TECHNICAL FIELD

The subject matter of the invention is a process for the preparation and isolation of vardenafil and salts thereof.

BACKGROUND AND PRIOR ART

Vardenafil, i.e. 2-[2-ethoxy-5-(4-ethylpiperazine-l-sulfonyl)-phenyl]-5-methy l-7-propyl-3H- imidazo[5,l-fJ[l,2,4]triazin-4-one, a well-known strong inhibitor of the phosphodiesterase which metabolizes cyclic guanosine 3 ',5 '-monophosphate (cGMP-PDE), is employed for therapeutic purposes, especially in erectile dysfunction treatment.

US patents US6362178 and Polish patent PLl 94801 disclose a process for the preparation of vardenafil hydrochloride trihydrate. The preparation proceeds according to the following s nthetic scheme:

MW = 312.4 g/mol MW = 410.9 g/mol MW = 488.6 g/mol

In this process, 2-[2-ethoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,l-fJ[l,2, 4]triazin-4-one (triazine, compound 1) is subjected to the chlorosulfonation reaction which yields 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5, 1 -fj[ 1 ,2,4]triazin-2-yl)benzene- sulfochloride (sulfochloride, compound 2). Subsequently, 4-ethoxy-3-(5-methyl-4-oxo-7-propyl- 3,4-dihydroimidazo[5,l-fJ[l,2,4]triazin-2-yl)benzenesulfochl oride (sulfochloride) is isolated from the reaction mixture. In a subsequent step, 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4- dihydro-imidazo[5,l-t][l,2,4]triazin-2-yl)benzenesulfochlori de (sulfochloride) is reacted with N-ethylpiperazine using methylene chloride as the solvent to afford vardenafil (compound 3) as a free amine.

The preparation of vardenafil disclosed in application US2007/0197535, in which methylene chloride is used as well, is similar.

The synthetic processes known in the art however involve the step of isolation of the sulfochloride as an intermediate. Additionally they are not environment friendly as they make use of the environmentally harmful methylene chloride. The need was felt for a better, faster, less cumbersome, cheaper and environmentally safer process for the preparation of vardenafil and salts thereof.

The present invention tries to address the above mentioned unmet needs and therefore an object of this invention is to provide an improved process for the preparation of vardenafil. Another object of the invention was to be able to prepare vardenafil using less synthetic steps than those described in the art. Another object of this invention is to provide a convenient solid form of vardenafil salts. A further object of the invention is to provide vardenafil salts in a suitable crystalline form.

SUMMARY OF THE INVENTION

A first aspect the invention relates to a process for the preparation of vardenafil and salts thereof, including the citric acid salt, wherein:

a) 2-[2-ethoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,l-fJ[l,2, 4]triazin-4-one is reacted with chlorosulfonic acid;

b) the resulting 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,l- fJ[l,2,4]triazin -2-yl) benzenesulfochloride is reacted without being isolated from the reaction mixture with N-ethylpiperazine;

c) vardenafil is isolated and optionally converted into a salt thereof, which can be optionally converted into vardenafil, which can and also be optionally converted into a salt thereof such as vardenafil hydrochloride, especially vardenafil hydrochloride trihydrate.

This process is advantageous because it does not require the isolation of the intermediate sulfochloride (2), a compound likely to show carcinogenic effects. Instead of being isolated, sulfochloride is reacted with N-ethylpiperazine. Additionally the costs associated with the process are reduced, as one step of isolation is avoided. A second aspect of the invention relates to vardenafil citric acid salt in solid state. This salt is advantageous because it can be rapidly precipitated and allows to obtain vardenafil or vardenafil salts of high purity. Pharmaceutical products are always required in high purity, so providing means to achieve such purity is always advantageous.

A third aspect of the invention relates to a process for the purification of vardenafil citric acid salt according to the second aspect of the invention and embodiments thereof, wherein vardenafil citric acid salt is dissolved in ethanol and vardenafil citric acid salt is crystallized or recrystallized from the resulting solution. This process allows to greatly enhance the purity of the product obtained.

A fourth aspect of the invention relates to a process for the preparation of vardenafil or salts thereof, wherein vardenafil citric acid salt according to the second aspect of the invention and embodiments thereof is treated with a strong inorganic base in aqueous medium and precipitated vardenafil is optionally treated with a suitable acid, preferably hydrochloric acid, to afford the corresponding salt.

