The present invention relates to processes for the preparation of Nelfinavir mesylate in crystalline or amorphous form. The present invention further relates to a process for the purification of nelfinavir mesylate.
Nelfinavir mesylate is chemically [3S-[2(2S*, 3S*), 3α, 4ap, 8αß]]-A/-(1,1-dimethylethyl)decahydro-2-[2-hydroxy-3-[(3-hydroxy-2- methylbenzoyl)amino]-4-(phenylthio)butyl]-3-isoquinoline carboxamide mono-methanesulfonate having the structure as depicted in Formula 1.
(Formula Removed)
FORMULA 1
Nelfinavir mesylate in combination with other antiretroviral agents is indicated for the treatment of HIV infection. Nelfinavir is a member of the group of drugs referred to as protease inhibitors.
J. Med. Chem. 1997, 40, 3979-3985 provides a process for the preparation of nelfinavir mesylate by dissolving nelfinavir free base in dichloromethane, followed by the addition of a solution of methanesulfonic acid in dichloromethane. The reaction mixture so obtained is concentrated to obtain nelfinavir mesylate as foam. US Patent No. 5,484,926 also provides similar process for the preparation of nelfinavir mesylate as foam by dissolving nelfinavir free base in a mixture of methanol and dichloromethane, followed by the addition of a solution of methanesulfonic acid in dichloromethane. The reaction mixture so obtained is concentrated to obtain the foam of nelfinavir mesylate. US '926 patent mentions said foam as a crude nelfinavir mesylate salt, which is purified by further processing steps including treatment with
solvent and antisolvent, filtering at cold temperature, and washing several times with ethyl ether.
PCT Publication No. WO 98/09951 provides a process for the preparation of amorphous nelfinavir mesylate wherein the process involves treating of nelfinavir free base with tetrahydrofuran followed by the addition of methane sulfonic acid. The solution obtained is added to an antisolvent such as methyl t-butyl ether or diethyl ether. The amorphous nelfinavir mesylate is isolated from the reaction mixture by using rotocone drier. WO '951 application also provides a process for isolating amorphous nelfinavir mesylate from an ethanolic solution by spray drying.
PCT Publication No. WO 06/021964 provides processes for preparing crystalline forms of nelfinavir mesylate, wherein the processes involve the addition of an antisolvent to a solution containing nelfinavir mesylate. The processes employ methanol, ethanol, isopropanol, or tetrahydrofuran as the solvent and acetone, methyl ethyl ketone, methyl isobutyl ketone, or 2-pentanone as the antisolvent. All the methods provided in WO '964 application involve cooling and stirring the reaction mixture below 5°C to isolate the crystalline nelfinavir mesylate.
PCT Publication No. WO 06/120525 provides a process for preparing crystalline Form I of nelfinavir mesylate, wherein the process involves heating a mixture containing acetone, nelfinavir free base and methane sulfonic acid at 55°C, and treating the solution obtained with charcoal at 55°C, followed by filtration. Form I of nelfinavir mesylate is isolated with a purity of 99.5% from the reaction mixture at 40°C after stirring.
The prior art processes for preparing amorphous nelfinavir mesylate involve treating the solution of nelfinavir mesylate with an antisolvent and also employ mechanical methods such as rotocone drying or spray drying. The prior art processes for preparing crystalline nelfinavir mesylate involve isolation of the final product only under hot or cold temperature conditions. Further, the prior art methods involve charcoal treatment and repeated washing to obtain nelfinavir mesylate in pure form.
The present inventors have developed a simple process for the preparation of amorphous nelfinavir mesylate without involving any antisolvent treatment and without employing mechanical methods. The present inventors have also developed a process to convert crude nelfinavir free base directly into pure crystalline nelfinavir mesylate having a purity of about 99.5% or above. The present inventors have further developed a process to convert crude nelfinavir mesylate into pure nelfinavir mesylate having a purity of about 99.5% or above. The present processes are simple and do not employ additional purification steps such as charcoal treatment, repeated washing or the treatment with antisolvents. The present process also facilitates the isolation of crystalline nelfinavir mesylate at ambient temperature conditions. Thus, the present invention provides simple, economic and industrially preferable process for preparing and purifying nelfinavir mesylate.
