WO2010010058A1 - Méthode de préparation de chlorhydrate d'alfuzosine anhydre - Google Patents

Méthode de préparation de chlorhydrate d'alfuzosine anhydre Download PDF

Info

Publication number
WO2010010058A1
WO2010010058A1 PCT/EP2009/059284 EP2009059284W WO2010010058A1 WO 2010010058 A1 WO2010010058 A1 WO 2010010058A1 EP 2009059284 W EP2009059284 W EP 2009059284W WO 2010010058 A1 WO2010010058 A1 WO 2010010058A1
Authority
WO
WIPO (PCT)
Prior art keywords
alfuzosin
peak
angle
relative intensity
camphorsulfonate
Prior art date
Application number
PCT/EP2009/059284
Other languages
English (en)
Inventor
Jacopo Zanon
Tiziana Piovesana
Andrea Nicole'
Original Assignee
Lundbeck Pharmaceuticals Italy S.P.A.
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 Lundbeck Pharmaceuticals Italy S.P.A. filed Critical Lundbeck Pharmaceuticals Italy S.P.A.
Publication of WO2010010058A1 publication Critical patent/WO2010010058A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a method of preparing anhydrous alfuzosin hydrochloride with a high degree of purity which allows it to be used as an active ingredient in medicaments.
  • the purification of the crude alfuzosin hydrochloride is achieved through novel process intermediates which are part of the invention as well.
  • State of the art Patent US No 4,315,007 (Applicant Synthelabo) describes a class of Ch adrenergic receptors antagonist drugs and processes for obtaining them.
  • alfuzosin chemical designation: ⁇ / 1 -(4-amino-6,7-dimethoxyquinazol-2-yl)- ⁇ / 1 - methyl- ⁇ / 2 -(tetrahydro-furoyl-2)-propylenediamine
  • hydrochloryde salt form thereof has been widely employed in the therapy of cardiovascular diseases and particularly as an anti-hypertensive drug.
  • two different examples of preparing alfuzosin hydrochloryde are described.
  • the first of the two processes for preparing alfuzosin hydrochloryde and described in the above-mentioned patent essentially involves the preparation of a reagent (i.e. ⁇ / 1 -methyl- ⁇ / 2 -(tetrahydrofuroyl-2)-propylenediamine) and the subsequent condensation reaction between such a reagent and 4-amino-2-chloro-6,7- dimethoxyquinazoline. After washing, the crude products obtained by filtrating the precipitate and evaporating the liquor obtained from the filtration, are crystallized from an ethanol/ether mixture. The reported melting point is 235 °C (with decomposition).
  • the second of the two reported synthesis examples is much more complex and describes the preparation of the compound from 4-amino-2-chloro-6,7- dimethoxyquinazoline and 3-methylaminopropionitrile, thus obtaining N-(4-amino- 2-chloro-6,7-dimethoxyquinazol-2-yl)-N-methyl-2-cyanoethylamine.
  • Such an intermediate is then hydrogenated in the presence of a Raney's nickel catalyst and after further treatments the obtained amine is treated with HCI.
  • N r (4- amino-2-chloro-6,7-dimethoxyquinazol-2-yl)-Nrmethylpropylene diammine hydrochloride is obtained with a m.p.
  • a solution of alfuzosin hydrochloride in an organic solvent is treated with a base (preferably an inorganic base selected from hydroxides, carbonates and bicarbonates of alkali metals such as sodium and potassium) to obtain the crude alfuzosin base in the form of non-crystalline solid or oily residue.
  • a base preferably an inorganic base selected from hydroxides, carbonates and bicarbonates of alkali metals such as sodium and potassium
  • a base preferably an inorganic base selected from hydroxides, carbonates and bicarbonates of alkali metals such as sodium and potassium
  • ketonic solvents are selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone and methyl tert-butyl ketone, whereas preferred alcoholic solvents are chosen from methanol, ethanol, isopropyl alcohol and ter-butyl alcohol.
  • the most preferred ketonic solvents are acetone and methyl isobutyl ketone and the most preferred alcoholic solvents are methanol and ethanol. More recently, in patent application WO2006/090268 Glen-Mark Pharmaceuticals
  • This compound being able to produce polymorphs, and also the problem of eliminating formation of impurities during the process of preparing the compound, determine the need for identifying novel processes of preparing this active ingredient so as to ensure a high purity thereof and then allow it to be pharmaceutically used.
