WO2010010058A1

WO2010010058A1 - Method of preparing anhydrous alfusozin hydrochloride

Info

Publication number: WO2010010058A1
Application number: PCT/EP2009/059284
Authority: WO
Inventors: Jacopo Zanon; Tiziana Piovesana; Andrea Nicole'
Original assignee: Lundbeck Pharmaceuticals Italy SpA
Current assignee: Lundbeck Pharmaceuticals Italy SpA
Priority date: 2008-07-21
Filing date: 2009-07-20
Publication date: 2010-01-28
Anticipated expiration: 2011-01-21
Also published as: IT1390760B1; ITPD20080215A1

Abstract

There is described a method of preparing anhydrous alfuzosin hydrochloride by means of a condensation reaction between N ₁-methyl-N ₂-(tetrahydrodrofuroyl-2)-propylenediamine and 4-amino-2-chloro-6,7-dimethoxyquinazoline. The obtained crude product is subsequently purified by further stages that include steps of preparing novel intermediates. The described alfuzosin synthesis and purification process allow to obtain this active ingredient with a high yield and purity, and therefore suitable to be employed as an active ingredient in medicaments.

Description

METHOD OF PREPARING ANHYDROUS ALFUZOSIN HYDROCHLORIDE

Field of the invention

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. For this purpose, 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. Among these alfuzosin [chemical designation: Λ/₁-(4-amino-6,7-dimethoxyquinazol-2-yl)-Λ/₁- methyl-Λ/₂-(tetrahydro-furoyl-2)-propylenediamine] in the hydrochloryde salt form thereof has been widely employed in the therapy of cardiovascular diseases and particularly as an anti-hypertensive drug. In the cited patent 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. Λ/₁-methyl-Λ/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. Thereby, N_r(4- amino-2-chloro-6,7-dimethoxyquinazol-2-yl)-Nrmethylpropylene diammine hydrochloride is obtained with a m.p. of 270 °C, which is conjugated with activated tetrahydrofuroyc acid. The resulting compound is subjected to various treatments, among which there is a basic treatment (in the particular instance 2N NaOH), and then dried and subsequently treated in 2-propanol with HCI/ethanol. In both cases, the only reported characterization of the obtained product Λ/r(4-amino-6,7- dimethoxyquinazol-2-yl)-Λ/₁-methyl-Λ/₂-(tetrahydrofuroyl-2)-propylenediamineΗCI is the melting point which is 235 °C (with decomposition) in the first example and 235 °C in the second example. In the patent at issue, polymorph forms of the compound are not mentioned.

Successively, in U.S. Patent No. 5,545,738 Synthelabo describes an alfuzosin hydrochloryde dihydrate and in the same patent refers to the different forms in which alfuzosin hydrochloride may exists, that is anhydrous, trihydrate and tetrahydrate forms. It further describes the preparation of this dihydrate form of alfuzosin hydrochloride from anhydrous alfuzosin hydrochloride obtained by means of dissolution in a mixture consisting in 4 parts of acetone and 1 part of water at reflux temperature (t° of about 60 °C) and cooling to room temperature. The precipitate is then filtrated and air-dried for 24 hours. The patent further reports that a precipitate indentified as the tetrahydrate form of alfuzosin hydrochloride is instead formed by stirring the alfuzosin hydrochloride solution in acetone:water 4:1 at ambient temperature. In addition, in patent application WO2006/030449 Hetero Drugs describes a crystalline form of alfuzosin base and its preparation from alfuzosin hydrochloride prepared according to the description in U.S. Patent No. 4,315,007. 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. Such a solid or oily residue is then hot- suspended in a ketonic or alcoholic solvent, or a mixture thereof, under stirring, and the crystalline precipitate is then filtrated or centrifuged. Preferred 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

Ltd. describes the preparation of alfuzosin and hydrochloride salt thereof, and novel crystalline forms of alfuzosin by substantially repeating example 2 of U.S. Patent No. 4,315,007 up to the point of the alfuzosin base preparation. Similarly, Dr Reddy's Lab in patent application US2007049756 and MSN Laboratories Limited in patent application WO2007/63556 describe different crystalline forms of alfuzosin hydrochloride obtainable by means of crystallization in alcoholic-type solvents and the corresponding amorphous forms. In particular, in US2007049756 all described and claimed forms show variable water contents which are inconsistent with the presence of anhydrous alfuzosin hydrochloride. 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. Summary

For the above-mentioned purposes, the inventors developed a novel process of preparing anhydrous alfuzosin hydrochloride which provides the preparation of the compound salt intermediates from known synthesis processes thereof. 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.

