WO2015001567A1 - Procédé pour la préparation de (s)-4-[(3-chloro -4-méthoxybenzyl)amino]-2-[2- (hydroxyméthyl)-1-pyrrolidinyl-n-(2-pyrimidinyl méthyl-5-pyrimidine carboxamide - Google Patents

Procédé pour la préparation de (s)-4-[(3-chloro -4-méthoxybenzyl)amino]-2-[2- (hydroxyméthyl)-1-pyrrolidinyl-n-(2-pyrimidinyl méthyl-5-pyrimidine carboxamide Download PDF

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WO2015001567A1
WO2015001567A1 PCT/IN2014/000436 IN2014000436W WO2015001567A1 WO 2015001567 A1 WO2015001567 A1 WO 2015001567A1 IN 2014000436 W IN2014000436 W IN 2014000436W WO 2015001567 A1 WO2015001567 A1 WO 2015001567A1
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formula
compound
chloro
pyrimidine
ethyl
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PCT/IN2014/000436
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English (en)
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Srinivasan Thirumalai Rajan
Sajja Eswaraiah
Komati Satyanarayana
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Msn Laboratories Private Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

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  • the present invention relates to an improved process for the preparation of (S)-4-[(3- chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-l-pyrrolidinyl]-N-(2-pyrimidinyl ethyl)-5-pyrimidine carboxamide which is represented by the following structural formula- 1.
  • (S)-4-[(3-Chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-l-pyrrolidinyl]-N- (2-pyrimidinylmethyl)-5-pyrimidine carboxamide is commonly known as "Avanafil”. It is a PDE5 inhibitor used for the treatment of erectile dysfunction. It acts by inhibiting a specific phosphodiesterase type-5 enzyme which is found in various body tissues, but primarily in the corpus cavernosum penis, as well as the retina. It is developed by Vivus and marketed under the brand name "Stendra".
  • Avanafil and its process for the preparation were first disclosed in US6656935.
  • the process disclosed in US6656935 is depicted in the following scheme:
  • the first aspect of the present invention is to provide a process for the preparation of ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio)pyrimidine-5-carboxylate compound of formula-7.
  • the second aspect of the present invention is to provide a process for the preparation of (S)-4-(3-chloro-4-methoxybenzylamino)-2-(2-(hydroxymethyl)pyrrolidin-l -yl)pyrimidine- 5-carboxylic acid compound of formula- 1 1.
  • the third aspect of the present invention is to provide an improved process for the preparation of Avanafil compound of formula- 1.
  • the fourth aspect of the present invention is to provide a crystalline solid of Avanafil, herein after designated as crystalline form-M.
  • the fifth aspect of the present invention is to provide a process for the purification of Avanafil.
  • the sixth aspect of the present invention is to provide another process for the purification of Avanafil.
  • the seventh aspect of the present invention relates to (3-chloro-4-methoxyphenyl) methanamine malate compound of formula-6b, a novel intermediate of Avanafil.
  • the eighth aspect of the present invention is to provide crystalline form of (3-chloro- 4-methoxyphenyl)methanamine malate compound of formula-6b, herein designated as crystalline form-S. Further the eighth aspect of the present invention also provides a process for the preparation of crystalline form-S of (3-chloro-4-methoxyphenyl)methanamine malate compound of formula-6b.
  • the ninth aspect of the present invention is to provide a process for the preparation of pyrimidin-2-ylmethanamine compound of formula- 12 (or) its acid addition salts.
  • the tenth aspect of the present invention relates to 2,4-bis(3-chloro-4-methoxybenzyl amino)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide (herein after designated as diamine impurity) and N-(3-chloro-4-methoxybenzyl)-4-(3-chloro-4-methoxybenzylamino)- 2-((S)-2-(hydroxymethyl)pyrrolidin- 1 -yl)-N-(2-((S)-2-(hydroxymethyl)pyrrolidin- 1 -yl)-5- (pyrimidin-2-ylmethylcarbamoyl)pyrimidin-4-yl)pyrimidine-5-carboxamide (herein after designated as dimer impurity), which are observed as impurities during the synthesis of A
  • Figure-1 Illustrates the PXRD pattern of crystalline form-M of Avanafil compound of formula- 1.
  • Figure-2 Illustrates the DSC thermogram of crystalline form-M of Avanafil compound of formula- 1.