  • the method of preparing anhydrous alfuzosin hydrochloride according to the invention comprises at least the steps of: a) converting crude alfuzosin hydrochloride to alfuzosin camphorsulfonate in an organic solvent and isolating the same in form of crystalline solid from the organic phase; b) converting alfuzosin camphorsulfonate to anhydrous alfuzosin hydrochloride in an organic solvent and separating the same in the form of crystalline solid.
  • the method of preparing anhydrous alfuzosin hydrochloride comprising the above-mentioned steps is an object of the invention.
  • the method object of the invention may also comprise the further step of preparing crude alfuzosin hydrochloride.
  • a further object of the invention is alfuzosin camphorsulfonate, the same being an essential intermediate to obtain anhydrous and crystalline alfusozin hydrochloride with a high purity and thus suitable to be employed as an active pharmaceutical grade ingredient in medicaments, according to the claims set forth hereinafter.
  • Figure 1 shows a representative XRPD diffractometric profile for anhydrous alfuzosin hydrochloride obtainable by the method according to the invention.
  • FIG. 2 shows a representative Nuclear Magnetic Resonance proton spectrum ( 1 H-NMR) obtained in deuterated dimethylsulfoxyde of alfuzosin camphorsulfonate obtainable by the method according to the invention.
  • FIG 3. The figure shows a representative IR spectrum for alfuzosin camphorsulfonate obtainable by the method according to the invention.
  • Figure 4. The figure shows a differential scanning calorimetry (DSC) of a representative sample of alfuzosin camphorsulfonate obtainable by the method according to the invention.
  • DSC differential scanning calorimetry
  • FIG. 5 shows an XRPD diffractometric profile for alfuzosin camphorsulfonate obtainable by the method according to the invention.
  • the method of preparing anhydrous alfuzosin hydrochloride object of the present invention refers to the diagram reported below, which comprises as the 1 st step the synthesis of crude alfuzosin HCI obtained according to known procedures already described in US Patent No. 4,315,007.
  • preparing anhydrous alfuzosin hydrochloride comprises that the crude alfuzosin HCI is preferably prepared by condensing /Vrmethyl- ⁇ k- (tetrahydrodrofuroyl-2)-propylenediamine and 4-amino-2-chloro-6,7-dimethoxy quinazoline in an organic solvent selected from alcoholic or ketonic solvents or a mixture thereof at solvent reflux temperature under nitrogen and vigorously stirring. The solid may then be separated by known means (e.g. by filtration), washed with organic solvents such as for example ethyl acetate, acetone, isopropyl ether and mixtures thereof and finally dried.
  • organic solvents such as for example ethyl acetate, acetone, isopropyl ether and mixtures thereof and finally dried.
  • the step of converting crude alfuzosin hydrochloride to solid crystalline alfuzosin camphorsulfonate comprises: a) treating crude alfuzosin HCI in chlorinated or ester organic solvents with basic aqueous solutions; b) separating the base- containing organic phase for the following conversion treatment to camphorsulfonate salt; c) isolating the alfuzosin camphorsulfonate salt obtained in the crystalline form by distilling the organic phase and/or recrystallization of and/or grinding the residue and/or adding an organic solvent selected from acetone, toluene or mixtures thereof.
  • crude alfuzosin hydrochloride is treated in a medium consisting of a chlorinated organic solvent, preferably methylene chloride, or alternatively ester, preferably ethyl acetate, with a basic aqueous solution selected from the group consisting of hydroxides, carbonates, bicarbonates of alkali metals (preferably Na and K) and alkylamines (preferably triethylamine) until obtaining a pH of at least 7 at room temperature (15-25 0 C) and under stirring.
  • a basic aqueous solution selected from the group consisting of hydroxides, carbonates, bicarbonates of alkali metals (preferably Na and K) and alkylamines (preferably triethylamine) until obtaining a pH of at least 7 at room temperature (15-25 0 C) and under stirring.
