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WO2009030095A1 - Procédé de préparation de vardénafil et de ses intermédiaires - Google Patents

Procédé de préparation de vardénafil et de ses intermédiaires Download PDF

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Publication number
WO2009030095A1
WO2009030095A1 PCT/CN2007/070648 CN2007070648W WO2009030095A1 WO 2009030095 A1 WO2009030095 A1 WO 2009030095A1 CN 2007070648 W CN2007070648 W CN 2007070648W WO 2009030095 A1 WO2009030095 A1 WO 2009030095A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
mixture
reaction
ice
Prior art date
Application number
PCT/CN2007/070648
Other languages
English (en)
Chinese (zh)
Inventor
Guanghui Tian
Jingshan Shen
Zheng Liu
Jin Zheng
Qingjie Zhao
Original Assignee
Topharman Shanghai Co., Ltd.
Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Topharman Shanghai Co., Ltd., Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences filed Critical Topharman Shanghai Co., Ltd.
Priority to PCT/CN2007/070648 priority Critical patent/WO2009030095A1/fr
Priority to CN2007801005392A priority patent/CN101965348B/zh
Publication of WO2009030095A1 publication Critical patent/WO2009030095A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a process for the preparation of vardenafil and an intermediate thereof. Background technique
  • Vardenafil (vardenafil, the API of ACE ), the structural formula is
  • 4-ketone a selective PDE5 inhibitor developed by Bayer in Germany in 2001, is clinically used for the treatment of ED.
  • the present invention provides a novel process for preparing vardenafil, and the present invention also provides a novel intermediate for the preparation of vardenafil and a process for the preparation thereof.
  • the invention also provides a preparation method of the compound represented by the above formula IV as follows:
  • the compound of the formula IV is obtained by a cyclization reaction in the presence of a compound of the formula V in the presence of a mixture of P0C 1 3 , PC1 3 , PC1 5 or any ratio thereof, and the reaction formula is
  • the preparation method of the compound of the above formula IV is as follows:
  • the compound of the formula IV is a compound of the formula V in the presence of a mixture of P0C1 3 , PC1 3 , PC1 5 or any ratio thereof, 50 ° C -
  • the reaction solution is poured into water, ice water mixture or crushed ice, and the precipitated solid is collected or extracted with an organic solvent, or poured into a mixture of ice and an organic solvent to separate the organic phase; or
  • the compound represented by VI is heated in a mixture of P0C1 3 , PC1 3 , PC1 5 or any ratio thereof in the presence of a mixture of 50 ° C - 120 ° C, and the reaction solution is poured into water, ice water mixture or crushed ice.
  • the precipitated solid is collected or extracted with an organic solvent, or the organic phase is separated by pouring a mixture of ice and an organic solvent; or the compound represented by the formula VI I is reacted with the compound represented by the formula VI II treated with hydrazine hydrate, and steamed.
  • solvents directly on P0C1 3 , PC1 3 , ? (In the presence of a mixture of 1 or 5 , in the presence of a mixture, after heating at 50 ° C - 120 ° C, the reaction solution is poured into water, ice water mixture or crushed ice, and the precipitated solid is collected or extracted with an organic solvent.
  • the organic phase is separated by pouring a mixture of ice and an organic solvent.
  • the organic solvent is dichloromethane, chloroform or ethyl acetate.
  • the reaction process of the method for preparing the compound of the above formula IV may be one of benzene, toluene, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran and 1,4-dioxane or It is carried out arbitrarily in the presence of a mixture.
  • the present invention provides another compound, as shown by the formula:
  • the present invention also provides a preparation method of the compound represented by the above formula:
  • the compound of formula ⁇ is obtained from the compound of formula IV in chlorosulfonate, chlorosulfonyl
  • reaction formula is Or by a halogenation reaction in the presence of a compound of the formula IX in the presence of a mixture of P0C 1 3 , PC1 3 , PC1 5 or any ratio thereof, the reaction formula is
  • the compound of the formula ⁇ is added with chlorosulfonic acid by the compound of the formula IV.
  • the reaction solution is poured into water, ice water mixture or crushed ice, and the precipitated solid is collected or extracted with an organic solvent, or poured into ice.
  • Isolating the organic phase from a mixture with an organic solvent; or the compound of formula IX at P0C 1 3 , PC1 3 , ? In the presence of a mixture of 1 or 5 , in the presence of a mixture, after heating at 50 ° C - 120 ° C, the reaction solution is poured into water, ice water mixture or crushed ice, and the precipitated solid is collected or extracted with an organic solvent.
  • the organic phase is separated by pouring a mixture of ice and an organic solvent.
  • the organic solvent is dichloromethane, chloroform or ethyl acetate.
  • the halogenation reaction in the preparation method of the compound represented by the above formula ⁇ can be carried out in benzene, toluene, , methane, trichloromethane, 1,2-dichloroethane, tetrahydrofuran and 1,4-dioxane, or any mixture thereof in the presence of any mixture.
