55 results about "Avanafil" patented technology

The invention discloses a method for preparing avanafil (Avanafil, I). The method comprises the steps of taking cytosine as an initial material; and orderly carrying out replacement, halogen addition and condensation reaction on a side chain 3-chlorine-4-methoxy benzyl halide (III), N-(2-methylpyrimidine) formamide (IV) and S-hydroxymethyl pyrrolidine (II), so as to obtain a target product avanafil (I). The preparation method is available in material, concise in technology, economic and environment-friendly, and suitable for the demands of industrial amplification.

The invention provides a novel intermediate IV which is used for preparation of avanafil. The intermediate has a general formula IV as described in the specification; and in the general formula IV, R represents a C1-20 alkylsulfinyl group or a C1-20 alkylsulfonyl group. The intermediate has high purity, is suitable for industrial production and can be subjected to a one-step chemical reaction to prepare avanafil. The invention also provides a preparation method for the intermediate and a method for preparing avanafil from the intermediate.

The invention provides an avanafil intermediate A and an avanafil intermediate B, and a synthetic method of the avanafil intermediates A and B and avanafil. The synthetic method of the avanafil comprises the following steps: reacting a compound with the formula (I) with 2-methylaminopyrimidine at a temperature ranging from -10 DEG C to 5 DEG C to obtain the avanafil intermediate A; agitating the avanafil intermediate A with 3-chloro-4-methoxybenzylamine at the temperature ranging from 0 DEG C to 3 DEG C and reacting for 0.2-0.4 hour to obtain the avanafil intermediate B; and agitating the avanafil intermediate B with L-prolinol at the room temperature and reacting for 18-22 hours to obtain the avanafil. The structural formulas of the avanafil intermediates A and B and the compound with the formula (I) are shown in the specification. The avanafil intermediates A and B provided by the invention are simple in structure and good in product quality; the cost of the synthetic method is low; the synthetic route of the whole process is short and reaction steps are few, so that the reaction time is shortened and the yield and the purity of the avanafil intermediates A and B, and the avanafil are also improved.

The invention relates to a composition for impotence and premature ejaculation. Specifically, the invention relates to a use of combination of dapoxetine or medical salts thereof and avanafil in preparation of a medicament for preventing or treating impotence and premature ejaculation, and further relates to a composition including the dapoxetine or medical salts thereof and avanafil. The composition disclosed by the invention has the characteristic of being excellent.

The invention relates to a preparation method of avanafil and a new compound provided in a preparation process. According to the method, 5-uracil carboxylic acid or an ester thereof is taken as the raw material, and the avanafil meeting the clinical requirements can be synthesized at a relatively cost; besides, the preparation method is simple and convenient to operate, mild in reaction conditions, high in yield, low in cost, environmentally friendly and suitable for industrial large-scale production of the avanafil.

The invention relates to a method for preparing avanafil. The method is characterized by comprising the step of enabling 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine to be subjected to hydrolysis, condensation, oxidation and substitution reaction sequentially, thereby preparing avanafil. The method has the advantages of being simple and convenient in operation, easy in product quality control, high in reaction yield, high in product purity, low in cost and applicable to industrial production and the like.

The invention relates to the field of the organic chemistry synthesis and in particular relates to a synthesis method of avanafil. The method comprises the following steps: carrying out nucleophilic substitution on raw materials which are 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine and 3-chloro-p-methoxy benzyl amine hydrochloride to obtain 4-(3-chloro-4-methoxy benzyl amine hydrochloride)-5-ethoxycarbonyl-2-methylthiopyrimidine, then sequentially carrying out oxidation reaction, nucleophilic reaction with L-prolinol, esterolysis and dehydration synthesis to finally obtain avanafil. The method has the advantages that the used raw materials are cheap and easily available; the cost is low; the operation is simple and convenient; the prepared final product has few impurities and is of a solid state. The final product can be directly re-crystallized to obtain a pure product; the product is high in purity and suitable for industrial production.

The invention relates to an avanafil preparation method. The method comprises the steps that a hydrolysis reaction is carried out on 4-(3-chlorin-4-methoxy benzyl amino)-2-methylehio pyrimidine-5-carboxylic acid ethyl ester, namely a compound (2) to obtain 4-(3-chlorin-4-methylehio pyrimidine)-2-methylehio pyrimidine-5-carboxylic acid, namely a compound (6); an acylation reaction is carried out on the compound (6) and thionyl chloride, and then the product and 2-sulfadoxine-pyrimethamine or a salt of 2-sulfadoxine-pyrimethamine are condensed to obtain 4-(3-chlorin-4-methylehio pyrimidine)-2-methylehio pyrimidine-N-(2- pyrimidine methyl)-5-pyrimidine formamide, namely a compound (7); the compound (7) is oxidized by metachloroperbenzoic acid to obtain 4-(3-chlorin-4-methylehio pyrimidine)-2-methylsulfonyl pyrimidine-N-(2-pyrimidine methyl)-5-pyrimidine formamide, namely a compound (8), a nucleophilic substitution reaction is carried out on the compound (8) and L-prolinol to obtain avanafil. The method is low in cost, easy and convenient to operate, high in product purity, high in reaction yield and suitable for industrialization scale production.