  • the two aqueous and organic phases, which are formed upon this treatment are separated and the base- containing organic phase is treated with camphorsulfonic acid with a molar ratio alfuzosin base:camphorsulfonic acid of at least 0.9, and preferably of 1.2 at room temperature (15-25°C) and under stirring.
  • the obtained crude alfuzosin camphorsulfonate is then purified and isolated in the crystalline state from the organic solvent medium, in which the conversion has been performed, by means of known in the art methods and preferably by distillation and/or by subsequent crystallization, thus subjecting the same to re-crystallization and/or grinding of the residue obtained from distillation and/or adding an organic solvent selected from acetone, toluene or mixtures thereof, and preferably toluene.
  • the mixture consisting of crude alfuzosin camphorsulfonate and organic solvent or mixtures of organic solvents is warmed up to the solvent distillation temperature and then distillation is gradually performed raising the temperature up to at least 100°-1 10°C under stirring.
  • the mixture is then allowed to slowly cool under stirring to room temperature (15-25 0 C).
  • the obtained solid is separated by known means (for example by filtration), washed and vacuum dried at a temperature ranging from 40 °C to 60 °C over a period of at least 12-24 hours, and preferably 16 hours, thus obtaining alfuzosin camphorsulfonate with the characteristics hereinafter described.
  • the subsequent conversion of crystalline alfuzosin camphorsulfonate to anhydrous alfuzosin hydrochloride is obtainable by: a) treating an aqueous solution of alfuzosin camphorsulfonate with a base and treating the mass with chlorinated or ester organic solvents; b) separating the organic phase by extraction of residual water in the organic phase and treating it with HCI/ethanol; c) separating by means of distillation and/or crystallization of the crystalline solid form of anhydrous alfuzosin hydrochloride, washing with ethanol and drying it.
  • crystalline alfuzosin camphorsulfonate is dissolved in water and treated with a base until obtaining a pH of at least 7, as previously mentioned for the crude alfuzosin hydrochloride, and the mass obtained is then treated with a solvent selected from a chlorinated solvent or an ester solvent and preferably from dichloromethane and ethyl acetate, at room temperature (15-25 0 C) and under stirring.
  • a solvent selected from a chlorinated solvent or an ester solvent and preferably from dichloromethane and ethyl acetate
  • Such organic phase is then treated at a temperature of 15-25°C with a solution of HCI/ethanol (EtOH), where HCI is in a concentration of at least 5% (w/w).
  • EtOH HCI/ethanol
  • the solvent is then distilled under reduced pressure and ethanol is added again to the residue.
  • An atmospheric pressure distillation at the ethanol distillation temperature is performed.
  • the residual mass is slowly cooled to 15-25°C and kept at this temperature for at least 1 hour.
  • the solid is then separated, washed with EtOH and dried, thus obtaining anhydrous alfuzosin hydrochloride, as a crystalline solid.
  • anhydrous alfuzosin hydrochloride through alfuzosin camphorsulfonate allows high purities to be achieved by means of a simple process, which in turn allow for obtaining pharmaceutical grade alfuzosin hydrochloride in few steps.
  • the characteristics and high crystallinity of the alfuzosin camphorsulfonate salt enhance its stability. Hence, this intermediate can be easily stored.
  • the method of preparing anhydrous alfuzosin hydrochloride object of the invention as a whole comprises the steps of: - converting crude alfusozin hydrochloride to alfuzosin camphorsulfonate by separating the same in a crystalline form, wherein the alfuzosin camphorsulfonate salt is obtainable by: a) treating crude alfuzosin HCI in chlorinated or ester organic solvents with basic aqueous solutions; b) separating the organic phase and treating the same with camphorsulfonic acid; c) isolating the alfusozin camphorsulfonate salt obtained in crystalline form by means of distillation of the organic phase and/or re-crystallization of and/or grinding the residue and/or adding an organic solvent selected from acetone, toluene or mixtures thereof; converting alfuzosin camphorsulfonate salt to anhydrous alfuzosin hydrochloride, wherein the anhydrous alfuz
