33 results about "Vilanterol" patented technology

An improved process for the preparation of vilanterol and pharmaceutically acceptable salts thereof is disclosed. More specifically the improved process for preparing intermediates for the preparation of vilanterol is disclosed.

The invention provides a dry powder inhalation medicine composition and a preparation method thereof. The composition is prepared from a coating agent with a specific particle size characteristic, lactose monohydrate with a specific particle size characteristic for a carrier and a micronized medicinal active ingredient, wherein the coating agent is an inhaling magnesium stearate or a mixture of the inhaling magnesium stearate and micronized lactose monohydrate; and the medicinal active ingredient is selected from at least one of glycopyrronium bromide, umeclidinium, indacaterol, formoterol, vilanterol, fluticasone and pharmaceutically available salt of the active ingredients. The preparation method comprises the following steps of sufficiently mixing and coating the coating agent and the lactose monohydrate, and uniformly mixing with the micronized medicinal active ingredients.

The invention provides a new Vilanterol intermediate compound 2. According to the invention, primary amino is introduced into a compound 5 through Delepine reaction, then di-tert-butyl dicarbonate is employed for amino protection, and the strategy greatly improves the yield and atom utilization rate. On the other hand, cheap and easily available urotropin is adopted in the invention to lower the cost, thus being easy for industrial large-scale production. Compared with the prior art, the yield of the method involved in the invention is increased to 65% by three-step reaction, also use of expensive di-tert-butyl iminodicarboxylate and cesium carbonate is avoided, the cost is reduced, the operation is simple, and the conditions are mild. Therefore, the method is suitable for industrial preparation of Vilanterol and its key intermediate (5R)-5-(2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl)-1, 3 oxazolidine-2-one. (formula of compound 2).

The invention provides a method for preparing a vilanterol intermediate (formula V) and a salt (formula VII) thereof, belonging to the field of chemical drug synthesis. The method comprises the steps of carrying out ring opening reaction on an epoxy compound 2,2-dimethyl-6-ethylene oxide-4H-benzo[d][1,3]dioxane and an amine chiral auxiliary to prepare a chiral compound V; then, separating the compound V from a mixture in a way of forming a crystal salt with an acid. A reagent used in the method provided by the invention is cheap and easily available, and hypertoxic chiral oxazaborolidine is prevented from being used, so that the cost is reduced, and the environment pollution is reduced.

The invention discloses a vilanterol trifluoromethanesulfonate-containing pharmaceutical preparation, which comprises the following main active ingredients: long-acting beta2 receptor agonist vilanterol trifluoromethanesulfonate, glucocorticoid drug fluticasone furoate and long-acting anticholinergic drug aclidinium bromide, or physiologically acceptable salts of the fluticasone furoate and aclidinium bromide, thus composing a compound preparation. The vilanterol trifluoromethanesulfonate has the effect of continuously dilating blood vessels for 24 hours; the fluticasone furoate is fast-acting potent glucocorticoid, and the duration time of the drug is longer than that of other glucocorticoids; the aclidinium bromide is long-acting cholinergic receptor antagonist, and combines with beta2 receptor agonist so as to play roles of synergism and reduction of adverse drug reaction. The vilanterol trifluoromethanesulfonate, the fluticasone furoate and the aclidinium bromide are combined for use to prepare an inhalable compound preparation which can be taken once daily due to 24-hour acting. The vilanterol trifluoromethanesulfonate-containing pharmaceutical preparation can enhance the curative effect, solves the compliance problem of patients with coexisting chronic obstructive pulmonary disease and asthma, thus being appreciable in application prospects.

The invention relates to a preparation method of vilanterol and a salt thereof. The preparation method comprises the following steps: in a solvent, reacting a mixture containing a compound shown as aformula I with succinic acid to obtain a compound shown as a formula II-1; and subjecting the obtained compound shown as the formula II-1 to reacting and conversion to obtain vilanterol and the salt thereof. The preparation method of the vilanterol and the salt thereof has the advantages of higher yield, high purity, easiness in refining, simplicity and convenience in operation and suitability forindustrialization.

The invention provides a preparation method of vilanterol, which comprises the following steps: 1) oxidation reaction: reacting a compound A with an oxidant to obtain a compound B; wherein the oxidantis selenium dioxide; 2) reductive amination reaction: carrying out condensation reaction on the compound B and a compound C to generate an imine intermediate, and carrying out a reaction on the imineintermediate under the action of a reducing agent to obtain a compound D; 3) reduction reaction: carrying out a reaction on the compound D with a chiral catalyst and a reducing agent to obtain a compound E, and 4) ring-opening reaction: performing deprotection ring-opening on the compound E under an acidic condition to obtain vilanterol. The method is advantaged in that the initial raw materialsare easy to obtain, the process is suitable for industrial production, the production yield is high and quality is stable.

