52 results about "Formic acid ethyl ester" patented technology

The present invention provides a process for the preparation of Olmesartan medoxomil by condensing the ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate with 4-[2-(trityl tetrazol-5-yl)phenyl]benzyl bromide to obtain ethyl 4-(1-hydroxy-1-methyl ethyl)-2-propyl-1-{4-[2-(trityl tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate and then hydrolyzing ethyl 4-(1-hydroxy-1-methyl ethyl)-2-propyl-1-{4-[2-(trityl tetrazol-5-yl)phenyl]phenyl}methyl imidazole-5-carboxylate to obtain trityl Olmesartan dihydrate followed by reacting trityl Olmesartan dihydrate with 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene to obtain trityl Olmesartan medoxomil and then deprotecting trityl Olmesartan medoxomil to obtain Olmesartan medoxomil.

The invention relates to a method for synthesizing febuxostat and an intermediate thereof, specifically a method for synthesizing 2-(3-formyl-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester. The method comprises the following steps: preparing 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate; enabling the product obtained in the step (a) to react in DMF (Dimethyl Formamide) in the presence of potassium carbonate and bromo-isobutane, adding water and ethyl acetate for extraction, concentrating to obtain an organic layer, and recrystallizing with DMF to obtain 2-(3-formyl-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester. The invention also relates to 2-(3-formyl-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester and 2-(3-formyl-4-hydroxyphenyl)-4-methyl-5-thiazoleethyl formate and application thereof to the preparation of febuxostat. The method of the invention has excellent performance.

The invention relates to a synthesis method of 8-nitro-2-tetrazol-5-yl-4-oxo-4H-1-benzopyran. The method comprises the following steps: firstly nitrifying hydroxyacetophenone taken as a starting material with a nitric acid so as to generate a mixture of 2-hydroxy-3-nitroacetophenone and 2-hydroxy-5-nitroacetophenone; salifying the mixture by using an inorganic base, carrying out separation and purification and then hydrolyzing with an acid so as to obtain 2-hydroxy-3-nitroacetophenone (A-2); carrying out a cyclization reaction on the 2-hydroxy-3-nitroacetophenone (A-2) and ethyl cyanoformate so as to generate 8-nirto-2-cyano-4-oxo-4H-1-benzopyran (A-3); and finally, reacting with sodium azide so as to generate the 8-nitro-2-tetrazol-5-yl-4-oxo-4H-1-benzopyran (A-6). According to the method, phosphorus oxychloride with an application risk and large pollution and an ammonia gas with strong stimulating smell are not used, so that the production is safe and environment-friendly; and the generation of waste gases is reduced at the same time, so that the synthesis process is shortened. Thus, the operation is simplified; the production cost is lowered; and the 8-nitro-2-tetrazol-5-yl-4-oxo-4H-1-benzopyran is high in purity.

The invention relates to a preparation process of ethyl chromane-4-formate. The preparation process is characterized by comprising the following steps of: carrying out Friedel-Crafts acylation reaction and cyclization, addition reaction, hydrolysis reaction and esterification reaction, wherein, in the Friedel-Crafts acylation reaction and cyclization, the Friedel-Crafts acylation reaction is carried out in the presence of anhydrous aluminium trichloride by using a compound of formula 1 and 3-chloropropionylchloride as initial raw materials, then carrying out cyclization on an obtained product and 10% NaOH to obtain a compound of formula 2; in the addition reaction, the addition reaction is carried out on the compound of formula 2 and trimethylsilyl cyanide in the presence of zinc iodide to obtain a compound of formula 3; in the hydrolysis reaction, the compound of formula 3 is hydrolyzed under the conditions of stannous chloride dihydrate, concentrated hydrochloric acid and acetic acid to obtain a compound of formula 4; and in the esterification reaction, the compound of formula 4 is esterified in the presence of concentrated sulfuric acid to obtain a compound of formula 5. According to the preparation process, expensive trifluoromethanesulfonic acid is replaced with cheap anhydrous aluminium trichloride in the Friedel-Crafts acylation step, and the yield is improved, so that the cost of preparing the compound is greatly reduced, and the high-quality product is obtained; and compared with the traditional method, the preparation process has obvious advantages.

The invention belongs to the technical field of pharmaceutical analysis, and particularly relates to a quantitative analysis method for potential genotoxic impurities in moxifloxacin hydrochloride starting raw material 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid ethyl ester, and the structure types of the potential genotoxic impurities comprise acyl halidesand unsaturated ketones. According to the invention, absolute ethyl alcohol and 2, 4-dichlorophenol are adopted; the method comprises the following steps: carrying out a derivatization reaction on 2,4, 5-trifluoro-3-methoxybenzoyl chloride to generate ethyl 2, 4, 5-trifluoro-3-methoxybenzoate, and carrying out separation and mass spectrometry detection by adopting (5% phenyl)-methyl polysiloxaneas a fixed phase derivative ethyl 2, 4, 5-trifluoro-3-methoxybenzoate and an impurity ethyl 3-(N, N-dimethylamino) acrylate. The method not only can realize effective separation of potential genotoxic impurities in the initial raw material, but also can quantitatively detect the genotoxic impurities, is simple, convenient and rapid to operate, strong in specificity, high in sensitivity, accurateand reliable, and has important significance for quality control and medication safety of moxifloxacin hydrochloride raw materials and preparations.

