- Preparation method of doxofylline
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The invention relates to a preparation method of doxofylline. The preparation method comprises the following steps: reacting theophylline with chloroacetaldehyde glycol under the action of a first solvent and a first catalyst to generate an intermediate 7-(2, 2-dimethoxyethyl)theophylline, and reacting the intermediate 7-(2, 2-dimethoxyethyl)theophylline with ethylene glycol to generate doxofylline. The first solvent is N, N-dimethylformamide is adopted as a first catalyst, a mixture of tetrabutylammonium chloride hydrate and potassium bromide or a mixture of tetrabutylammonium chloride hydrate and potassium iodide is adopted as a first catalyst, and the reaction time can be obviously shortened and the reaction efficiency can be improved when the reaction system is used; and sulfuric acid is adopted as a second catalyst to replace p-toluenesulfonic acid (a genotoxicity suspected substance) or hydrosulfate in the prior art, so that the toxicity of a reaction solution is effectively reduced, and the obtained doxofylline is high in purity, high in yield and controllable in impurity. The preparation method of doxofylline is low in cost, high in yield, simple to operate, environment-friendly and beneficial to large-scale production of drugs.
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Paragraph 0034-0036; 0039-0041; 0044-0045; 0048-0049; 0052
(2021/08/11)
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- Novel method for simple, convenient, green and industrial production of doxofylline
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The invention provides a novel method for simple, green and industrial production of doxofylline. The doxofylline is prepared by direct condensation of theophylline, chloro-acetaldehyde tripolymer andethylene glycol. The method has the advantages of cheap and easily available raw materials, short steps, short reaction time, high production efficiency, simple operation and environment friendliness. Green and industrial production of doxofylline is effectively realized, meanwhile, the product quality and yield are improved, and the method has very important meanings for researching similar synthesis.
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Paragraph 0050-0069
(2020/06/20)
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- Preparation method of doxofylline
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The invention discloses a preparation method of doxofylline. The method comprises: S1, in a first solvent, in the presence of an alkali, heating theophylline and halogenated acetal to carry out an alkylation reaction to obtain an intermediate; and S2, in a second solvent, in the presence of a catalyst, heating the intermediate and ethylene glycol to carry out an acetal exchange reaction so as to obtain the doxofylline. According to the route designed by the invention, quality control points can be increased in the doxofylline preparation process, the impurity content is favorably controlled, the risk of drug registration declaration is reduced, the total yield reaches 85 percent or above, the operation is simple, and high-risk reaction is avoided.
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Paragraph 0040; 0043-0044; 0047-0048; 0051-0052; 0055-0056
(2020/12/10)
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- Preparation method of doxofylline
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The invention discloses a preparation method of doxofylline. The preparation method comprises the following steps: subjecting theophylline and bromoacetaldehyde dimethyl acetal to a substitution reaction in a reaction solvent under the action of an acid-binding agent to generate 7-(2,2-dimethoxyethyl) theophylline; subjecting 7-(2,2-dimethoxyethyl) theophylline and ethylene glycol to an acetal cyclization reaction in a reaction solvent under the action of a catalyst to generate a crude doxofylline product; and heating and dissolving the crude doxofylline product, carrying out crystallizing, filtering, and drying under reduced pressure successively to obtain doxofylline. According to the method, reaction conditions are easy to control; product purity reaches 99.9% or above; product separation and purification are easy and convenient; and the method is suitable for industrial production.
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Paragraph 0049; 0068
(2020/01/25)
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- Synthetic method of doxofylline
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The invention discloses a synthetic method of doxofylline and belongs to the technical field of organic synthesis. The method comprises the following step: theophylline and 2-chloromethyl-1,3-dioxolane are subjected to a reaction at 60-110 DEG C in an aprotic solvent under the action of alkali and a phase transfer catalyst, and doxofylline is synthesized, wherein the mole ratio of theophylline, 2-chloromethyl-1,3-dioxolane and the alkali is 1:1-2:1-3, the phase transfer catalyst accounts for 3%-5% of the molar weight of theophylline, and the phase transfer catalyst is selected from one or moreof tetrabutylammonium chloride, tetrabutylammonium bromide and tetrabutylammonium fluoride. The provided new synthetic method of doxofylline is short in reaction time and only needs 3-6 h, is low inreaction temperature which is lower by 20-30 DG C than that of the conventional method, is high in yield which is 10% or higher than that of the conventional method, and is beneficial to industrial production of the drug.
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Paragraph 0007; 0017-0026
(2018/12/13)
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- Preparation methods of doxofylline
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The invention discloses preparation methods of doxofylline. The preparation methods include the steps: under the action of an acid-binding agent, carrying out a condensation reaction of theophylline and halogenated acetaldehyde dimethyl acetal in a polar solvent, to obtain an intermediate 7-(2,2-dimethoxy ethyl)theophylline; and then, with soluble hydrosulfate as a catalyst, carrying out a condensation cyclization reaction of the intermediate 7-(2,2-dimethoxy ethyl)theophylline with ethylene glycol in a solvent, to obtain doxofylline; or, firstly, carrying out a condensation cyclization reaction of halogenated acetaldehyde dimethyl acetal and ethylene glycol to obtain halogenated acetaldehyde ethylene acetal, and carrying out a condensation reaction with theophylline, to obtain doxofylline. The soluble hydrosulfate is used as the catalyst and replaces conventional p-toluenesulfonic acid, moreover, and anisole and other solvents are used for replacing methylbenzene used in a conventional reaction route, so that under a condition of ensuring high yield of the product, the toxicity of the solution in the synthesis reaction is reduced, and the difficult problem that residual toxicity easily exists in the finished product is solved.
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Paragraph 0051; 0052; 0054
(2017/01/23)
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- Preparation method of doxofylline
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The invention provides a preparation method of doxofylline and particularly relates to a synthetic method of bromoacetaldehyde ethylene acetal represented as the formula II and the doxofylline. The method includes the steps of preparing the side-chain bromoacetaldehyde ethylene acetal represented as the formula II through a one-pot reaction of acetaldehyde, ethylene glycol and bromine, and then carrying out a N-alkylation reaction to the compound represented as the formula II with theophylline to prepare the doxofylline. The synthetic method is carried out with easy-to-obtain raw materials, is low in cost, is high in yield, is simple in processes, is economical and environment-friendly, and is beneficial to industrial scale-up production of the drug.
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Paragraph 0029; 0041; 0042
(2016/11/21)
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- Method for treating benign prostate hyperplasia
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A method of treating and/or preventing renal dysfunction in a patient, such as renal colic or contrast nephropathy by administering to a patient, a compound of the formula: is described herein. Administration of dyphylline in a sustained release oral dosage form is preferred.
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- Method of kidney treatment
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A method of treating and/or preventing renal dysfunction in a patient, such as renal colic or contrast nephropathy by administering to a patient, a compound of the formula: is described herein. Administration of dyphylline in a sustained release oral dosage form is preferred.
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- Pharmaceutical composition with anti-bronchospasmodic and anti-tussive activity
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A pharmaceutical composition with anti-bronchospasmodic and anti-tussive activity which contains an effective amount of the compound of formula STR1 together with at least one pharmaceutically acceptable carrier or diluent. The composition may be administered orally, parenterally, rectally or by means of an aerosol.
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