Therefore, 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. Brief description of the drawings Figure 1. The figure shows a representative XRPD diffractometric profile for anhydrous alfuzosin hydrochloride obtainable by the method according to the invention.

Figure 2. The figure shows a representative Nuclear Magnetic Resonance proton spectrum (¹H-NMR) obtained in deuterated dimethylsulfoxyde of alfuzosin camphorsulfonate obtainable by the method according to the invention.

Figure 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.

Figure 5. The figure shows an XRPD diffractometric profile for alfuzosin camphorsulfonate obtainable by the method according to the invention. Detailed description of the invention In one embodiment 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.

tetrahydro-furan-2-{3-methylamιno-propyl) 2-chlαro-6,7-dιmethoxy-quιnazolιnyl- carboxyamide ₄-amιne

Crude alfuzosin hydrochloride

Alfuzosin camphorsulfonate

Alfuzosin hydrochloride

In general, preparing anhydrous alfuzosin hydrochloride comprises that the crude alfuzosin HCI is preferably prepared by condensing /Vrmethyl-Λk- (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.

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.

In particular, 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 (15-25⁰C) 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. In particular, 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 (15-25⁰C). 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. In particular, 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 (15-25⁰C) and under stirring. The aqueous and organic phases are separated and the organic phase is extracted with water and then treated to reduce the water content below 0.1 % (w/w). 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). 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. The preparation of 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. In addition, the characteristics and high crystallinity of the alfuzosin camphorsulfonate salt enhance its stability. Hence, this intermediate can be easily stored.

Therefore, 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 alfuzosin hydrochloride salt is obtainable by: a) treating an aqueous solution of alfuzosin camphorsulfonate salt with a base and treating the mass with chlorinated or ester organic solvents as mentioned in the previous step; b) separating the organic phase and extracting the residual water in the organic phase and treating the same with HCI/ethanol; c) separating the crystalline solid form of anhydrous alfuzosin hydrochloride by means of distillation and/or crystallization, washing with ethanol and drying it.

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 /V₁- methyl-Λ/₂-(tetrahydrofuroyl-2)-propylenediamine and 4-amino-2-chloro-6,7- dimethoxyquinazoline.

Using this process of preparing, there are obtained 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

Molecular weight: 425.9

Molecular composition:

C H N Cl

Calculated (percentage): 53.58 6.63 16.44 8.32

Found (oercentaαe): 53.60 6.83 16.38 8.25

X-ray diffraction: 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.

From this analys, it is apparent that the obtained 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 Λ/₁-(4-amino-6,7- dimethoxyquinazol-2-yl)-Λ/₁methyl-Λ/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: 0₂₉H₄₃N₅Or₈S

Molecular weight: 622.73

Molecular composition:

C H N S Calculated (percentage): 55.93 6.96 1 1.25 5.15 Found (percentage): 55.86 7.02 1 1 .15 5.18

Melting point: 205.5 °C

\ H-NMR Spectrum (dmso-c/6, 300MHz, δ ppm): 1 1.42 (s, 1 H, SO₃H); 8.73 (s, 1 H,

NH₂), 8.53 (s, 1 H, NH₂); 7.87 (bt, 1 H, CONH); 7.67 (s, 1 H, ArH); 7.31 (s, 1 H, ArH);

4.21 (m, 1 H); 3.91 (s, 3H, CH₃); 3.90-3.71 (m, 2H); 3.84 (s, 3H, CH₃), 3.66 (t, 2H);

3.19 (s, 3H, CH₃); 3.15 (q, 2H); 9.90 (d, 1 H); 2.70 (m, 1 H); 2.40 (d, 1 H); 2.31 -2.02

(m, 2H); 1.94 (t, 1 H); 1.91 -1.69 (m, 7H); 1.28 (m, 2H); 3.18 (s, 3H, CH₃); 0.75 (s,

3H, CH₃).