The invention discloses an avanafil intermediate as well as a preparation method and application thereof. The avanafil intermediate is a compound having a general formula as shown in the description, wherein R in the general formula is selected from C1-C4 alkyl. The preparation method of the intermediate comprises the steps a-d in the synthesis route as shown in the description. The invention also discloses an application of the intermediate. Each reaction step for preparing avanafil from the intermediate has the advantages of simple operation, mild reaction conditions, easily available reaction raw materials, high reaction yield and the like, the products are easy to separate and purify; the total yield of prepared avanafil is increased to 40% and the HPLC purity reaches up to 99.8%; the preparation cost of avanafil is greatly reduced, the quality of avanafil is ensured, and thus the intermediate is very much in line with industrial production requirements and has practical value.

The present invention provides a high performance liquid chromatography analysis method for avanafil and a preparation thereof, and belongs to the technical field of drug analysis. According to the high performance liquid chromatography analysis method, a chromatographic column selecting an octadecyl-bonded silica gel as a filler is selected, the specification is 4.6 mm*150 mm, 5 [mu]m, 4.6 mm*200 mm, 5 [mu]m, 4.6 mm*250 mm, 5 [mu]m, 4.6 mm*150 mm, 3.5 [mu]m, 4.6 mm*200 mm, 3.5 [mu]m, 4.6 mm*250 mm, 3.5 [mu]m, the mobile phase is an acetonitrile-buffer salt according to a ratio of 30-70:70-30, the flow rate is 5-1.5 ml/min, the column temperature is 30-40 DEG C, the wavelength of an ultraviolet detector is 200-300 nm, and the injection volume is 5-50 [mu]l. According to the present invention, the method only uses the ordinary liquid chromatograph, the requirement on the equipment is not high, the two mediums selected by the mobile phase are generally easy to obtain, the feasibility is high, the operation process is simple and convenient, the applicability is good, and the method can be widely used in avanafil and the preparation thereof.

The invention provides a preparation method of avanafil, and specifically relates to the technical field of pharmaceutical chemistry. The preparation method of avanafil comprises the following steps:sequentially carrying out cyclization and chlorination reactions on methyl thiourea sulfuric acid and diethyl ethoxymethylene malonate which serve as initial raw materials to obtain 4-chloro-2-methylthiopyrimidine-5-carboxylic acid ethyl ester; then substituting and hydrolyzing with 3-chloro-4-methoxybenzylamine; condensing with 2-pyrimidinemethanamine to obtain a key intermediate, namely, 4-[(3-chloro-methoxybenzyl)amino]-2-methylthio-N-(2-pyrimidine methyl)-5-pyrimidine formamide; oxidizing the intermediate and reacting with L-prolinol to generate the avanafil. The preparation method has theadvantages of easy availability of raw materials, easiness and convenience in operation, mild reaction conditions and higher product yield.

The invention relates to an amorphous form of avanafil, a preparation method, application and a medicine composition of the amorphous form of avanafil. The amorphous form of avanafil has no obvious characteristic peak in powder X-ray diffraction pattern based on Cu-K alpha radiation and shows a valuable characteristic in drug preparation; the amorphous form is high in purity and stable, and the in-vivo absorption of the amorphous form is superior to that of a crystal form.

The invention provides a preparation method of an avanafil important intermediate. The target compound (3-chloro-4-methoxybenzylamine) is prepared according to a route shown as the specification. The preparation method provided by the invention has the advantages of cheap and easily available raw materials, short technical route, mild reaction conditions, low equipment requirement, and small health hazard to operators, and is in line with the idea of green chemistry. The method has high yield, and can obtain product with high purity, thus being suitable for industrial production.