A fifth aspect of the invention relates to a process for the preparation of vardenafil hydrochloride trihydrate, wherein vardenafil is suspended in acetone water mixture and subsequently concentrated hydrochloric acid is added and the precipitated vardenafil hydrochloride trihydrate is obtained.

A sixth aspect of the invention relates to a process for the preparation of vardenafil hydrochloride trihydrate according to the first and/or fourth aspects of the invention, wherein vardenafil is suspended in acetone water mixture and subsequently concentrated hydrochloric acid is added and the precipitated vardenafil hydrochloride trihydrate is obtained.

A seventh aspect of the invention relates to the use of vardenafil citric acid salt in solid state for the preparation of vardenafil or salts thereof by treating vardenafil citric acid salt with a strong inorganic base in aqueous medium and precipitating vardenafil, which could optionally be treated with a suitable acid, preferably hydrochloric acid, to afford the corresponding salt.

An eighth aspect of the invention relates to a process for the preparation of vardenafil and its citric acid salt, wherein: a) 2-[2-ethoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,l-fj[l ,2,4]triazin-4-one is reacted with chlorosulfonic acid;

b) the resulting 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,l- fJ[l,2,4] triazin- 2-yl)benzenesulfochloride is reacted with N-ethylpiperazine in a homogeneous mixture of tetrahydrofuran with water;

c) the reaction mixture is separated into organic and inorganic phases;

d) the organic phase is optionally isolated from the inorganic phase;

e) the organic phase is precipitated with citric acid to afford vardenafil citric acid salt. A ninth aspect of the invention relates to a process for the purification of the crystalline vardenafil citric acid salt, characterized in that the vardenafil citric acid salt is dissolved in ethanol and the vardenafil citric acid salt is recrystallized from the resulting solution.

'Aqueous solvent mixture' should be understood as an homogeneous solvent mixture comprising water. This includes among others water and alcohol mixtures (such as methanol, ethanol, n-propanol isopropanol, etc), water and acetone mixtures and water and tetrahydrofuran mixtures.

DETAILED DISCLOSURE OF INVENTION

In an embodiment of the first aspect of the invention step b) takes place in water or in aqueous solvent mixtures, preferably in homogeneous mixtures of tetrahydrofuran with water. In these embodiments the need of using harmful methylene chloride as a solvent, which is difficult to dispose of, has been eliminated. Instead in a preferred embodiment, THF is used, which is easy to regenerate and dispose of.

Additionally, the person skilled in the art will appreciate that chlorides, such as the compound of formula 2, hydrolyze in water to sulfonic acids; therefore, substitution with amines to yield amides is not possible. In order to avoid these problems, extraction or isolation of the chloride is necessary and the next reaction needs to be carried out in non-aqueous medium, as employed in the processes discussed above and known in the art. However, it has been unexpectedly found that chloride of formula 2 is sufficiently stable in the presence of water, so that it can be efficiently reacted with N-ethylpiperazine in the next stage. In a preferred embodiment of the invention, the reaction mixture after chloride synthesis is poured onto ice and THF. The ice decomposes the unreacted chlorosulfonic acid and the THF dissolves chloride 2. As a result, a homogeneous mixture forms. The troublesome stage of chloride isolation can thus be avoided along with any losses involved which reduce process yield. As a result, the process of the invention can be carried out in one reactor. In a preferred embodiment, the reaction mixture of step b) is separated into organic and inorganic phases.

In a preferred embodiment, in step c) vardenafil is converted into vardenafil citric acid salt, preferably by adding citric acid to the organic phase according the preferred preceding embodiment. More preferably, vardenafil citric acid salt is converted into vardenafil, which is further converted into another salt thereof, such as vardenafil hydrochloride, especially vardenafil hydrochloride trihydrate. In these embodiments the process for vardenafil and salts thereof isolation has also been much simplified: vardenafil citrate is isolated directly from the reaction mixture after crystallization, as a citric acid salt. This is a particularly convenient form, because it is readily soluble and may be converted into other pharmaceutically acceptable vardenafil salts in a simple way and also can be subjected to further purification; when obtained in the crystalline form, it is a particularly beneficial and stable form of the active substance.

In a further preferred embodiment, the salt obtained in step c) from vardenafil is dissolved in an aqueous solution and treated with a strong base to afford vardenafil free base.