  • the present invention provides a third compound, as shown in the formula
  • the invention also provides a preparation method of the compound represented by the above formula II as follows:
  • the compound of the formula ⁇ is prepared by reacting a compound of the formula m with 1-ethylpiperazine, which
  • the reaction formula is ; Or a base and a compound represented by the formula ⁇ dissolved in halogenated alkane, benzene, toluene, tetrahydrofuran, or a lower aliphatic ketone or ether solvent, adding - ethylpiperazine reaction.
  • the invention also provides a preparation method of the compound of the formula I, wherein the compound of the formula I is obtained by hydrolysis reaction of the compound of the formula II, and the reaction formula is
  • the solvent for the above reaction is added with one of an alkali metal alkoxide, an alkali metal, an alkaline earth metal hydride, an organic base or a mixture thereof, or one of hydrochloric acid, sulfuric acid, phosphoric acid or an organic acid. It is a mixture of any ratio.
  • the above organic base means an organic amine, a metal salt of an amine, a hydroxide, a carbonate or a carbon.
  • the above organic acid means citric acid, tartaric acid or maleic acid.
  • the compound of the formula ⁇ used in the method for producing the compound of the above formula I can be obtained by the aforementioned method.
  • the preparation of the compound of formula (I) can also be carried out by the following reaction
  • the method for preparing vardenafil disclosed in the present invention reduces the side reaction and impurity generation in some existing method steps, improves the yield of the reaction, and is easy to control the reaction conditions, and has strong industrial applicability.
  • the invention is further illustrated by the following examples.
  • the following examples are only intended to more specifically illustrate the preferred embodiments of the present invention and are not intended to limit the technical solutions of the present invention.
  • the technical solutions of the present invention are all technical solutions for achieving the object of the present invention. That is, the temperatures and reagents used in the following examples can be replaced with the corresponding temperatures and reagents described above to achieve the objects of the present invention.
  • the solvent or reagent used in the test was produced by Sinopharm Chemical Reagent Co., Ltd.; the melting point was determined by BUCHI-510 melting point apparatus, the temperature was not corrected; the mass spectrum was recorded by Finnigan MAT-95 mass spectrometer; the nuclear magnetic resonance spectrum was in Var ian Mercury. Completed on the instrument 300, all spectra are consistent with the speculated structure, and the characteristic peaks are represented by conventional abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet.
  • Room temperature means 20 - 25 °C.
  • the compound of the formula IV is added to the P0C1 3 or PC1 3 under an ice bath, and after 10 minutes, the temperature is slowly raised to 50 ° C - 120 ° C (preferably 80 ° C) for 1 to 10 hours, and the ring closure is completed. Cool to room temperature. After cooling off the P0C1 3 or PC1 3 under ice-cooling, the residue is slowly poured into water, ice-water mixture or crushed ice, and the product is extracted with cooled dichloromethane, dried over anhydrous sodium sulfate, minus The solvent was distilled off at least in an amount, and recrystallized from petroleum ether to give a compound of the formula IV.
  • the compound represented by the formula ⁇ is prepared by the sulfonation of 1-ethylpiperazine with a compound of the formula m in the presence of an acid-binding agent:
  • the compound of the formula ⁇ is dissolved in a solvent, an acid binding agent is added, the temperature is kept below 10 ° C, and about 1.1 molar equivalent of 1-ethylpiperazine is slowly added dropwise, and the reaction is returned to room temperature, and the reaction is 1 ⁇ After 3 hours, distilled water was added, and the organic solvent was extracted, washed with saturated aqueous ammonium chloride and saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to give a white powder.
  • the above solvent may be selected from a halogenated alkane such as dichloromethane, chloroform or 1,2-dichloroethane, benzene, toluene, a lower aliphatic ketone such as acetone, or an ether solvent such as tetrahydrofuran, ethylene glycol monomethyl ether or the like.
  • a halogenated alkane such as dichloromethane, chloroform or 1,2-dichloroethane
  • benzene toluene
  • a lower aliphatic ketone such as acetone
  • an ether solvent such as tetrahydrofuran, ethylene glycol monomethyl ether or the like.
  • the acid binding agent may be an inorganic base such as a carbonate, a hydrogencarbonate or a hydroxide; or an organic base such as triethylamine.
  • the reaction solvent is selected from the group consisting of water and water and methanol, ethanol, isopropanol, tert-butanol, ethylene glycol, ethylene glycol monomethyl ether, tetrahydrofuran, N, N-dimethylformamide, dioxane a mixture of one or several solvents.
  • a base or an acid may be added to the reaction solvent.