Figure 2 shows the above reported proton spectrum. LR. (KBr cm r^'U¹ ).\ 3369.18, 3198.96, 2951 .00, 1736.52, 1607.24, 1528.85,

1495.66, 1395.34, 1280.14, 1241 .76, 1 165.82, 1039.10.

A representative I. R. spectrum of the alfuzosin camphorsulfonate obtained by the described method is shown in figure 3.

Differential scanning calorimetry (DSC): differential scanning calorimetry has been conducted by using a perforated aluminum crucible. Figure 4 shows a characteristic DSC profile. Alfuzosin camphorsulfonate exhibits an endothermic event characterized by an onset at 207 °C. The endothermic event is associated with the compound melting.

X-ray diffraction: 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.

The following examples of synthesis process object of the invention, provided for illustrative and not limitative purposes, relate to the different steps embodying the method as a whole as previously described both in general and detailed terms. Although described in detail hereinafter, the conversion from crude alfuzosin hydrochloride to alfuzosin free base is not a step per se because the base is kept in an organic phase and is not isolated from such a medium. Therefore, the examples are described with the only purpose to underline the yields and purities obtainable by the different treatments. Indeed, the base separation seems to cause neither yield nor purity increases, the preparation through camphorsulfonate salt being the characterizing aspect of the method object of the invention. Example 1. Preparation of alfuzosin camphorsulfonate

In a 2 L jacketed vessel provided with mechanical stirring 141 g (0.330 moles) of crude alfuzosin hydrochloride, 335 ml_ of water, 1410 ml_ of methylene chloride, 33 ml_ of an aqueous solution of 30% sodium hydroxide were loaded. The mass was kept under stirring for at least 30 min, then the stirring was interrupted to allow the phase separation. The organic phase was loaded and extracted with 335 ml_ of water, then reloaded again and 83 g (0.36 moles) of camphorsulfonic acid at a temperature of about 20 °C were added, thus obtaining a complete dissolution. Distillation of dichloromethane under reduced pressure, until the residue could be stirrable, by keeping the jacket temperature to about 40 °C was then performed.