The present invention discloses a new synthesis method of a long-acting beta2 receptor agonist vilanterol, and provides a completely-new synthesis method of a long-acting beta2 receptor agonist vilanterol. According to the method, the idea that the Schiff base is firstly produced and then reduction is performed is adopted to effectively avoid disadvantages of harsh reaction conditions (such as anhydrous reaction), expensive reagents and the like of the existing process, and the method has characteristics of easily available raw materials, short route, high yield, and market competitiveness.

The invention discloses a preparation method of a vilanterol intermediate and belongs to the field of drug synthesis. The method is characterized in that 4-hydroxy-mandelic acid is taken as a raw material and is subjected to formylation reaction to obtain 4-hydroxy-3-formyl mandelic acid; an aldehyde group is reduced to obtain 3-hydroxymethyl-4-hydroxyphenylglycolic acid. The invention provides anovel intermediate of vilanterol; the raw material of the intermediate is easy to obtain; synthesis reaction conditions are mild and the operation is simple; in addition, by using the intermediate tosynthesize the vilanterol, a synthetic route is greatly shortened, and the production cost is reduced; the preparation method is suitable for industrial production.

The invention discloses a method for preparing Vilanterol, and belongs to the field of drug synthesis. The method includes the steps: (1) performing addition reaction on salicyloyl and glyoxylic acidto generate an intermediate 1; (2) performing chiral resolution on the intermediate 1 to obtain a chiral intermediate 2; (3) performing acylation reaction on the intermediate 2 and an intermediate 3 to generate an intermediate 4; (4) reducing the intermediate 4 to obtain the Vilanterol. The intermediate 3 is obtained by performing Darebin reaction on an intermediate 5. Raw materials are easily obtained, a synthetic route is short, production cost is reduced, reaction conditions are mild, and the method is simple in operation and suitable for industrial production.

The invention discloses a method for synthesizing Vilanterol midbody 2-(2,2-dimethyl-4H-1,3-benzodiazepine-6-group)-2-carbonyl ethyl carbamate tert-butyl ester (II) by virtue of solid acid catalysis,which belongs to the technical field of organic catalysis. According to the method, the solid acid is used to catalyze the synthesis of Vilanterol midbody (II),so that the defect in the prior art by adopting organic strong acid can be solved, the recycling of the catalyst is realized, and the pressure of environmental protection can be alleviated. The solid acid catalyzed synthesis route of the invention is environment-friendly and meets the requirements of modern pollution-free industrialized production.

The invention provides a vilanterol intermediate as well as a preparation method and application thereof, and relates to the technical field of chemical synthesis. According to the vilanterol intermediate, the compound shown in the formula I is salt of the compound shown in the formula II, the solid compound shown in the formula I is obtained from the oily compound shown in the formula II, the purity reaches up to 99.0% or above, when the compound shown in the formula I is used for preparing vilanterol and pharmaceutically acceptable salt thereof, purification through tedious separation methods such as column chromatography is not needed, materials are easy to measure accurately, the quality control of the vilanterol intermediate is facilitated, various defects caused by the fact that the compound shown in the formula II is an oily substance are effectively overcome, and the quality of vilanterol and pharmaceutically acceptable salt thereof can be better guaranteed.

The invention provides a pulsatile controlled-release tablet containing fluticasone furoate and vilanterol. The pulsatile controlled-release tablet can reach plasma concentration at midnight and early morning, so the purpose of chrono-chemotherapy is achieved. The pulsatile controlled-release tablet comprises a floating layer and a tablet core. The floating layer uses hydrophilic high molecules and fatty alcohol as adjuvant materials, so the floating layer can retain for a certain period of time in the stomach; when the tablet contacts with gastric juice, the surface of the floating layer hydrates to form gel, so the size of the tablet becomes larger; when the gel is smaller than the concentration of the gastric juice, the tablet is allowed to float above contents in the stomach; and the tablet core appears along with dissolution of the skeleton of the floating layer, so drugs are released from the tablet core.

The invention discloses a method for synthesizing a vilanterol intermediate tert-butyl 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-carbonylethylcarbamate by catalysis with modified reduced graphene oxide with a high carboxylation edge, and belongs to the technical field of organic catalysis. The method utilizes an acidic catalytic reaction of the relatively large amount of carboxyl groups at the edge of reduced graphene oxide to overcome the disadvantage that an adopted organic strong acid is difficult to recover in the prior art, solve the problem of heterogeneous phase and difficult recyclingapplication of a catalyst, and reduce environmental protection pressure. The catalytic synthesis method adopting graphene is environmentally friendly, and meets requirements of modern green industrial production.

The invention relates to a method for synthesizing (1R)-1-(2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl)-2-nitroethanol, and the route of the method is as follows: the (1R)-1-(2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl)-2-nitroethanol synthesized by adopting the synthesis method is applied to preparation of (5R)-5-(2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl)-1, 2, 4-triazole-3-yl)-2-nitroethanol, and the (1R)-1-(2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl)-2-nitroethanol is used as a raw material. The method can be used for preparing 2, 3-oxazolidine-2-ketone, reaction steps can be shortened, and the method has the advantages of being high in reaction conversion number, high in atom economy, suitable for industrial production and the like. Compared with the currently reported asymmetric Henry reaction synthesis route, the method has the advantages that the price of the catalyst required by the synthesis route is low, the molar yield of the alpha-nitroketone reduction step is greater than 85%, and the method has the characteristics of high asymmetric selectivity and easiness in production.