  • the method object of the invention can also comprise the further step of preparing crude alfuzosin hydrochloride and in this case the compound is preferably prepared by means of conjugation using a condensation reaction between /V 1 - methyl- ⁇ / 2 -(tetrahydrofuroyl-2)-propylenediamine and 4-amino-2-chloro-6,7- dimethoxyquinazoline.
  • anhydrous alfuzosin hydrochloride having characteristics completely similar as those of the product described in US Patent No. 5,545.738, as will be apparent from the characterization reported below, and a novel alfuzosin salt, that is alfuzosin camphorsulfonate having characteristics of high purity and crystallinity. Therefore, alfuzosin camphorsulfonate having at least one of the characteristics hereinafter described is a further object of the invention. Characterization of anhydrous alfuzosin hydrochloride
  • Anhydrous alfuzosin hydrochloride obtainable by the method of preparation object of the invention has the following characteristics: Molecular formula: C19H28CIN5
  • anhydrous alfuzosin hydrochloride appears as a white crystalline solid.
  • the obtained compound exhibits the XRPD profile reported in figure 1 and/or comprising the peaks reported in the following table.
  • anhydrous alfuzosin hydrochloride has the same characteristics as the compound cited as anhydrous alfuzosin hydrochloride in U.S. Patent No. 5,545,738. Characterization of alfuzosin camphorsulfonate
  • Alfuzosin camphorsulfonate [tetrahydro-furan-2-carboxylic acid ⁇ / 1 -(4-amino-6,7- dimethoxyquinazol-2-yl)- ⁇ / 1 methyl- ⁇ / 2 -(tetrahydro-furoyl-2)-propylenediamine] (7,7- dimethyl-2-oxo-bicycl[2,2,1 ]ept-1 -yl)-methanesulfonate, obtainable by the process object of the invention has at least one of the following structural and/or physicochemical characteristics: Molecular formula: 0 29 H 43 N 5 Or 8 S
  • Figure 2 shows the above reported proton spectrum.
  • LR. (KBr cm r ' U 1 ). ⁇ 3369.18, 3198.96, 2951 .00, 1736.52, 1607.24, 1528.85,
  • DSC Differential scanning calorimetry
  • alfuzosin camphorsulfonate appears as a white crystalline solid.
  • the obtained compound exhibits the XRPD profile depicted in figure 5 and/or comprising the peaks reported in the following table.
  • Alfuzosin camphorsulfonate yield 70%; purity determined by HPLC 99.38%.
  • Example 2 Preparation of anhydrous alfuzosin hydrochloride from alfuzosin camphorsulfonate Into a 2 L 4-neck flask, 320 ml_ of water and 142 g of alfuzosin camphorsulfonate were loaded portionwise under stirring. 35 ml of 30% NaOH and 1420 ml_ of CH 2 CI 2 were added to the so obtained solution, and the biphasic solution was kept under stirring at a temperature of about 20 °C for 30 min.
  • the mass was kept at such a temperature until obtaining an amount of residue of about 300 ml_.
  • the distillation being stopped, the mass was cooled in 1 hour about at 20 °C, then filtered and the panel was washed with 50 ml_ of EtOH.
  • the obtained crystalline solid was vacuum dried at 50°C for about 12 hours yielding 85 g (0.199 moles) of ⁇ / 1 -(4-amino-6,7-dimethoxyquinazol-2-yl)- ⁇ / 1 methyl- ⁇ / 2 -(tetrahydro-furoyl-2)-propylenediamine] hydrochloride (alfuzosin hydrochloride) as a white crystalline solid.
  • Alfuzosin hydrochloride yield 87.5%; purity determined by HPLC 99.8%
  • Example 3 Preparation of alfuzosin base in a solution of CH 2 CI 2 38g (0.082 moles) of alfuzosin hydrochloride (purity 97% determined by HPLC), 75 ml_ of H 2 O and 75 ml_ of K 2 CO 3 in a saturated aqueous solution are loaded in a glass jacketed reactor; the mixture is extracted twice with 150 ml_ of CH 2 CI 2 . The aqueous phase is discarded and the organic solution washed twice with 75 ml_ of purified water.
  • the dichloromethane solution contains about 27.7g (0.071 moles) of ( ⁇ )tetrahydro- furan-2-carboxylic acid [3-[4-amino-6,7-dimethoxy-quinazolin-2-yl]-methyl-amino]- propyl]-amide.