  • Figure-3 Illustrates the PXRD pattern of crystalline form-S of (3-chloro-4-methoxyphenyl) methanamine malate compound of formula-6b.
  • Figure-4 Illustrates the DSC thermogram of crystalline form-S of (3-chloro-4- methoxyphenyl)methanamine malate compound of formula-6b.
  • suitable solvent used in the present invention is selected from, but not limited to "ester solvents” such as ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate and the like; "ether solvents” such as tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,4-dioxane and the like; “hydrocarbon solvents” such as toluene, hexane, heptane, pet ether, xylene, cyclohexane and the like; “polar aprotic solvents” such as dimethyl acetamide, dimethylsulfoxide, dimethylformamide, N-methyl-2- pyrrolidone and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and
  • suitable base used herein the present invention is selected from inorganic bases like "alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; "alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; organic bases such as triethyl amine, tribenzylamine, isopropyl amine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, dimethylaminopyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1-methylimidazole, 1 ,2,4-triaozle or mixtures thereof.
  • inorganic bases like "alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium
  • suitable oxidizing agent used herein is selected from sodium hypochlorite ⁇ NaOCl ⁇ ; calcium hypochlorite ⁇ Ca(OCl) 2 ⁇ ; sodium bromate ⁇ NaBr0 3 ⁇ ; Dess-Martin periodinane (DMP); oxalyl chloride/dimethyl sulfoxide (Swern oxidation); trichloroisocyanuric acid; TEMPO; pyridiniumchlorochromate (PCC); potassium dichromate; manganese dioxide; oxone; chromium trioxide; N- chlorosuccinimide/dimethylsulfide; Peracids such as metachloro perbenzoic acid, performic acid, peracetic acid and perbenzoic acid.
  • the "suitable chlorinating agent" used in the present invention is phosphoryl chloride or thionyl chloride.
  • phase transfer catalyst used herein is selected from tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetrabuty ammonium tribromide, tetrabutyl ammonium trifluoro methanesulfonate, tetrabutyl ammonium bisulfate, tetrabutyl ammonium nitrate and the like.
  • acid addition salts refers to a salt which is formed by reacting the compound with an acid selected from inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; (or) organic acids such as malic acid, oxalic acids, maleic acid, fumaric acid, acetic acid and the like.
  • Avanafil substantially free of dimer and diamine impurities refers to Avanafil containing dimer impurity and diamine impurity, each one, in an amount of less than about 0.1 area% as measured by HPLC. Specifically, Avanafil as disclosed herein containing diamine and dimer impurity, each one, in an amount less than 0.07 area% by HPLC, more specifically less than about 0.05 area% by HPLC.
  • the first aspect of the present invention provides a process for the preparation of ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio)pyrimidine-5-carboxylate compound of formula-7, comprising of:
  • the condensation of compound of formula-5 with compound of formula-6 (or) its acid addition salts is carried out in presence of inorganic base such as alkali metal hydroxides, alkoxides, carbonates and bicarbonates, preferably sodium carbonate in place of organic base such as triethyl amine, which is reported in prior art.
  • inorganic base such as alkali metal hydroxides, alkoxides, carbonates and bicarbonates, preferably sodium carbonate in place of organic base such as triethyl amine, which is reported in prior art.
  • the main advantage of the present invention is that, it minimizes the usage of number of solvents being used like for example carrying out two or three stages of the process in a single solvent.
  • the suitable solvent used is toluene.
  • toluene is used as a solvent which is carried over into next stage as the reaction mixture. Hence the use of multiple solvents is avoided and further the toluene solvent can be recycled and reused. This has a great impact during scale-up.
  • suitable chlorinating agent used in step-a) of the above aspect is phosphoryl chloride or thionyl chloride.
  • a preferred embodiment of the present invention provides a process for the preparation of ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio)pyrimidine-5- carboxylate compound of formula-7, comprising of:
  • the (3-chloro-4-methoxyphenyl) methanamine hydrochloride compound of formula- 6a used in step-(b) of the above aspect of the present invention is prepared by chlorination of the (4-methoxyphenyl)methanamine with sulfuryl chloride in acetic acid provides compound of formula-6a.
  • Another preferred embodiment of the present invention provides a process for the preparation of ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio)pyrimidine-5- carboxylate compound of formula-7, comprising of:
  • step-b) purifying the compound obtained in step-b) using water to provide pure compound of formula-7.