The invention discloses a preparation method of a diclazuril impurity A. The diclazuril impurity A is obtained through the procedures of condensation reaction of a diclazuril intermediate (3-butyloxycarbonylamino-3-oxopropionyl)-butyl carbamate or (3-ethoxycarbonylamino-3-oxopropionyl)-ethyl carbamate (compound I) used as a starting material with sodium nitrite in a polar solvent and under acid catalysis, decoloration, crystallization and drying. The synthesis route is short, the starting material is easy to obtain, reaction conditions are mild, operation is easy and convenient, the impurity can be obtained without column chromatography, the purity of the prepared impurity can reach 99.5% or above, and the impurity can serve as a reference substance to be used for quality research.

The present invention discloses processes comprising a) reacting ethyl isonipecotate with 1-bromo-2-chloroethane in the presence of an organic base in a solvent to form ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (II) or a salt thereof. Process step a) may be included in a process for preparing umeclidinium bromide that comprises further process steps: b) reacting ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (II) or a salt thereof with lithium diisopropylamide in a solvent to form ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (III); c) reacting ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (III) with phenyl lithium in a solvent to form 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (IV); and d) reacting 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (IV) with ((2-bromoethoxy)methyl) benzene in a solvent to form 4-[hydroxyl(diphenyl)methyl]-1-[2-(phenylmethyl)oxy]ethyl]-1-azoniabicyclo[2.2.2]octane bromide (I), umeclidinium bromide. A process comprising d) reacting 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol with ((2-bromoethoxy)methyl) benzene in a solvent to form 4-[hydroxyl(diphenyl)methyl]-1-[2-(phenylmethyl)oxy]ethyl]-1-azoniabicyclo[2.2.2]octane bromide (I), umeclidinium bromide, wherein the solvent is selected from cyclic ethers such as tetrahydrofuran, aromatic solvents, such as toluene, ketones such as acetone and protic solvents such as water or combinations thereof, optionally wherein the solvent is water is also disclosed. Umeclidinium bromide obtainable from the disclosed processes, ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (II) and pharmaceutical compositions are also disclosed.

The invention discloses a novel synthesis method of 2-aminopyrazinyl-5-formic acid, which comprises the following steps: carrying out hydrazinolysis reaction on accessible 2,5-ethyl diformate pyrazine to hydrazinolyze the monoester, reacting with a sodium nitrate solution, refluxing in toluene and tert-butyl alcohol to obtain a key intermediate 2-ethyl formate-5-Boc-amino-pyrazine, and refluxing in hydrochloric acid to obtain the 2-aminopyrazinyl-5-formic acid. The method has the advantages of mild and simple reaction conditions, low cost and high yield, is simple to operate and suitable for industrial production, and has great economic significance.

The invention discloses a method for preparing 1-ferrocenyl-3-aryl-3-(ethyl dicarboxylate methine)-acetone, and the method comprises the following steps: adding choline chloride and urea into a dry three-necked flask, and stirring to a transparent solution at 80 DEG C to obtain a deep eutectic solvent; cooling to room temperature, adding ferrocenyl chalcone and diethyl malonate, slowly heating, refluxing for reacting, and performing TLC monitoring until the reaction is finished; cooling the reaction mixture to room temperature, adding a small amount of water, immediately precipitating solids,performing suction filtering, washing the filter cake with water, and drying to obtain the 1-ferrocenyl-3-aryl-(ethyl dicarboxylate methine)-acetone with a yield of over 81%. The filtrate is concentrated and recovered to obtain the deep eutectic solvent, which can be reused. The invention provides a simple, convenient, green and environment-friendly method for the synthesis of the compound, meanwhile, the catalyst can be recycled, and the reaction cost is reduced.

The invention discloses a preparation method of a prohexadione calcium intermediate. The method comprises the following steps: dissolving 3, 5-ethyl dihydroxybenzoate in a solvent, adding formic acid and a catalyst, heating to 100-150 DEG C for reaction, cooling to 20-30 DEG C after the reaction is finished, filtering to recover the catalyst, and carrying out reduced pressure evaporation on filtrate to recover unreacted formic acid and the solvent, thereby obtaining the 3, 5-dioxocyclohexyl ethyl formate. According to the process, acetone is not used, a large amount of waste salt is not generated, and the process is environment-friendly, high in yield and purity and suitable for large-scale industrial production.