  • the base is selected from the group consisting of alkali metal alkoxides, alkali metal or alkaline earth metal hydrides, amines (preferably triethylamine), amine gold hydrochloric acid, sulfuric acid, phosphoric acid, organic acids (such as citric acid, tartaric acid, maleic acid) or a mixture of them.
  • the specific procedure can be carried out by dissolving the compound of the formula ⁇ in a mixed solvent of water and tert-butanol, adding an equivalent amount of sodium hydroxide, and heating at 70 ° C for 2 hours to completely convert into the compound of the formula I.
  • the compound of the formula I I I in the invention can also be obtained from the corresponding carbonyl compound IX chloro group, and the reaction formula is as follows:
  • Both of the above reactions can be carried out in P0C 1 3 , PC 1 3 , PC 1 5 or a mixture thereof, and the reaction can also be carried out in an organic solvent such as benzene, toluene, dichloromethane, chlorine. Imitation or 1,2-dichloroethane.
  • the compound of formula IV in the invention may also be a compound of formula VI I Compounds of formula VI II treated with hydrazine hydrate
  • Another preparation method of the compound of the formula IV is: after the reaction of the compound represented by the formula VI I with the compound of the formula VI II is completed, the solvent is distilled off, and one of P0C1 3 , PC1 3 , PC1 5 is added immediately or Several reactions, after the reaction is completed, are poured into crushed ice and extracted with an organic solvent.
  • the compound represented by VI II in the invention can be obtained by the method of J. Chem. Soc. Perkin Trans. 1; EN; 1980; 1139-1146, from o-ethoxybenzidine and hydrazine hydrate in ethanol. The reaction is obtained.
  • the compound represented by VI I in the invention is a known compound and can be obtained by a method (J. Chem. Soc. Perkin Trans. 1; EN; 1980; 1139-1146).
  • the compound of the formula X involved in the invention is obtained by a conventional method of organic chemistry, and is obtained by reacting butyryl chloride with D, L-alanine.
  • the method for preparing vardenafil disclosed in the present invention reduces some existing method steps
  • the side reaction and the generation of impurities increase the yield of the reaction, the reaction conditions are easily controlled, and have strong industrial applicability.
  • o-Ethyl benzamidine hydrochloride (VIII) (2. Olg, 10 mmol) was dissolved in ethanol (15 mL), and 85% hydrazine hydrate (0.59 mL, 10 ⁇ ol) was slowly added dropwise in an ice bath. After completion, the reaction was carried out in an ice bath for 30 minutes, and stirred at room temperature for 1 hour. Then, a solution of the product 2 (2.58 g) in ethanol (15 mL) was added, and the mixture was heated to reflux for 3 hours, and the solid was filtered, and the solvent was evaporated to give an oil.
  • VIII o-Ethyl benzamidine hydrochloride
  • the compound III (0.43 g, 1 mmol) was dissolved in dichloromethane (20 mL), triethylamine (0.20 g, 2 ⁇ ol) was added, and the mixture was diluted with ice-cooling, and then diluted dropwise with dichloromethane (5 mL).
  • o-Ethyl benzamidine hydrochloride ( VIII ) (2. Olg, 10 mmol) was dissolved in ethanol (15 mL), and 85% hydrazine hydrate (0.59 mL, 10 ⁇ ol) was slowly added dropwise in an ice bath. After completion, the reaction was carried out in an ice bath for 30 minutes, and stirred at room temperature for 1 hour. Then, a solution of the product of Preparation 2 (2.58 g) in ethanol (15 mL) was added, and the mixture was heated under reflux for 3 hours, filtered, and the solvent was evaporated to give an oil. P0C1 3 (3mL), heated under reflux for 3 hours, TLC observed the reaction was complete, Evaporate excess phosphorus oxychloride under reduced pressure, slowly pour the residue into crushed ice, and immediately use dichloromethane.
  • the product was extracted (30 mL), and the organic phase was washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, and evaporated to dryness.
  • the compound III (0.43 g, 1 mmol) was dissolved in tetrahydrofuran (20 mL), triethylamine (0.20 g, 2 ⁇ ol) was added, and the N-ethylpiper diluted with tetrahydrofuran (5 mL) was slowly added dropwise under ice cooling.
  • the oxazine (0.114g, 1mmol) was removed from the ice bath and allowed to react to room temperature for 2 hours. The solvent was evaporated under reduced pressure.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne un procédé permettant de préparer du vardénafil et ses intermédiaires. Le procédé est nouveau. L'invention concerne également de nouveaux intermédiaires permettant de préparer du vardénafil ainsi que ses préparations. Le procédé de préparation du vardénafil a réduit les réactions secondaires lors des procédés de la technique antérieure et d'autre étapes, a amélioré le rendement et est aisé à mettre en œuvre. Il présente par conséquent une excellente applicabilité industrielle.
PCT/CN2007/070648 2007-09-06 2007-09-06 Procédé de préparation de vardénafil et de ses intermédiaires WO2009030095A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/CN2007/070648 WO2009030095A1 (fr) 2007-09-06 2007-09-06 Procédé de préparation de vardénafil et de ses intermédiaires
CN2007801005392A CN101965348B (zh) 2007-09-06 2007-09-06 伐地那非的制备方法及其中间体