  • Example 4 Preparation of alfuzosin camphorsulfonate salt obtained from a solution of alfuzosin base in CH 2 CI 2
  • 14.2 g (0.061 moles) of ( ⁇ )camphoM O-sulfonic acid ( ⁇ ) were added portionwise to such a solution under vigorous stirring.
  • the mixture was kept under stirring for 2-3 hours at ambient temperatures and under nitrogen and then concentrated by distillation (atmospheric pressure, 40°C) of 150 ml_ of methylene chloride.
  • the product was obtained in the form of a white crystalline powder, isolated by means of filtration, washed with 50 ml of toluene, vacuum dried at 50 °C overnight, thus obtaining 26 g (0.042 moles) of ⁇ / r (4-amino-6,7-dimethoxyquinazol-2-yl)- ⁇ / 1 methyl- ⁇ / 2 -(tetrahydro-furoyl-2)-propylenediamine] (7,7-dimethyl-2-oxo-bicycl [2,2,1 ]ept-1 -yl)-methanesulfonate (alfuzosin camphorsulfonate).
  • Alfuzosin camphorsulfonate salt yield 82%; purity determined by HPLC 99.4% Example 5.
  • Preparation of alfuzosin salt camphorsulfonate from alfuzosin base In a glass jacketed reactor, 20 g (0.051 moles) of alfuzosin base (0.051 mol), 200 ml_ methylene chloride were loaded. The mixture was kept under stirring, at room temperature under nitrogen for 30 min, and then 14.2 g (0.061 mol) of ( ⁇ )camphor- 10-sulfonic acid ( ⁇ ) are added portionwise and under vigorous stirring.
  • Alfuzosin camphorsulfonate salt yield 82%; purity determined by HPLC 99.9% Example 6.
  • Preparation of alfuzosin salt camphorsulfonate from alfuzosin base in ethyl acetate solution In one glass jacketed reactor 30 g (0,076 moles) of alfuzosin base, 150 ml_ of ethyl acetate, 21.2 g (0,091 moles) of ( ⁇ )camphoM 0-sulfonic acid ( ⁇ ) were loaded.
  • Alfuzosin camphorsulfonate salt was obtained in the form of white crystalline powder and isolated by means of filtration, washed with 30 ml_ of ethyl acetate, vacuum dried at 50 °C overnight, thus obtaining 42 g (0.067 moles) of ⁇ / r (4-amino- 6,7-dimethoxyquinazol-2-yl)- ⁇ / 1 methyl- ⁇ / 2 -(tetrahydro-furoyl-2)-propylenediamine] (7,7-dimethyl-2-oxo-bicycl[2,2,1 ]ept-1 -yl)-methanesulfonate (alfuzosin camphorsulfonate).
  • Alfuzosin camphorsulfonate salt yield 88%; purity determined by HPLC 97%
  • Example 7 Preparation of alfuzosin camphorsulfonate from crude alfuzosin hydrochloride treated with NaOHZCH 2 CI 2
  • 232 g 0.544 moles of crude alfuzosin hydrochloride, 500 ml_ of water, 55 ml_ of a 30% aqueous solution of sodium hydroxide and 2320 ml_ of methylene chloride were added.
  • the mass was kept under stirring for at least 30 min and, the stirring being stopped, the phases were separated.
  • the organic phase was reloaded and extracted with 550 ml_ of water, then reloaded again and 137 g (0.590 moles) of camphorsulfonic acid at a temperature of about 20 °C were added thereto over about 15 min. A complete dissolution is observed. Distillation of dichloromethane under reduced pressure, until the residue could be stirred, by keeping the jacket temperature about 40 °C was then performed. 2300 ml_ of toluene were added to the obtained oily residue and the mass was heated up to distillation temperature (87 0 C). The solvent was then distilled by progressively heating the mass, continuing the distillation until the internal temperature of about 1 10°C was reached.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne un procédé de préparation de chlorhydrate d'alfuzosine anhydre par réaction de condensation entre la N 1-méthyl-N 2-(tétrahydrodrofuroyl-2)-propylènediamine et la 4-amino-2-chloro-6,7-diméthoxyquinazoline. Le produit brut obtenu est ensuite purifié par d'autres étapes dont des étapes de préparation de nouveaux intermédiaires. Le processus de synthèse et de purification d'alfuzosine décrit permet d'obtenir le principe actif d'une grande pureté avec un rendement élevé, qui convient donc pour être utilisé en tant que principe actif dans les médicaments.
PCT/EP2009/059284 2008-07-21 2009-07-20 Méthode de préparation de chlorhydrate d'alfuzosine anhydre WO2010010058A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITPD2008A000215A IT1390760B1 (it) 2008-07-21 2008-07-21 Metodo di preparazione di alfuzosin cloridrato anidro
ITPD2008A000215 2008-07-21