In a further preferred embodiment, the organic phase is basified using a strong inorganic base, preferably NaOH, to achieve a pH of the reaction mixture in the range of 8 to 13, followed by separation into organic and inorganic phases by increasing ionic strength, for example by the addition of an inorganic salts, preferably sodium chloride. Even more preferably the pH of the reaction mixture is in the range of 9 to 9.5.

In an embodiment, the vardenafil solution in the organic phase, preferably THF, is separated; in a preferred embodiment, this is achieved by adding sodium chloride to the reaction mixture after condensation with N-methylpiperazine. The mixture is salted out and the aqueous and organic (THF/vardenafil) phases are separated. The isolation of vardenafil in a solid form from the mixture using known methods is troublesome; it has been unexpectedly achieved within an embodiment of the invention by adding citric acid to the reaction mixture. The resulting vardenafil citric acid salt unexpectedly readily crystallizes from the reaction mixture. A second aspect of the invention relates to vardenafil citric acid salt in solid state, preferably in crystalline form. A preferred embodiment the invention relates to a crystalline form of vardenafil citric acid salt, having a X-Ray Powder Diffraction pattern comprising peaks at 2theta angle at 5.58, 8.00, 13.90 and 16.21 ; more preferably to a crystalline form of vardenafil citric acid salt having a X-Ray Powder Diffraction pattern comprising peaks at 2theta angle at 5.58, 6.94, 8.00, 13.18, 13.43, 13.90, 15.07, 15.23, 15.90, 16.21, 16.54 and 16.85.

A third aspect of the invention relates to a process for the purification of vardenafil citric acid salt, wherein vardenafil citric acid salt is dissolved in ethanol and vardenafil citric acid salt is recrystallized from the resulting solution. Preferably vardenafil citric acid salt is prepared according to the first aspect of the invention and its related embodiments. Even more preferably vardenafil citric acid salt is dissolved in hot ethanol, preferably heated to the boiling point of ethanol, and the resulting solution is additionally filtered before crystallization. In a preferred embodiment of the first and fourth aspects of the invention and its related embodiments, the salt obtained is vardenafil hydrochloride trihydrate salt

In an eight aspect, the invention relates to a process for the preparation of vardenafil and its citric acid salt, characterized in that 2-[2-ethoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,l-fJ [ 1 ,2,4]triazin-4-one is reacted with chlorosulfonic acid and the resulting 4-ethoxy-3-(5-methyl- 4-oxo-7-propyl-3,4-dihydro-imidazo[5,l-fJ[l,2,4]triazin-2-yl )benzenesulfochloride is reacted with N-ethylpiperazine in a homogeneous mixture of tetrahydrofuran (THF) with water; the reaction mixture is separated into organic and inorganic phases and the resulting vardenafil is precipitated from the separated organic phase using citric acid whereby this directly affords a vardenafil citric acid salt. Vardenafil citric acid salt so obtained is optionally dissolved in an aqueous solution and treated with a strong base in order to precipitate vardenafil as a free base.

In a preferred embodiment of the eight aspect, the invention relates to a process characterized in that the resulting salt is optionally dissolved in an aqueous solution and treated with a strong base to afford the corresponding vardenafil free base.

In one embodiment of the previous aspect, the reaction mixture obtained following the addition of N-ethylpiperazine is alkalized by a strong inorganic base, preferably NaOH until the pH value is 8 to 13, preferably between 9 and 9.5 and, subsequently, it is separated into organic and inorganic layers by increasing the ionic strength, preferably by the addition of an inorganic salt, in particular NaCl to precipitate vardenafil as free base.

Another aspect of the invention is a process of preparation of vardenafil hydrochloride trihydrate, wherein the said process involves the treatment of vardenafil citric acid salt with a strong inorganic base in aqueous medium and the precipitated vardenafil is optionally treated with hydrochloric acid whereby vardenafil is obtained in the corresponding hydrochloride trihydrate forms.

Further purification is optionally done by suspending the resulting vardenafil suspended in acetone in the preferably in the presence of water and addition of an equimolar amount of concentrated hydrochloric acid to afford the vardenafil hydrochloride trihydrate as a precipitate which can optionally be washed with acetone and dried.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1 shows a scheme of an embodiment of the synthesis process of the invention while referring to respective embodiments of specific stages.