1400 ml_ of toluene were added to the obtained oily residue and the mass was heated up to distillation temperature. The solvent was distilled by progressively heating the mass, keeping on with the distillation until reaching the internal temperature of about 1 10°C. The mass was left to stir and slowly cooled to 20 °C and then allowed to stir at 20 °C for some hours. The solid obtained, filtrated, and after washing the panel with 100 ml_ of toluene, was oven-dried under reduced pressure at a temperature of 55 °C for about 12 hours yielding 142 g (0.458 moles) of Λ/₁-(4-amino-6,7-dimethoxyquinazol-2-yl)-Λ/₁methyl-Λ/₂-(tetrahydro-furoyl-2)- propylenediamine] (7,7-dimethyl-2-oxo-bicycl[2,2,1 ]ept-1 -yl)-methanesulfonate (alfuzosin camphorsulfonate) as a white crystalline solid. 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 CH₂CI₂ 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 stirring being stopped, the phases were separated and the organic phase was extracted with 350 ml_ of H₂O, then treated with 4 g of siliporite and 4 g of decoloring carbon for about 30 min. The solid residue was discarded by filtration and washed with 70 ml_ of CH₂CI₂. The combined organic phases were loaded in a 2 L reactor and 100 g of about 8.5% HCI/EtOH solution were added. The so obtained solution was concentrated until reaching the minimal stirrable amount by means of distillation under reduced pressure and by keeping an internal temperature of about 20 °C. 300 ml_ of EtOH were then added and the mass was heated up to 80 °C at atmospheric pressure while distilling the solvent. 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 Λ/₁-(4-amino-6,7-dimethoxyquinazol-2-yl)-Λ/₁methyl- Λ/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 CH₂CI₂ 38g (0.082 moles) of alfuzosin hydrochloride (purity 97% determined by HPLC), 75 ml_ of H₂O and 75 ml_ of K₂CO₃ in a saturated aqueous solution are loaded in a glass jacketed reactor; the mixture is extracted twice with 150 ml_ of CH₂CI₂. 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 CH₂CI₂ In a glass jacketed reactor, 200 ml_ of an alfuzosin free base in a methylene chloride solution (10% w/v), corresponding to about 20 g of alfuzosin free base (0.051 moles), were loaded. 14.2 g (0.061 moles) of (±)camphoM O-sulfonic acid (β) 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. 200 ml_ of toluene were then added and the residual methylene chloride was removed by distillation up to an internal temperature of 1 10°C. The solution was cooled to 20°C, the crystallization started about 60°C, and the mixture was kept under stirring at room temperature overnight. 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 Λ/_r(4-amino-6,7-dimethoxyquinazol-2-yl)- Λ/₁methyl-Λ/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 (β) are added portionwise and under vigorous stirring. The mixture obtained and kept under stirring for 2-3 hours at ambient temperatures and under nitrogen, was concentrated by distillation (atmospheric pressure, 40°C) of 150 ml_ of methylene chloride. 200 ml_ of toluene were then added and the residual methylene chloride removed by distillation up to an internal temperature of 1 10°C. The solution was slowly cooled at 20 °C and kept under stirring at such a temperature overnight. The crystallization onset was observed about 60 °C. The product obtained in the form of a white crystalline powder was isolated by means of filtration, washed with 50 ml of toluene, and vacuum dried at 50 °C overnight, thus obtaining 26 g (0.042 moles) of Λ/r(4-amino-6,7- dimethoxyquinazol-2-yl)-Λ/₁methyl-Λ/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 99.9% 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 (β) were loaded.

The mixture was heated at 50 °C under nitrogen for 2 hours without reaching the complete dissolution and then cooled at 20 °C and kept under stirring overnight. 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 Λ/_r(4-amino- 6,7-dimethoxyquinazol-2-yl)-Λ/₁methyl-Λ/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 NaOHZCH₂CI₂ In a 3 L jacketed reactor provided with mechanical stirring, 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 (87⁰C). The solvent was then distilled by progressively heating the mass, continuing the distillation until the internal temperature of about 1 10°C was reached. The obtained mass was slowly cooled up to 20 °C, allowed to stir at 20 °C for some hours, then the obtained solid was filtrated by washing the panel with 200 ml_ of toluene, oven-dried under reduced pressure at a temperature of 55 °C for about 12 hours yielding 285 g (0.458 moles) of Λ/₁-(4-amino-6,7-dimethoxyquinazol-2-yl)-Λ/₁methyl-Λ/₂- (tetrahydro-furoyl-2)- propylenediamine] (7,7-dimethyl-2-oxo-bicycl[2,2,1 ]ept-1 -yl)- methanesulfonate (alfuzosin camphorsulfonate) as a white crystalline solid. Alfuzosin camphorsulfonate: yield 84%; purity determined by HPLC 99.38%.

Claims

1. A method of preparing anhydrous alfuzosin hydrochloride comprising at least the steps of: converting crude alfuzosin hydrochloride to alfuzosin camphorsulfonate in an organic solvent and isolating the same in form of a crystalline solid from the organic phase; converting alfuzosin camphorsulfonate to anhydrous alfuzosin hydrochloride in an organic solvent and separating the same in form of a crystalline solid.

2. The method of preparing anhydrous alfuzosin hydrochloride according to claim 1 , wherein the conversion of crude alfuzosin hydrochloride to crystalline alfuzosin camphorsulfonate is obtainable by:

- treating crude alfuzosin hydrochloride in an organic solvent selected from the groups consisting of chlorinated or ester solvents with a base aqueous solution;

- separating the aqueous phase and organic phase and treating the organic phase with camphorsulfonic acid in stoichiometric ratios (base:acid);

- isolating crystalline alfuzosin camphorsulfonate.