A first aspect of the invention provides a process for the preparation of amorphous nelfinavir mesylate, wherein the process comprises,
a) dissolving nelfinavir mesylate in a Ci.3 alkanol,
b) removing the solvent from the solution obtained in step a) by distillation,
and
c) isolating amorphous nelfinavir mesylate from the reaction mixture thereof.
The nelfinavir mesylate used as the starting material can be present in any solid form and prepared according to the methods provided in US Patent No. 5,484,926, or PCT Publication No. WO 98/09951, WO 06/021964, or WO 06/120525. The nelfinavir mesylate is dissolved in a Ci_3 alkanol. The d_3 alkanol is preferably methanol. The dissolution of nelfinavir mesylate in Ci-3 alkanol is carried out at a temperature of between about 40°C and about 60°C. The solution is optionally filtered and the solvent is removed by distillation. The distillation is carried out at a temperature from about 20°C to about 75°C under vacuum. The amorphous nelfinavir mesylate can directly be removed from the reaction vessel after distillation. Alternatively, the amorphous nelfinavir mesylate can be further treated with an organic solvent selected from the group consisting of aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, and petroleum ether, followed by for about 10 minutes to about 5 h at about 25°C to about 30°C. The amorphous

nelfinavir mesylate can subsequently be isolated from the reaction mixture by filtration.
A second aspect of the invention provides a process for the preparation of crystalline nelfinavir mesylate, wherein the process comprises:
a) combining nelfinavir free base, one or more solvents selected from the
group consisting of Ci-3 alkanols and cyclic ethers, and a ketone solvent;
b) treating the reaction mixture obtained in step a) with methane sulfonic acid,
c) stirring the reaction mixture obtained in step b), and
d) isolating crystalline nelfinavir mesylate from the reaction mixture thereof.
The nelfinavir free base which is used as the starting material can be prepared according to the method provided in PCT Publication No. WO 06/120525. The starting nelfinavir free base can be present in crude form. The nelfinavir free base, one or more solvents selected from the group consisting of Ci_3 alkanols and cyclic ethers, and a ketone solvent are combined together. The C-|.3 alkanol is preferably methanol. The cyclic ether is preferably tetrahydrofuran. The ketone solvent is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, or 2-pentanone. The ketone solvent is preferably acetone. The combined mixture of nelfinavir free base, one or more solvents selected from the group consisting of d-a alkanols and cyclic ethers, and a ketone solvent is preferably in the form of a slurry. The slurry is treated with methanesulfonic acid. Methanesulfonic acid may be used per se or in the form of a solution in an organic solvent. The reaction mixture is heated to a temperature of about 40°C to about 60°C. The heating can be carried out for about 10 minutes to about 5 h, and the reaction mixture is subsequently cooled to about 25°C to about 30°C. The reaction mixture is stirred for about 10 minutes to about 5 h at about 25°C to about 30°C. Nelfinavir mesylate is isolated from the reaction mixture by filtration in pure form. Preferably, the nelfinavir mesylate so obtained has a purity of about 99.5% or above, more preferably a purity of about 99.8% or above. The pure nelfinavir mesylate is isolated as a crystalline solid, preferably isolated as Form I.
The pure crystalline nelfinavir mesylate so obtained can be further converted into amorphous nelfinavir mesylate by using suitable solvents and antisolvents. The

suitable solvent for preparing amorphous nelfinavir mesylate is preferably tetrahydrofuran, and the suitable antisolvent is selected from the group consisting of cyclohexane, diisopropyl ether, n-heptane, toluene and hexanes. The pure crystalline nelfinavir mesylate can also be converted into amorphous form by the method disclosed in the previous aspect of the present invention.
