cinacalcet hydrochloride is prepared by carrying out asymmetric reduction ammonification on 3-(3-(trifluoromethyl)phenyl)propyl-1-amine and 1-(naphthyl-1-yl)ethyl ketone. The asymmetric reduction ammonification is performed by carrying out asymmetric induction by combining a Hantzsch ester and a chiral phosphine ligand. The 3-(3-(trifluoromethyl)phenyl)propyl-1-amine is prepared by the following steps: carrying out Heck coupling reaction on 3-bromo-1-trifluoromethyl benzene and acrylonitrile to obtain 3-(3-(trifluoromethyl)phenyl)acrylonitrile, and carrying out catalytic hydrogenation. The catalyst of the Heck coupling reaction is tetra(triphenylphosphine) palladium, DBA palladium or palladium acetate. The method for synthesizing cinacalcet hydrochloride greatly lowers the production cost, and is suitable for industrialized mass production. The method for synthesizing the 3-(3-(trifluoromethyl)phenyl)propyl-1-amine greatly lowers the production cost, and has higher yield.

The invention discloses a method for synthesizing calcimimetics hydrochloride intermediates by a micro passage reactor, and belongs to the field of medicine synthesis in organic synthesis. According to the method, p-trifluoromethylcinnamic acid is added into an organic solvent; then, active carbon loaded noble metal catalysts are added; an obtained mixture is used as a first material; the first material is conveyed to a preheating module of the micro passage reactor to be heated; after being preheated, the material enters a reaction module group; hydrogen gas is conveyed to a reaction module group of the micro passage reactor to react with the preheated first material in the step (1) for reaction; reaction liquid flowing out from a temperature lowering module is collected; post treatment is performed to obtain calcimimetics hydrochloride intermediates 3-(3-trifluoromethyl phenyl)propionate. The synthesis method provided by the invention has the advantages that the reaction time can beeffectively shortened; the potential safety hazards of hydrogen leakage combustion blasting is greatly reduced; the method is applicable to the process of synthesizing the calcimimetics hydrochlorideintermediates.

The invention relates to a method used for detecting cinacalcet hydrochloride isomerides via HPLC method, and belongs to the technical field of medicine. According to the method, HPLC method is adopted for detection of cinacalcet hydrochloride isomerides, and chromatographic conditions are defined as following: the adopted chromatographic column is Phenomenex Lux 5<mu> Cellulose-3 column (250mm*4.6mm, 5<mu>m), the adopted mobile phase is acetonitrile and a 0.01mol / L buffered saline solution, flow velocity is controlled to be 0.8 to 1.2ml / min, column temperature is controlled to be 25 to 35 DEG C, detection wave length is controlled to be 222nm, sample amount is controlled to be 10<mu>L. High performance liquid chromatography is adopted to detect two isomerides of cinacalcet hydrochloride in a synthesis finished product, accurate control on the quality of cinacalcet hydrochloride is realized, and it is beneficial for optimizing of technology, and increasing of product quality and safety.

The invention discloses a cinacalcet hydrochloride solid dispersion and a preparation method thereof and a cinacalcet hydrochloride oral solid dosage form. The cinacalcet hydrochloride solid dispersion is prepared from cinacalcet hydrochloride and hydroxy propyl cellulose according to a hot-melt extrusion technology, wherein the weight ratio of cinacalcet hydrochloride to hydroxy propyl celluloseranges from 1:0.5 to 1:3. The preparation method comprises the following steps: uniformly mixing cinacalcet hydrochloride and hydroxy propyl cellulose based on the weight ratio; adding the mixture into a hot-melt extrusion machine for thermally melting and extruding; cooling and crushing the extruded materials to obtain the product. According to the preparation method, hydroxy propyl cellulose isused as a carrier; cinacalcet hydrochloride and hydroxy propyl cellulose are processed according to the hot-melt extrusion technology based on a certain weight ratio to prepare the solid dispersion; the solid dispersion is further processed into the solid form which is high in dissolution ratio in a neutral medium. The method is simple in process, convenient to operate, wide in raw material source, low in raw material price, and suitable for industrial mass production.