Publications (1)

Publication Number Publication Date
WO2010010058A1 true WO2010010058A1 (fr) 2010-01-28

Family

ID=40481739

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2009/059284 WO2010010058A1 (fr) 2008-07-21 2009-07-20 Méthode de préparation de chlorhydrate d'alfuzosine anhydre

Country Status (2)

Country Link
IT (1) IT1390760B1 (fr)
WO (1) WO2010010058A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104244715A (zh) * 2012-02-02 2014-12-24 陶氏益农公司 杀虫组合物及与其相关的方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006030449A1 (fr) * 2004-09-16 2006-03-23 Hetero Drugs Limited Base d'alfuzosine cristalline
WO2007063556A2 (fr) * 2006-12-07 2007-06-07 Msn Laboratories Limited Processus industriel ameliore pour la preparation de chlorhydrate d'alfuzosine et de ses nouveaux polymorphes
WO2009007987A1 (fr) * 2007-07-11 2009-01-15 Alembic Limited Procédé amélioré pour la préparation d'alfuzosine et de son nouveau polymorphe

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006030449A1 (fr) * 2004-09-16 2006-03-23 Hetero Drugs Limited Base d'alfuzosine cristalline
WO2007063556A2 (fr) * 2006-12-07 2007-06-07 Msn Laboratories Limited Processus industriel ameliore pour la preparation de chlorhydrate d'alfuzosine et de ses nouveaux polymorphes
WO2009007987A1 (fr) * 2007-07-11 2009-01-15 Alembic Limited Procédé amélioré pour la préparation d'alfuzosine et de son nouveau polymorphe

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
M. S. REDDY ET AL.: "An improved and commercially viable process for the preparation of Alfuzosin hydrochloride", ARKIVOC, vol. XIII, 2007, pages 41 - 46, XP002522710 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104244715A (zh) * 2012-02-02 2014-12-24 陶氏益农公司 杀虫组合物及与其相关的方法

Also Published As

Publication number Publication date
ITPD20080215A1 (it) 2010-01-22
IT1390760B1 (it) 2011-09-23

Similar Documents

Publication Publication Date Title
EP2534131B1 (fr) Procédés de synthèse et d'isolement de n-(bromoacetyle)-3,3-dinitroazetidine et composition le comprenant
US20220024885A1 (en) Methods for producing viloxazine salts and novel polymorphs thereof
US8378106B2 (en) Method for preparing argatroban monohydrate and a process for its synthesis
WO2015124764A1 (fr) Procédé de synthèse de dabigatran étexilate mésylate, intermédiaires de ce procédé et nouveau polymorphe de dabigatran étexilate
CN110114346A (zh) 用于制备r-6-羟基-8-[1-羟基-2-[2-(4-甲氧基苯基)-1，1-二甲基乙基氨基乙基]-2h-1，4-苯并噁嗪-3(4h)-酮盐酸盐的改进方法
SK8332002A3 (en) Novel processes for making- and a new crystalline form of leflunomide
WO2016150283A1 (fr) Hydrate de dichlorhydrate de 2-isopropoxy-5-méthyl-4-(4-pipéridyl)aniline, son procédé de préparation et utilisations associées
WO2015049698A2 (fr) Procédé pour le régorafénib
JPH11116570A (ja) ジヒドロピリジン誘導体の製造法
WO2006030449A1 (fr) Base d'alfuzosine cristalline
WO2010010058A1 (fr) Méthode de préparation de chlorhydrate d'alfuzosine anhydre
US8952148B2 (en) Process for the preparation of taurolidine and its intermediates thereof
CN112094219B (zh) 一种制备钾离子竞争性阻滞剂中间体的方法
EP3794001B1 (fr) Intermédiaires et procédés pour la préparation de linagliptine et de ses sels
WO2017021466A1 (fr) Procédé de préparation de chlorhydrate d'ivabradine solide
WO2005030698A1 (fr) Procede de preparation de voglibose
WO2011117876A1 (fr) Procédé amélioré pour la préparation de base libre d'amlodipine et des sels d'addition d'acide de celle-ci
KR20090014225A (ko) （ｒ）-5-（2-아미노에틸）-1-（6,8-디플루오로크로만-3-일）-1,3-디히드로이미다졸-티온 히드로클로라이드의 다형체
WO2015104602A2 (fr) Procédé de préparation d'anagliptine et de ses intermédiaires
TW202019872A (zh) 稠合三環γ-胺基酸衍生物的製備方法及其中間體
EP2072510A1 (fr) Forme cristalline d'azélastine
US11040983B1 (en) Cocrystal of varenicline and oxalic acid, pharmaceutical composition thereof, and methods of use thereof
EP2540717B1 (fr) Oxalate de lamivudine et procédé de préparation associé
WO2023100110A1 (fr) Procédé de préparation de brivaracétam
WO2022035434A1 (fr) Co-cristal de varénicline et d'acide oxalique, composition pharmaceutique correspondante et méthodes d'utilisation correspondantes

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09780817

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09780817

Country of ref document: EP

Kind code of ref document: A1