3. The method of preparing anhydrous alfuzosin hydrochloride according to claim 1 , wherein the conversion of crude alfuzosin hydrochloride to crystalline alfuzosin camphorsulfonate is obtainable by:

- treating an aqueous solution of alfuzosin camphorsulfonate with a base and treating the mass with chlorinated or ester organic solvents; - separating the organic phase by extracting the residual water in the organic phase and treating the same with HCI/ethanol;

- separating the crystalline solid form of anhydrous alfuzosin hydrochloride.

4. Alfuzosin camphorsulfonate. 5. The Alfuzosin camphorsulfonate according to claim 4 having at least one of the following characteristics:

- molecular composition: C H N S

Calculated (%): 55 .93 6.96 1 1 .25 5.15

Found (%): 55 .86 7.02 1 1 .15 5.18;

- ¹H-NMR Spectrum (dmso-c/6, 300MHz, δ ppm): 1 1.42 (s, 1 H, SO₃H); 8.73 (s, 1 H, NH₂), 8.53 (s, 1 H, NH₂); 7.87 (bt, 1 H, CONH); 7.67 (s, 1 H,

ArH); 7.31 (s, 1 H, ArH); 4.21 (m, 1 H); 3.91 (s, 3H, CH₃); 3.90-3.71 (m, 2H); 3.84 (s, 3H, CH₃), 3.66 (t, 2H); 3.19 (s, 3H, CH₃); 3.15 (q, 2H); 9.90 (d, 1 H); 2.70 (m, 1 H); 2.40 (d, 1 H); 2.31 -2.02 (m, 2H); 1.94 (t, 1 H); 1.91 - 1.69 (m, 7H); 1.28 (m, 2H); 3.18 (s, 3H, CH₃); 0.75 (s, 3H, CH₃). 6. The Alfuzosin camphorsulfonate according to claim 5 having at least one of the following characteristics: melting point 205.5°C;

I. R. spectrum (KBr cm^"1): 3369.18, 3198.96, 2951.00, 1736.52, 1607.24, 1528.85, 1495.66, 1395.34, 1280.14, 1241.76, 1 165.82, 1039.10;

Differential scanning calorimetry (DSC) with a endothermin event characterized by an onset at 207 °C;

X-ray diffraction profile comprising the following peaks:

Peak No. 1 Angle (2Θ) 5.670 Relative intensity (%) 89; Peak No. 2 Angle (2Θ) 6.890 Relative intensity (%) 48;

Peak No. 3 Angle (2Θ) 9.130 Relative intensity (%) 27;

Peak No. 4 Angle (2Θ) 1 1.190 Relative intensity (%) 30;

Peak No.

5 Angle (2Θ) 13.680 Relative intensity (%) 31 ;

Peak No.

6 Angle (2Θ) 14.480 Relative intensity (%) 59; Peak No. 7 Angle (2Θ) 15.090 Relative intensity (%) 76;

Peak No. 8 Angle (2Θ) 15.580 Relative intensity (%) 30;

Peak No. 9 Angle (2Θ) 15.890 Relative intensity (%) 30;

Peak No. 10 Angle (2Θ) 16.890 Relative intensity (%) 100;

Peak No. 1 1 Angle (2Θ) 18.170 Relative intensity (%) 39; Peak No. 12 Angle (2Θ) 19.420 Relative intensity (%) 77;

Peak No. 13 Angle (2Θ) 20.570 Relative intensity (%) 53;

Peak No. 14 Angle (2Θ) 22.370 Relative intensity (%) 46; Peak No. 15 Angle (2Θ) 23.870 Relative intensity (%) 52;

Peak No. 16 Angle (2Θ) 24.470 Relative intensity (%) 72;

Peak No. 17 Angle (2Θ) 25.700 Relative intensity (%) 43;

Peak No. 18 Angle (2Θ) 26.590 Relative intensity (%) 88; Peak No. 19 Angle (2Θ) 28.050 Relative intensity (%) 37;

Peak No. 20 Angle (2Θ) 28.350 Relative intensity (%) 37;

Peak No. 21 Angle (2Θ) 29.670 Relative intensity (%) 40.

7. Alfuzosin camphorsulfonate obtainable with a method of preparing according to claim 2.