The invention discloses a method for synthesizing Vilanterol midbody 2-(2,2-dimethyl-4H-1,3-benzodiazepine-6-group)-2-carbonyl ethyl carbamate tert-butyl ester (II) by virtue of solid acid catalysis,which belongs to the technical field of organic catalysis. According to the method, the solid acid is used to catalyze the synthesis of Vilanterol midbody (II),so that the defect in the prior art by adopting organic strong acid can be solved, the recycling of the catalyst is realized, and the pressure of environmental protection can be alleviated. The solid acid catalyzed synthesis route of the invention is environment-friendly and meets the requirements of modern pollution-free industrialized production.

The invention discloses a method for detecting a genotoxic impurity containing bromohexyl in vilanterol triphenylacetate. The genotoxic impurity is selected from VL02imp4 of a structural formula I, VL02imp6 of a structural formula II and / or VL02imp8 of a structural formula III. The method is based on a gas chromatography-flame ionization detector, and the chromatographic conditions are as follows: 5% diphenyl-95% dimethyl polysiloxane is used as a capillary chromatographic column of a stationary liquid; the initial temperature is 35-45 DEG C, the temperature is increased to 315-325 DEG C at the speed of 13-18 DEG C / min, and the temperature is maintained The carrier gas is nitrogen, the flow velocity is 0.8-1.2 ml / min, the constant flow mode is adopted, and the split ratio is (8: 1)-(12: 1); the sample introduction temperature is 250 DEG C; the sample size is 1 microliter; the detection temperature is 315-325 DEG C, the flow rate of nitrogen is 25ml / min, the flow rate of hydrogen is 40ml / min, and the flow rate of air is 400ml / min.

The invention discloses a preparation method and application of a vilanterol EP impurity 2, and the preparation method comprises the following steps: dissolving a compound with a structure as shown in a formula I in a first organic solvent, adding acid and a dewatering agent, and reacting with 2, 2-dimethoxypropane under a heating condition to obtain a compound with a structure as shown in a formula II; dissolving the compound with the structure as shown in the formula II in a second organic solvent, adding N-t-butyloxycarboryl-glycine-N '-methoxyl-N'-methyl amide, adding n-butyllithium at low temperature, and reacting for 1 hour to obtain a compound with the structure as shown in the formula III, namely the vilanterol EP impurity 2. The method has the advantages of easily available raw materials, few steps, high yield and low cost, and fills the technical blank of preparation of the vilanterol EP impurity 2. A cheap and high-quality impurity reference substance can be provided for quality research of vilanterol, and the method has important significance on safe medication of vilanterol.

The invention belongs to the technical field of medicinal chemistry, and particularly relates to application of Vilanterol in preparation of a medicament for resisting coronavirus infection. According to the application, a new function of the Vilanterol is found, and the Vilanterol has a relatively strong inhibition effect on the enzymatic activity of target papaya-like protease Plpro of the coronavirus, especially novel coronavirus, and has the potential of being developed into a medicine for treating and preventing the coronavirus, especially resisting the novel coronavirus.

The present invention relates to the preparation method of vilanterol and salt thereof, it comprises the following steps: in solvent, the mixture containing the compound of formula I is reacted with succinic acid to prepare the compound of formula II-1; The reaction transforms vilanterol and its salts. The preparation method of vilanterol and its salt of the present invention has higher yield, high purity, easy refining and simple operation, and is suitable for industrialization.

The invention discloses a method for preparing vilanterol, which belongs to the field of drug synthesis. The method comprises the following steps: (1) addition reaction of salicyl alcohol and glyoxylic acid to generate intermediate 1; (2) intermediate 1 undergoes chiral resolution to obtain chiral intermediate 2; (3) intermediate 2 and intermediate Intermediate 3 undergoes acylation reaction to generate intermediate 4, wherein intermediate 3 is obtained by Delbin reaction of intermediate 5; (4) intermediate 4 is reduced to obtain vilanterol. The invention has easy-to-obtain raw materials, short synthesis route, reduced production cost, mild reaction conditions, simple operation and is suitable for industrialized production.

The invention discloses a synthesizing method of a vilanterol intermediate and belongs to the field of drug synthesis. According to the synthesizing method of the vilanterol intermediate, 4-hydroxymandelic acid serving as the raw material is prepared through electrophilic substitution reaction into 3-hydroxymethyl-4-hydroxymandelic acid. The prepared new vilanterol intermediate is simple in raw material acquisition and operation, and when applied to synthesizing vilanterol, can greatly shortens the synthetic route and reduce the production cost, thereby being applicable to industrial production.