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2007/070648 WO2009030095A1 (fr) 2007-09-06 2007-09-06 Procédé de préparation de vardénafil et de ses intermédiaires

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013057205A1 (fr) 2011-10-20 2013-04-25 Technische Universitaet Wien Dérivés de diazabicycloalcane et de diazaspiroalcane comme inhibiteurs de la phosphodiestérase-5
WO2013075680A1 (fr) 2011-11-24 2013-05-30 Zentiva, K.S. Procédé de préparation et d'isolement de sels de vardénafil utilisant des acides
CN109553591A (zh) * 2019-01-15 2019-04-02 齐鲁天和惠世制药有限公司 一种富马酸喹硫平中间体的制备方法
US11806314B2 (en) 2013-12-09 2023-11-07 Respira Therapeutics, Inc. PDE5 inhibitor powder formulations and methods relating thereto

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999024433A1 (fr) * 1997-11-12 1999-05-20 Bayer Aktiengesellschaft Imidazotriazinones a substitution 2-phenyle utilisees comme inhibiteurs des phosphodiesterases
WO2002050076A2 (fr) * 2000-12-18 2002-06-27 Bayer Aktiengesellschaft Procede de production d'imidazotriazinones a substitution sulfonamide
WO2002089808A1 (fr) * 2001-05-09 2002-11-14 Bayer Healthcare Ag Nouvelle utilisation d'imidazotriazinones substituees 2-phenyl
US20060264624A1 (en) * 2005-05-20 2006-11-23 Alexander Heim-Riether Methods for synthesizing imidazotriazinones

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999024433A1 (fr) * 1997-11-12 1999-05-20 Bayer Aktiengesellschaft Imidazotriazinones a substitution 2-phenyle utilisees comme inhibiteurs des phosphodiesterases
WO2002050076A2 (fr) * 2000-12-18 2002-06-27 Bayer Aktiengesellschaft Procede de production d'imidazotriazinones a substitution sulfonamide
WO2002089808A1 (fr) * 2001-05-09 2002-11-14 Bayer Healthcare Ag Nouvelle utilisation d'imidazotriazinones substituees 2-phenyl
US20060264624A1 (en) * 2005-05-20 2006-11-23 Alexander Heim-Riether Methods for synthesizing imidazotriazinones

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013057205A1 (fr) 2011-10-20 2013-04-25 Technische Universitaet Wien Dérivés de diazabicycloalcane et de diazaspiroalcane comme inhibiteurs de la phosphodiestérase-5
WO2013075680A1 (fr) 2011-11-24 2013-05-30 Zentiva, K.S. Procédé de préparation et d'isolement de sels de vardénafil utilisant des acides
US11806314B2 (en) 2013-12-09 2023-11-07 Respira Therapeutics, Inc. PDE5 inhibitor powder formulations and methods relating thereto
US12364701B2 (en) 2013-12-09 2025-07-22 Respira Therapeutics, Inc. PDE5 inhibitor powder formulations and methods relating thereto
CN109553591A (zh) * 2019-01-15 2019-04-02 齐鲁天和惠世制药有限公司 一种富马酸喹硫平中间体的制备方法

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CN101965348B (zh) 2013-11-13
CN101965348A (zh) 2011-02-02

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