The invention provides a method for detecting the content of residual solvent benzene and isopropylidene acetone in Avanafil, which comprises the steps of solution preparation and gas chromatography detection. The preparation the test sample solution includes the steps of weighing a test sample, placing the test sample in a volumetric flask, adding N- methyl pyrrolidone (NMP), strongly shaking todissolve, then diluting by water to a scale, and shaking well. The method has the advantages that the separation degree between each target peak to be detected and the adjacent impurity peak is high,there is no mutual interference, and accurate detection for benzene and isopropylidene acetone can be simultaneously realized. In addition, the method is simple and convenient to operate, easy to control and low in detection cost, and has good linear relationship, specificity, system applicability, sensitivity and high added sample recovery.

The invention provides a preparation method of an avanafil intermediate. The preparation method comprises the following steps: dissolving a starting raw material 4-(3-chloro-4-methoxybenzylamino)5-ethoxycarbonyl-2-methylthiopyrimidine in a reaction solvent; adding metal porphyrin as a catalyst, thoroughly stirring for dispersing uniformly, and transferring to a reaction kettle; inflating an oxidizing gas at room temperature, and reacting while stirring to produce 4-(3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylsulfinylpyrimidine. According to the preparation method, with substituentmetal porphyrin as the catalyst and air or oxygen as an oxidant, a sulfoxide intermediate of avanafil is prepared through catalytic oxidation of a thioether compound under a normal temperature condition; after a reaction, a target product is easily separated from the catalyst and has the characteristics of high yield, good purity and the like; the difficulty of separation and purification of theproduct in the later stage is greatly reduced; the recycled catalyst can be reused; the preparation cost can be significantly reduced.

The invention relates to a pharmaceutical composition for treating male erectile dysfunction and application thereof and belongs to the field of medicines. The invention provides a pharmaceutical composition with active ingredients containing avanafil by aiming at overcoming the defects that an existing medicine for treating the male erectile dysfunction has adverse effects and is short in action time or slowness for taking effect. The pharmaceutical composition can be used for obviously shortening an erection latent period and obviously prolonging an ejaculation latent period and has a good treatment effect on neuropathic ED.

The invention provides a preparation method of an Avanafil intermediate. The preparation method comprises the following steps: dissolving 4-hydroxy-2-methylthio-ethyl 5-pyrimidinecarboxylate and potassium carbonate in DMF to obtain a mixed solution, adding methanesulfonyl chloride into the mixed solution under the stirring condition, continuously stirring after addition until a reaction is ended, adding water and ethyl acetate into a reaction solution, carrying out extraction and liquid separation, carrying out vacuum concentration on an organic phase to prepare 4-methanesulfonic sulfonic ester-2-methylthio-ethyl 5-pyrimidinecarboxylate; dissolving the obtained 4-methanesulfonic sulfonic ester-2-methylthio-ethyl 5-pyrimidinecarboxylate into DMF, adding a (3-chloro-4-methoxy)Benzylamine hydrochloride to obtain mixed liquor, adding triethylamine into the mixed liquor under the stirring condition, continuously stirring after addition until a reaction is ended, adding water and ethyl acetate, carrying out extraction and liquid separation, carrying out vacuum concentration on an organic phase, and recrystallizing to prepare 4-(3-chloro-4-methoxybenzylamino)-5- ethyloxycarbonyl-2-methylthiopyrimidine. The invention has advantages of less environmental pollution, high product yield, safe post-processing and simple operation.

The invention discloses a refining method for avanafil. An avanafil bulk drug prepared by using the refining method has a particle size of no more than 30 [mu]m; so in the process of drying, an organic solvent can be easily volatilized and solvent residues are low in amount. The refining method comprises the following concrete steps: adding a crude avanafil product into an organic solvent and carrying out heating to a reflux state; after complete dissolving of solids, carrying out standing for cooling to 40 to 20 DEC C; then carrying out stirring for cooling to 10 to -10 DEG C and maintaining the temperature for 1 to 3 h; carrying out filtering; and subjecting a filter cake obtained in the previous step to vacuum drying. The organic solvent is a combination of two solvents, wherein one solvent is a strongly polar solvent and the other solvent is a moderately polar or non-polar solvent.

Disclosed is a method for preparing avanafil (I) by using cytosine as the starting material. The preparation steps comprise: using cytosine as the raw material, and enabling the cytosine to react with side chain 3-chlorine-4-methoxybenzyl halogen, N-(2-methylpyrimidine) methanamide and S-hydroxymethyl pyrrolidine, to prepare the target product avanafil (I). For the preparation method, the raw material is easily obtained, and the process is simple, economical, and environmentally friendly, so the method meets the requirement of industrial boost.