The invention relates to a method for synthesizing a pharmaceutical intermediate sulfur-containing nitrogen heterocyclic amine compound. The method comprises that ethyl 4-methyl-3-oxo-pentanoate, dichloromethane and sulfonyl chloride as raw materials undergo a reaction, the reaction product is subjected to pH adjustment until pH of 7, the treated reaction product is extracted so that ethyl 2-chloro-4-methyl-3-oxopentanoate is obtained, the ethyl 2-chloro-4-methyl-3-oxopentanoate and thiourea undergo a reaction in the presence of ethanol as a solvent to produce ethyl 2-amino-4-isopropylthiazole-5-formate, isoamyl nitrite is added into ethyl 2-amino-4-isopropylthiazole-5-formate in the presence of tetrahydrofuran as a solvent to obtain 4-isopropylthiazole-5-formate, a NaOH solution is addedinto the 4-isopropylthiazole-5-formate in the presence of anhydrous methanol as a solvent so that 4-isopropylthiazole-5-formic acid is obtained, the 4-isopropylthiazole-5-formic acid and azophosphoryldiphenyl ester undergo a reaction in the presence of tert-butyl alcohol as a solvent and triethylamine, the reaction product is extracted, the extract is washed so that 5-N-BOC-4-isopropylthiazole isobtained, the 5-N-BOC-4-isopropylthiazole and HCl undergo a reaction in the presence of anhydrous methanol as a solvent to produce 4-isopropyl-5-aminothiazole. The method has the advantages of clearprocesses, less waste, high yield, raw material saving and operation easiness.

The invention belongs to the field of medicines and especially relates to a preparation method for pranlukast. The method comprises the following steps: A) adding 4-bromobenzoic acid and thionyl chloride into a solvent and reacting, thereby acquiring 4-bromo-benzoyl chloride; B) adding the 4-bromo-benzoyl chloride acquired in the step A), alkali and 3-amino-2-ethyl iodobenzoate into the solvent and reacting, thereby acquiring 2-iodine-3-(4-bromobenzamide) ethyl benzoate; C) adding the 2-iodine-3-(4-bromobenzamide) ethyl benzoate acquired in the step B), alkali and 1-(1H-tetrazole-5-group) aceton into the solvent and reacting, thereby acquiring 4-bromine-N-(4-oxo-2-(1H-tetrazole-5-group)-4H-benzopyrone-8-group) benzamide; D) adding the 4-bromine-N-(4-oxo-2-(1H-tetrazole-5-group)-4H-benzopyrone-8-group) benzamide acquired in the step C), catalyst and alkali into the solvent and reacting, thereby acquiring the product. The method provided by the invention is simple and practicable in process, low in production cost and high in yield.

The invention belongs to the field of drug synthesis, and relates to a preparation method of an anticancer drug intermediate, in particular to a preparation method of ethyl 3,4-bis(2-methoxyethoxy)benzoate. This preparation method has research reports in many documents or patents, but all need the participation of organic solvents such as acetonitrile, acetone or DMF. The present invention does not need to use the solvent in the existing documents or patents, but can obtain products with high yield and purity, is a green and environment-friendly preparation method, and is suitable for industrial production.

The invention provides a preparation method of Filgotinib, comprising the following steps: (1) reacting 2-amino-6-bromopyridine with p-toluene derivatives to prepare compound 1; (2) compound 1 and isothiocyanate formic acid Ethyl reaction to prepare compound 2; (3) compound 2 reacted with hydroxylamine hydrochloride and N,N-diisopropylethylamine to prepare compound 3; (4) compound 3 reacted with cyclopropanoyl chloride to obtain compound 4; ( 5) Compound 4, N-bromosuccinimide was reacted with azobisisobutyronitrile to obtain compound 5; (6) Compound 5 was reacted with thiomorpholine-1,1-dioxide to obtain Filgotinib. The route for synthesizing Filgotinib in the present invention is coupling first and then ring closing, the raw materials are cheap, the reaction operation is simple, the product is easy to purify, and the yield is high, which is suitable for commercial scale production.

The invention belongs to the technical field of drug analysis, in particular to a moxifloxacin hydrochloride starting material 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo- Quantitative analysis method for potential genotoxic impurities in ethyl 3‑quinolinecarboxylate. The structure types of potential genotoxic impurities include acid halides and unsaturated ketones. The present invention adopts absolute ethanol and 2,4,5-trifluoro-3-methoxybenzoyl chloride to carry out derivatization reaction to generate 2,4,5-trifluoro-3-methoxybenzoic acid ethyl ester, adopts ( 5% phenyl)-methyl polysiloxane is a fixed relative derivative 2,4,5-trifluoro-3-methoxy ethyl benzoate and impurity 3-(N,N-dimethylamino)acrylic acid Ethyl esters were separated and detected by mass spectrometry. The method can not only realize the effective separation of potential genotoxic impurities in the starting raw materials, but also can quantitatively detect the genotoxic impurities. The operation is simple and fast, with strong specificity, high sensitivity, accuracy and reliability. It is of great significance to the quality control and drug safety of preparations.

The invention discloses a preparation method of ethyl benzoate, comprising the following steps: putting sodium benzoate, toluene, and a phase transfer catalyst into a pressure kettle, replacing the air in the kettle with nitrogen, and feeding ethyl chloride at a certain temperature and pressure. After the reaction, the catalyst and the sodium chloride produced by the reaction are filtered off, the solvent toluene is recovered, and the finished product is obtained by rectification under reduced pressure. Compared with the current esterification process, the present invention has the advantages of high product yield, no serious corrosion of equipment, zero discharge of "waste water", and the like.