  • malate salt compound of formula-6b in the condensation reaction with compound of formula-5 will substantially increase the yield & purity of compound of formula-7, which in-turn enhances the yield as well as purity of the final compound.
  • the second aspect of the present invention provides a process for the preparation of (S)-4-(3-chloro-4-methoxybenzylamino)-2-(2-(hydroxymethyl)pyrrolidin-l-yl) pyrimidine-5- carboxylic acid compound of formula- 11 , comprising of:
  • the third aspect of the present invention provides an improved process for the preparation of Avanafil compound of formula- 1 , comprising of:
  • a preferred embodiment of the present invention provides a process for the preparation of Avanafil compound of formula- 1 , comprising of:
  • Another preferred embodiment of the present invention provides a process for the preparation of Avanafil compound of formula- 1 , comprising of:
  • the fourth aspect provides a crystalline solid of (S)-4-[(3-chloro-4-methoxybenzyl) amino]-2-[2-(hydroxymethyl)-l -pyrrolidinyl]-N-(2-pyrimidinylmethyl)-5-pyrimidine carboxamide i.e. avanafil.
  • Avanafil obtained by the process of the present invention is a crystalline solid, which is designated as crystalline form-M.
  • the crystalline form-M of the present invention is characterized by:
  • the fifth aspect of the present invention provides a process for the purification of
  • Avanafil compound of formula- 1 comprising the following steps of:
  • the suitable solvent is selected from ester solvents, ketone solvents, nitrile solvents, hydrocarbon solvents and alcoholic solvents, preferably ethyl acetate, acetone, acetonitrile, toluene and methanol.
  • a preferred embodiment of the present invention provides a process for the purification of Avanafil compound of formula-1 , comprising of:
  • Another preferred embodiment of the present invention provides a process for the purification of Avanafil compound of formula-1 , comprising of
  • Another preferred embodiment of the present invention provides a process for the purification of Avanafil, comprising of:
  • the above purification method avoids the formation of degradation impurities and thereby enhances the purity of avanafil.
  • the sixth aspect of the present invention provides a process for the purification of Avanafil compound of formula-1 , comprising of:
  • the seventh aspect of the present invention provides (3-chloro-4-methoxyphenyl) methanamine malate compound of formula-6b, useful compound in the synthesis of Avanafil.
  • the eighth aspect of the present invention provides a crystalline solid of (3-chloro-4- methoxyphenyl)methanamine malate compound of formula-6b, herein designated as crystalline form-S.
  • the crystalline form-S is characterized by
  • the eighth aspect of the present invention also provides a process for the preparation of crystalline form-S of (3-chloro-4-methoxyphenyl)methanamine malate compound of formula-6b, comprising of:
  • step-(b) adding a suitable solvent selected from hydrocarbon solvents and chloro solvents to the wet solid obtained in step-(b),
  • a preferred embodiment of the present invention provides a process for the preparation of crystalline form-S of (3-chloro-4-methoxyphenyl)methanamine malate compound of formula-6b, comprising of:
  • the ninth aspect of the present invention provides a process for the preparation of pyrimidin-2-ylmethanamine compound of formula- 12 (or) its acid addition salts, comprising of:
  • the alcoholic solvent is selected from methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol and 2-butanol.
  • the conversion of compound of formula- 12 into its acid addition salt is carried out by treating the compound of formula- 12 with a suitable acid selected from inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; (or) organic acids such as malic acid, oxalic acid, maleic acid, furmaric acid and acetic acid.
  • the tenth aspect of the present invention relates to diamine impurity and dimer impurity, which are observed as impurities during the synthesis of Avanafil.
  • the diamine and dimer impurities are represented by the following structural formula
  • the Diamine and Dimer impurities are characterized by ⁇ NMR, IR and Mass spectral data.
  • the Dimer impurity is observed at 1.75 RRT in HPLC and it is synthesized according to the scheme represented below.
  • the Diamine impurity is observed at 1.79 RRT in HPLC and it is prepared according to the scheme represented below.
  • Deschlorodesmethoxy Impurity Aminomethyl Impurity PXRD analysis of the crystalline Avanafil and its intermediate compounds of the present invention was carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.