Figure 2 shows the XRPD spectrum of the crystalline vardenafil citric acid salt of the invention;

Figure 3 shows the IR spectrum of the salt. Figure 4 presents the XRPD spectrum of the resulting vardenafil. Figure 5 shows the XRPD spectrum of the resulting vardenafil hydrochloride trihydrate. BEST MODE OF CARRYING OUT THE INVENTION EXAMPLES

The following examples are further illustrative of the scope of this invention. These examples however should not be construed to limit the scope of the invention.

Example 1.

Preparation of the vardenafil citric acid salt. 13.5 mL (0.2 mol) of chlorosulfonic acid was added to a flask and, subsequently, cooled to a temperature of -5°C to 0°C. 6.25 g of triazine (0.02 mol, formula 1) was added to the cooled acid; 2-[2-ethoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,l-fJ[1.2, 4]triazin-4-one) at a temperature below 5°C; subsequently, the flask was stirred at room temperature for 1 hour. Thereafter, the reaction mass was poured into a mixture of 200 g of ice and 100 mL of THF. While maintaining a temperature of below 15°C, 6.4 mL (0.05 mol) of N-ethylpiperazine was added to the sulfochlonde solution in THF, followed by 30% NaOH solution until the pH was 9 to 9.5 . Subsequently, 50 g of sodium chloride (0.855 mol) was added and the organic and aqueous phases were separated. The aqueous phase was extracted again with 100 mL of THF.

5.76 g (0.03 mol) of citric acid was added to the pooled organic layers and the content was heated to 50 - 70°C. Subsequently, the mixture was allowed to crystallize. When the solution was cool, the vardenafil citrate was isolated and dried. 10.55 g of white precipitate was obtained (0.0155 mol, yield: 87.5%); melting point: 166 - 168°C.

Example 2.

Purification of the crystalline vardenafil citric acid salt.

The crystallization of vardenafil as a crystalline citric acid salt proceeds according to the following scheme.

680,6 g/mol

350 mL of rectified EtOH was added to 10 g of the resulting vardenafil citric acid salt and the resulting mixture was allowed to boil. The resulting solution was filtered and allowed to crystallize. Subsequently, the crystalline precipitate was isolated, washed with rectified EtOH and dried to afford 8.7 g of off-white precipitate as the required product. NMR analysis of the product confirmed the structure of the compound. XRPD analysis was also carried out in order to determine the crystalline structure of the salt.

Ή NMR:

5=11.7 ppm (s); 7.87 ppm (m); 7. 4 ppm (d); 4.22 ppm (dd); 2.95 ppm (s); 2.83 ppm (t); 2.53 ppm (mm); 1.75 ppm (m); 1,33 ppm (t); 0,95 ppm (m).

Figure 2 shows the XRPD spectrum of the resulting salt.

The table below shows the list of identified reflection angles (2Θ), inter-planar distances (d) and relative intensities (I/IO) for the vardenafil citric acid salt of the invention.

Figure 3 shows the IR spectrum of the resulting salt.

Example 3.

Isolation of vardenafil as a free amine.

2 g (2.93 mmol) of vardenafil citrate was dissolved in 150 mL of water. 10% NaOH solution was added to the solution until maintaining the the pH about 9-10.

The precipitated vardenafil solution (free amine) was collected and washed twice with 25 mL of water. 1.43 g of precipitate (2.93 nmol) was obtained; yield: 100%.

Figure 4 shows the XRPD spectrum of the resulting vardenafil. Example 4.

Preparation of vardenafil hydrochloride trihydrate.

5 ml of acetone and 0.5 mL of water was added to 2 g (4.09 mmol) of the free amine. An equimolar volume of concentrated hydrochloric acid was added to the resulting suspension. The resulting precipitate was collected , washed with acetone and dried. 1 ,45 g of white precipitate (2,5 mmol) was obtained; yield: 61%.

The diffractogram (XRPD) of the resulting vardenafil hydrochloride trihydrate is consistent with that known in the art, e.g. disclosed in WO2004/006894.

Water content (KF method): 9.42%.

CI ^" ion content: 6.3%.

Figure 5 shows the XRPD spectrum of the resulting vardenafil hydrochloride trihydrate.

X-Ray powder diffraction data were obtained by methods known in the art using an X-Ray powder diffractometer PANalytical X'Pert PRO equipped with RTMS detector (X'Celerator), a variable goniometer and X-Ray tube with Cu target anode (Cu radiation). Scans were performed over a range 2 to 40 degrees 2Θ, continuously, with a scan rate of 0.0336 degree/min