The invention relates to an Avanafil preparation and a preparation method thereof. The Avanafil preparation consists of the following components in percentage by weight: 10-55% of Avanafil, 2-20% of a disintegrating agent, 18-25% of an acidifying agent, 0.2-10% of an adhesive, 0.2-1.0% of a lubricating agent, 0.1-0.5% of coloring agent and the balance of a filling agent; after raw auxiliary material mixing, wet process palletizing and drying, tablets are finally obtained. The preparation can be used for curing male erectile dysfunction and is taken approximately 30 minutes before sexual behavior, and the maximum frequency of dosage is one time a day. The preparation has good stability and dissolution rate, and also has the advantages of better curative effect, quicker action and lower dosage.

Nanosized avanafil (AVA) invasomes with enhanced transdermal delivery are provided. AVA invasomes were prepared with a vesicular size of 109.92 nm and an entrapment efficiency of 96.98%. The AVA invasomal film showed enhanced ex vivo permeation bioavailability compared to a raw AVA film.

The invention discloses a preparation method of avanafil. The method comprises the steps: carrying out amino protective reaction for cytosine (compound 1) which is used as a starting raw material and di-tert-butyl dicarbonate ester to obtain an intermediate I; enabling the intermediate I to firstly react with hexamethyl-disilazane and then to have friedel-crafts reaction with ethyl chloroformate in the existence of aluminum trichloride to obtain an intermediate II; preparing an intermediate III by virtue of substitution reaction between the intermediate II and 4-bromomethyl-2-chlorine-1-metoxybenzene; facilitating the reaction between the intermediate III and sulfonyl chloride to generate activated ester, and then enabling the activated ester to have condensation reaction with L-prolinol to obtain an intermediate IV, and carrying out the hydrolysis reaction for the intermediate IV to obtain an intermediate V; enabling the intermediate V to firstly react with CDI and then to have acylation reaction with 2-pyrimidinemethanamine oxalate to obtain avanafil. According to the method, raw materials for the reaction in each step are simple and easy to obtain, the operation is simple, the yield is high, the cost is low, and the industrialized production is easy to realize.

Formulations are provided for the oral administration of avanafil, a Type V phosphodiesterase inhibitor (“PDE V inhibitor”), and analogs thereof. The formulations are orally disintegrating tablets (ODTs) that rapidly dissolve or disintegrate in the oral cavity. The tablets contain an absorption enhancing composition that increases the duodenal absorption of the active agent, following transfer from the low pH environment of the stomach to the more basic pH of the duodenum. Methods for administering the active agent using the dosage forms are provided. The invention also encompasses a method of selecting components and compositions to incorporate in the formulations which will facilitate increased absorption of the active agent in the duodenum and thus serve as “absorption enhancing compositions” herein. Also provided are methods for manufacturing orally disintegrating tablets to optimize the physical properties of the dosage forms, particularly hardness and disintegration time.

The invention discloses a method for detecting avanafil and related impurities thereof, ammonium formate-acetonitrile is taken as a mobile phase, and avanafil is analyzed and identified by adopting an analysis method of UPLC (Ultra Performance Liquid Chromatography) compatible with LC-MS (Liquid Chromatography-Mass Spectrometry), so that avanafil synthesized by adopting a specific synthesis route and related impurities thereof can be effectively separated; and a new method is provided for key process parameter control and quality control of the avanafil bulk drug.

The invention provides an avanafil effervescent dry suspension and a preparation method thereof. The avanafil effervescent dry suspension comprises avanafil, an effervescent disintegrant, a filler, a suspending agent and other optional medicinal auxiliary materials, wherein the other medicinal auxiliary materials are one or more of a flow aid, a sweetener, essence and a colouring agent, the effervescent disintegrant is composed of an acidic substance and an alkali substance, the weight ratio of avanafil to the acidic substance is 1:(6-25), and the weight ratio of the acidic substance to the alkali substance is 2.5:1 or more. The avanafil effervescent dry suspension is rapid to disperse, fast in effectiveness, high in bioavailability and good in stability, and has the avanafil dissolution rate up to 89% or more.

The present invention provides a novel use of a phosphodiesterase 5 activity inhibitor, namely, as a ripening agent for inducing maturation of zebrafish oocyte, which belongs to the technical field ofaquatic products. The phosphodiesterase 5 activity inhibitor comprises Sildenafil Citrate, Tadalafil and Avanafil. The experiment shows that Sildenafil Citrate, Tadalafil and Avanafil exhibit a dose-dependent, time-dependent and period-dependent manner in promoting oocyte maturation, and moreover, the efficiency of inducing oocyte maturation in zebrafish is higher. In addition, the phosphodiesterase 5 activity inhibitor can be used not only for inducing maturation of zebrafish oocyte, but also for inducing maturation of other fish oocytes, so that the phosphodiesterase 5 activity inhibitor has good application prospect.