  • DSC Differential scanning calorimetric
  • Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 2000 instrument. HPLC method of Analysis:
  • Avanafil and its related substances were analyzed by HPLC with the following chromatographic conditions:
  • a liquid chromatograph is equipped with variable wavelength UV-detector and integrator; Column: Kromasil C-18, 250x4.6mm, 5 ⁇ or equivalent; Flow rate: 1.5 mL/minute; Elution: Gradient; Wavelength: 245 nm; Column temperature: 30°C; Injection volume: 5 ⁇ ,; Run time: 60 minutes; Needle wash: Diluent; Diluent: Acetonitrile: buffer (40:60 v/v); Mobile phase A: Buffer (100%); Mobile phase B: Acetonitrile : Water : methanol (75:20:5 v/v);
  • Buffer preparation Transfer about 1.0 ml of Trifluroacetic acid in 1000 ml of mill-Q-water, allow dissolving, then adding 1.0 ml of triethylamine and mixing well. Filter this solution through 0.22 ⁇ filter paper.
  • Avanafil and its related substances can also be analyzed by HPLC with the following chromatographic conditions:
  • a liquid chromatograph is equipped with variable wavelength UV-detector and integrator; Column: Purospher star RP 18 endcapped, 250 x 4.0 mm, 5 ⁇ or equivalent; Flow rate: 1.5 ml/minute; Elution: Gradient; Wavelength: 245 nm; Column temperature: 30°C; Injection volume: 5 ⁇ ; Run time: 60 minutes; Needle wash: Diluent; Diluent: Acetonitrile: Buffer (40:60 v/v); Mobile phase A: Buffer (100%); Mobile phase B: Acetonitrile : Water: Methanol (75: 20: 5 v/v); Buffer preparation: Transfer about 1.0 ml of trifluoro acetic acid in 1000 ml of mill-Q-water, allow to dissolve, then add 1.0 ml of triethylamine and mix well.
  • Avanafil and its related substances can also be analyzed by chiral HPLC with the following chromatographic conditions:
  • a liquid chromatograph is equipped with variable wavelength UV-detector; Column: Chiral pack-IA-3, 250 x 4.6 mm, 3 ⁇ or equivalent; Flow rate: 1.5 ml/minute; Elution: Isocratic; Wavelength: 236 nm; Column temperature: 35°C; Injection volume: 20 ⁇ ; Run time: 60 minutes; Diluent: Methanol:Solution-A(l :9 v/v); Solution-A: n- Hexane:Ethanol: Diethyl amine (60:40:0.1 v/v/v): Needle wash: Methanol; Concentration: 1.0 mg/mL; Solution-B: Ethanol:Isopropyl alcohol (45:55 v/v): Mobile phase composition: n- Hexane:Solution-B:Diethylamine:Trifluoroacetic acid (80:20:0.2:0.1 v/v.
  • Avanafil obtained by the present invention is having purity about 99.7% by HPLC. Even though the process of the present invention is not proceeding through chromatographic purification, controls all the impurities to below ICH limits in which few of them are controlled to not detected level.
  • Avanafil obtained by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
  • the present invention is represented schematically as follows:
  • the organic layer was washed with water followed by with 25% aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure. Methanol (200 ml) followed by Malic acid (83.08 g) were added to the obtained compound and heated to 60-65°C and stirring the reaction mixture for 15 minutes. Cooled the reaction mixture to 25-30°C and stirred for 60 minutes. Filtered the precipitated solid and washed with methanol. The obtained solid was dissolved in water (300 ml) by heating to 85-90°C. Cooled the reaction mixture to 0-5°C and stirred for 1 1 ⁇ 2 hour. Filtered the precipitated solid, washed with water and then dried to get title compound.
  • 1,4-dioxane 500 ml
  • Raney nickel 60 g
  • pyrimidine-2- carbonitrile 100 gms
  • Hydrogen gas was passed into the vessel at a pressure of 7 kg/cm2.
  • the reaction mixture was heated to 65-70°C and stirred for 50 hours.
  • the reaction mixture was cooled to 30-35°C and released the hydrogen gas pressure. Filtered the reaction mixture through hyflow bed, washed with dioxane. Distilled off the solvent from the filtrate to obtain a residue.
  • the obtained residue was cooled to 30-35°C and added methanol (400 ml) into it.