The invention discloses a method for preparing cinacalcet hydrochloride and belongs to the field of synthesis and preparation of chemical drugs. The method disclosed by the invention comprises the following steps: taking bromo-alpha,alpha,alpha-trifluorotoluene (II) and acryloyl chloride (III) as raw materials, and preparing m-trifluoromethyl acrylketone (IV) through a coupled reaction; carrying out an addition reaction between (IV) and (R)-1-(1-naphthyl) ethamine (V) so as to generate (R)-3-(1-(1-naphthyl)ethylamino)-1-(3-trifluoromethyl)phenyl)-1-acetone (VI); reducing (VI) to prepare N-((1R)-1-(1-naphthyl)ethyl)-3-(3-trifluoromethyl)phenyl)-1-propylamine (cinacalcet) (VII); carrying out a salt forming reaction on cinacalcet, thereby obtaining N-((1R)-1-(1-naphthyl)ethyl)-3-(3-trifluoromethyl)phenyl)-1-propylamine hydrochloride, namely the cinacalcet hydrochloride (I). According to the route, the cheap and readily available bromo-alpha,alpha,alpha-trifluorotoluene (II) and acryloyl chloride (III) are taken as the raw materials, a few steps are needed, usage of compounds of a heavy metal Pd and metal reducing agents LiAlH4, NaBH4 and the like is avoided, and the method is safe, environmentally friendly and economic and is suitable for large-scale industrial production.

The invention provides a method for synthesizing calcimimetic cinacalcet hydrochloride; the method comprises the steps of preparing methylsulfonyl-3-(3-trifluoromethylphenyl)propionate; preparing (R)-(+)-1-(1-naphthyl)ethyltribenzyllamine; preparing N-((1R)-1-(1-napthyl)ethyl)-3-(3-(trifluoromethyl)phenyl)propyl-1-tribenzylamine; preparing N-((1R)-1-(1-napthyl)ethyl)-3-(3-(trifluoromethyl)phenyl)propylamine hydrochloride. The synthetic route of the method has the advantages of low price and easy access of materials, good operational simplicity, high yield and the like.

The invention relates to an improved process for preparing cinacalcet hydrochloride. The invention provides an efficient and economic process for preparing cinacalcet hydrochloride which is suitable for industrial implementation i.e., affords cinacalcet hydrochloride with high purity, and uses small volumes of acidifying agent and solvents. The invention also related to a process for preparing a cinacalcet carboxylate salt, including cinacalcet acetate

The present invention relates to the polymorph form II of Cinacalcet hydrochloride, methods for the preparation of pure form II of Cinacalcet hydrochloride, and pharmaceutical compositions comprising the new polymorphic form in an pharmaceutically effective amount The present invention also provides novel solvates of Cinacalcet hydrochloride, methods for the preparation of these solvates, the use of these novel solvates for the preparation of pure Cinacalcet hydrochloride, the use of these novel solvates for the preparation of polymorphic form II of Cinacalcet hydrochloride and pharmaceutical compositions comprising the acetic acid solvate of Cinacalcet hydrochloride.

Provided is amorphous cinacalcet hydrochloride, processes for the preparation thereof, and pharmaceutical compositions therewith.

The invention particularly discloses a method for preparing a cinacalcet hydrochloride intermediate (R)-N-(1-(naphthalen-1-yl)ethyl-3-(trifluoromethyl)phenyl)propanamide. The method comprises the following steps: 3-(3-trifluoromethylphenyl)propionic acid used as a raw material is condensed with N,N-carbonyldimidazole (CDI) to obtain an intermediatet, and the intermediate is condensed with (R)-1-(1-naphthyl)ethylamine to obtain the final product cinacalcet intermediate. The method has the advantages of avoiding of the use of an acyl halide reagent, no generation of acidic gas, environmental protection, low device requirements, mild reaction temperature, realization of high yield, few impurities and high purity of the product, and suitableness for large-scale production.

The invention provides a method for synthesizing cinacalcet hydrochloride intermediate in a microchannel reactor. The method comprises the steps that 3-(3-trifluoromethylphenyl)-2-acrylic acid and a supported noble metal catalyst are added into an organic solvent A to react with hydrogen to generate 3-(3-trifluoromethylphenyl)propionic acid; after the reaction, filtration is conducted, and a catalyst B and thionyl chloride are added into filtrate to react to generate 3-(3-trifluoromethylphenyl)propionyl chloride, and the two intermediates are all finished in the microchannel reactor. By usingefficient mass transfer and heat transfer of the microchannel reactor, time of hydrogenation is effectively shortened, generation of esterification by-products in the hydrogenation process is prevented, the purity and yield of products are improved, palladium carbon is recovered and applied ,mechanically for many times, cumbersome operation in the kettle reaction process is overcome, and at the same time, materials generated in the reaction can be directly used for the next reaction; and the usage amount of the thionyl chloride in the preparation process of acyl chloride is reduced, waste discharge is reduced, and a green process for synthesizing cinacalcet hydrochloride intermediate is provided.