  • Raney nickel (18 g) was added to a mixture of 2-cyanopyrimidine (30 g) and 2- butanol (150 ml) in an autoclave and applied 4-5 kg/cm2 hydrogen pressure. The reaction mixture was heated to 75-80°C and stirred for 15 hours. Cooled the reaction mixture to 25- 30°C and hydrogen gas pressure was released. Filtered the reaction mixture through hyflo bed and washed with 2-butanol. Carbon (1.5 g) was added to the filtrate at 25-30°c and stirred for 15 minutes. Filtered the reaction mixture through hyflo bed and washed with 2- butanol.
  • Diethyl 2-(ethoxymethylene)malonate compound of formula-2 (100 g) was added to a mixture of 2-methyl-2-pseudothiourea sulfate compound of formula-3 (77.24 g) and water (300 ml) at 25-30°C.
  • Sodium carbonate solution (98.04 g of sodium carbonate in 300 ml of water) was slowly added to the reaction mixture at 25-30°C and stirred for 12 hours at the same temperature. After completion of the reaction, quenching the reaction mixture with dilute hydrochloric acid and stirred for 1 hour at 15-20°C. Filtered the precipitated solid and washed with water to obtain title compound. This wet solid taken into next step.
  • step-a The wet solid obtained in step-a) was dissolved in toluene (800 ml) at 85-90°C.
  • the reaction mixture was kept aside for 15 minutes and both the organic and aqueous layers were separated.
  • Phosphoryl chloride 106.36 g was added to the organic layer at 85-90°C.
  • the reaction mixture was further heated to 100-105°C and stirred for 6 hours.
  • the reaction mixture was cooled to 35-40°C and quenched with water. Both the organic and aqueous layers were separated; the aqueous layer was extracted with toluene (600 ml). All the organic layers were combined and washed with water.
  • This organic layer containing ethyl 4-chloro-2-(methylthio) pyrimidine-5-carboxylate compound of formula-5 was taken to the next step without distillation.
  • Step-c) Preparation of ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio) pyrimidine-5-carboxylate (Formula-7) (3-Chloro-4-methoxyphenyl) methanamine hydrochloride compound of formula-6a (76.98 g) was added to the organic layer containing ethyl 4-chloro-2-(methylthio) pyrimidine-5-carboxylate compound of formula-5, which is obtained in step-b). Water (100 ml), followed by sodium carbonate (110.3 g) were added to the reaction mixture at 25-30°C and stirred for 4 hours at the same temperature. After completion of the reaction, water was added to it.
  • Diethyl 2-(ethoxymethylene)malonate compound of formula-2 (100 g) was added to a mixture of 2-methyl-2-pseudothiourea sulfate compound of formula-3 (77.24 g), sodium carbonate (98.04 g) and water (1000 ml) at 25-30°C and stirred for 18 hours at 25-30°C.
  • the reaction mixture was poured into pre-cooled dilute hydrochloric acid solution (150 ml) at 10- 15°C and stirred for 1 hour at 10-15°C. Filtered the precipitated solid and washed with chilled water.
  • the wet solid obtained in step-a) was dissolved in toluene (800 ml) by heating the reaction mixture to 85-90°C.
  • the reaction mixture was kept aside for 15 minutes and both the organic and aqueous layers were separated.
  • the organic layer was heated to 110-115°C to remove water from it. Cooled the reaction mixture to 55-60°C.
  • Phosphoryl chloride (106.36 g) was added to the organic layer at 55-60°C, heated the reaction mixture to 100-105°C and then stirred for 4 hours.
  • the reaction mixture was cooled to 0-5°C and then quenched with water at a temperature below 40°C.
  • the reaction mixture was heated to 40-45 °C and separated both the organic and aqueous layers.
  • the organic layer was washed with 5% sodium carbonate solution followed by water.
  • the organic layer containing the title compound is taken to the next step.
  • Example-ll Preparation of Avanafil (Formula-1)
  • reaction mixture was stirred for 3 hours at 0-5°C.
  • Triethyl amine (8.87 ml) was added to the reaction mixture at 0-5°C and stirred for 2 hours.
  • l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride 24.39 g
  • hydroxybenzotriazole 17.19 g
  • triethyl amine 23.59 ml
  • the reaction mixture further stirred for 18 hours at 0-5°C.
  • Water was added to the reaction mixture at below 10°C and the temperature of the reaction mixture was raised to 25-30°C.
  • Reaction mixture was extracted with ethyl acetate. Washed the organic layer with 10% aqueous potassium carbonate solution, followed by sodium chloride solution.
  • PXRD pattern of the obtained compound is represented in figure- 1 and DSC thermogram of the obtained compound is represented in figure-2.
  • Example-13 Purification of Avanafil using methanol
  • Avanafil 50 g was dissolved in methanol (1 100 ml) at 65-70°C. Carbon (15 g) was added to the reaction mixture and stirred for 15 minutes at the same temperature. Filtered the reaction mixture through hyflow bed, washed with methanol. The reaction mixture was cooled to 0-5°C and stirred for 2 hours. Filtered the precipitated solid, washed with methanol and then dried to get title compound.
  • PXRD and DSC patterns of the obtained compound are similar to the PXRD and DSC patterns of the compound obtained in example- 12.
  • Example-14 Purification of Avanafil using acetonitrile
  • Avanafil (2.0 g) was dissolved in acetonitrile (40 ml) at 80-85°C. The reaction mixture was cooled to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with acetonitrile and then dried to get pure Avanafil.
  • Example-15 Purification of Avanafil using toluene
  • Avanafil (2.0 g) was dissolved in toluene (20 ml) at 105-1 10°C. The reaction mixture was cooled to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with toluene and then dried to get pure Avanafil.
  • Avanafil (2.5 g) was dissolved in acetone (85 ml) by heating the reaction mixture to 55-60°C. The reaction mixture was cooled to 0-5°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with acetone and then dried to get pure Avanafil.
  • Example-17 Purification of Avanafil using dichloromethane and n-pentane
  • Avanafil (2.0 g) was dissolved in dichloromethane (20 ml) at 25-30°C.
  • n-pentane 100 ml was added to the above solution at 25-30°C and stirred for 10 hours at 25-30°. Filtered the precipitated solid, washed with n-pentane and then dried to get pure Avanafil.
  • PXRD and DSC patterns of the obtained compound are similar to the PXRD and DSC patterns of the compound obtained in Example- 12.
  • reaction mixture was cooled to 40-450°C and carbon (24 g) was added to it.
  • the reaction mixture was heated to 65-70°C and stirred for 15 minutes. Filtered the reaction mixture through hyflo bed and washed the bed with aqueous isopropanol. The filtrate was cooled to 0-5°C and stirred for 1 1 ⁇ 2 hour. Filtered the precipitated solid, washed with isopropanol and then dried to get pure Avanafil.

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Abstract

La présente invention concerne un procédé amélioré pour la préparation d'un composé de (S)-4- [(3-chloro -4-méthoxybenzyl) amino]-2-[2-(hydroxyméthyl)-1-pyrrolidinyl]-N-(2-pyrimidinyl éthyl)-5-pyrimidine carboxamide de formule-1 représenté par la formule développée suivante.
PCT/IN2014/000436 2013-07-01 2014-06-30 Procédé pour la préparation de (s)-4-[(3-chloro -4-méthoxybenzyl)amino]-2-[2- (hydroxyméthyl)-1-pyrrolidinyl-n-(2-pyrimidinyl méthyl-5-pyrimidine carboxamide WO2015001567A1 (fr)

Applications Claiming Priority (4)

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IN2915CH2013 2013-07-01
IN2915/CHE/2013 2013-07-01
IN888CH2014 2014-02-24
IN888/CHE/2014 2014-02-24

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CN108395377A (zh) * 2018-01-16 2018-08-14 吴江信凯医药科技有限公司 一种3-氯-4-甲氧基苄胺盐酸盐的制备方法
CN108690000A (zh) * 2018-06-29 2018-10-23 苏州中联化学制药有限公司 一种阿伐那非的精制方法
CN108707141A (zh) * 2018-07-09 2018-10-26 苏州中联化学制药有限公司 阿伐那非的制备方法
CN109232542A (zh) * 2018-09-25 2019-01-18 重庆奥舍生物化工有限公司 一种制备医药化合物阿伐那非的方法
CN109280050A (zh) * 2018-09-25 2019-01-29 重庆奥舍生物化工有限公司 一种医药化合物阿伐那非的制备方法
CN109280049A (zh) * 2018-09-25 2019-01-29 重庆奥舍生物化工有限公司 一种医药化合物阿伐那非的合成方法
CN109438421A (zh) * 2018-11-13 2019-03-08 扬州市三药制药有限公司 一种阿伐那非中间体的精制纯化方法
CN109553607A (zh) * 2017-09-25 2019-04-02 镇江圣安医药有限公司 嘧啶甲酰胺衍生物及其制备方法、组合物、制剂和用途
CN109776505A (zh) * 2019-03-14 2019-05-21 扬州市三药制药有限公司 一种阿伐那非的制备方法
CN111208232A (zh) * 2020-01-20 2020-05-29 山东省药学科学院 一种阿伐那非及其制剂中有关物质的分析方法
CN113880817A (zh) * 2021-12-07 2022-01-04 嘉实（湖南）医药科技有限公司 一种阿伐那非杂质d及其合成方法和应用
CN113917027A (zh) * 2021-10-11 2022-01-11 山东省药学科学院 一种阿伐那非及其中间体的光学异构体分离检测方法
CN114280174A (zh) * 2021-12-07 2022-04-05 嘉实（湖南）医药科技有限公司 一种阿伐那非及其相关杂质的检测方法

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CN104557730A (zh) * 2015-01-27 2015-04-29 江苏嘉逸医药有限公司 阿伐那非关键中间体的制备方法
CN106198766A (zh) * 2015-05-04 2016-12-07 南京从医药科技有限公司 一种阿伐那非及其制剂的高效液相色谱分析方法
CN105439964A (zh) * 2015-12-09 2016-03-30 河北大学 一种阿伐那非中间体的制备方法
CN105924402A (zh) * 2016-05-06 2016-09-07 蚌埠中实化学技术有限公司 一种2-胺基甲基嘧啶盐酸盐的制备方法
CN109553607A (zh) * 2017-09-25 2019-04-02 镇江圣安医药有限公司 嘧啶甲酰胺衍生物及其制备方法、组合物、制剂和用途
CN108395377A (zh) * 2018-01-16 2018-08-14 吴江信凯医药科技有限公司 一种3-氯-4-甲氧基苄胺盐酸盐的制备方法
CN108690000A (zh) * 2018-06-29 2018-10-23 苏州中联化学制药有限公司 一种阿伐那非的精制方法
CN108707141A (zh) * 2018-07-09 2018-10-26 苏州中联化学制药有限公司 阿伐那非的制备方法
CN109280049B (zh) * 2018-09-25 2021-02-02 重庆奥舍生物化工有限公司 一种医药化合物阿伐那非的合成方法
CN109280049A (zh) * 2018-09-25 2019-01-29 重庆奥舍生物化工有限公司 一种医药化合物阿伐那非的合成方法
CN109280050A (zh) * 2018-09-25 2019-01-29 重庆奥舍生物化工有限公司 一种医药化合物阿伐那非的制备方法
CN109280050B (zh) * 2018-09-25 2021-01-29 重庆奥舍生物化工有限公司 一种医药化合物阿伐那非的制备方法
CN109232542A (zh) * 2018-09-25 2019-01-18 重庆奥舍生物化工有限公司 一种制备医药化合物阿伐那非的方法
CN109438421A (zh) * 2018-11-13 2019-03-08 扬州市三药制药有限公司 一种阿伐那非中间体的精制纯化方法
CN109776505A (zh) * 2019-03-14 2019-05-21 扬州市三药制药有限公司 一种阿伐那非的制备方法
CN109776505B (zh) * 2019-03-14 2021-07-27 扬州市三药制药有限公司 一种阿伐那非的制备方法
CN111208232A (zh) * 2020-01-20 2020-05-29 山东省药学科学院 一种阿伐那非及其制剂中有关物质的分析方法
CN113917027A (zh) * 2021-10-11 2022-01-11 山东省药学科学院 一种阿伐那非及其中间体的光学异构体分离检测方法
CN113880817A (zh) * 2021-12-07 2022-01-04 嘉实（湖南）医药科技有限公司 一种阿伐那非杂质d及其合成方法和应用
CN114280174A (zh) * 2021-12-07 2022-04-05 嘉实（湖南）医药科技有限公司 一种阿伐那非及其相关杂质的检测方法
CN114280174B (zh) * 2021-12-07 2023-12-29 嘉实（湖南）医药科技有限公司 一种阿伐那非及其相关杂质的检测方法

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