A third aspect of the invention provides a process for the purification of nelfinavir mesylate, wherein the process comprises:
a) adding crude nelfinavir mesylate to a mixture of one or more solvents
selected from the group consisting of Ci-3 alkanols and cyclic ethers, and a
ketone solvent;
or adding a mixture of one or more solvents selected from the group consisting of Ci-3 alkanols and cyclic ethers, and a ketone solvent to crude nelfinavir mesylate,
b) stirring the reaction mixture obtained in step b), and
c) isolating pure nelfinavir mesylate from the reaction mixture thereof.
The crude nelfinavir mesylate used as the starting material has a purity of about 99% or below. It can be prepared according to the method provided in US Patent No. 5,484,926. The crude nelfinavir mesylate is added to a mixture of one or more solvents selected from the group consisting of Ci_3 alkanols and cyclic ethers, and a ketone solvent. Alternatively, a mixture of one or more solvents selected from the group consisting of Ci_3 alkanols and cyclic ethers, and a ketone solvent can be added to crude nelfinavir mesylate. The Ci-s alkanol is preferably methanol. The cyclic ether is preferably tetrahydrofuran. The ketone solvent is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, or 2-pentanone. The ketone solvent is preferably acetone. The addition is carried out at a temperature of about 20°C to about 60°C. The reaction mixture is optionally maintained at about 40°C to about 60°C for about 1 h to about 5 h after the addition. The reaction mixture is subsequently cooled to about 25°C to about 30°C followed by stirring for about 10 minutes to about 5 h at the same temperature. Pure nelfinavir mesylate having a purity of about 99.5% or above is isolated from the reaction mixture by filtration. The pure nelfinavir mesylate is preferably isolated as a crystalline solid, more preferably isolated as Form I.

Figure 1 depicts the X-ray powder diffraction pattern of Form I of nelfinavir mesylate. Figure 2 depicts the X-ray powder diffraction pattern of amorphous nelfinavir mesylate.
In the following section preferred embodiments are described by way of examples to illustrate the process. However, these are not intended in any way to limit the scope of the claims. Several variants of these examples would be evident to persons ordinarily skilled in the art.
EXAMPLE 1
PREPARATION OF FORM I OF NELFINAVIR MESYLATE:
Methane sulfonic acid (4.2 g) was added into a slurry of nelfinavir free base (25 g; HPLC Purity: 99.2%) in acetone (188 ml) and methanol (10 ml) at 25°C to 30°C and stirred at the same temperature for about 1 h. The reaction mixture was heated to 50°C to 55°C and stirred for 2 h. The reaction mixture was cooled to 25°C to 30°C and stirred for further 2 h. The solid product was filtered, washed with acetone (50 ml) and dried at 70°C to 75°C under vacuum to obtain the title compound.
Yield: 25 g
HPLC Purity: 99.9%
EXAMPLE 2
PURIFICATION OF NELFINAVIR MESYLATE:
Nelfinavir mesylate (25 g; HPLC Purity: 98.83%) was added into a mixture of acetone (188 ml) and methanol (10 ml) at 50°C to 55°C, and stirred for 2 h at the same temperature. The reaction mixture was subsequently cooled to 25°C to 30°C and stirred for further 2 h at 25°C to 30°C. The solid product was filtered, washed with acetone (50 ml), and dried at 70°C to 75°C under vacuum to obtain the title compound as crystalline Form I. Yield: 21 g
HPLC Purity: 99.82%
EXAMPLE 3
PURIFICATION OF NELFINAVIR MESYLATE:
Nelfinavir mesylate (25 g; HPLC Purity: 98.83%) was added into a solution of acetone (188 ml) and methanol (10 ml) at 25°C to 30°C. The reaction mixture was heated to 50°C to 55°C and stirred for 2 h at the same temperature. The reaction mixture was subsequently cooled to 25°C to 30°C and stirred for further 2 h. The solid product was filtered, washed with acetone (50 ml) and dried at 70°C to 75°C under vacuum to obtain the title compound as crystalline Form I. Yield: 21.2 g HPLC Purity: 99.70%
EXAMPLE 4
PREPARATION OF AMORPHOUS NELFINAVIR MESYLATE:
Nelfinavir mesylate (25 g) was dissolved in methanol (75 ml) at 60°C to 65°C. The solution so obtained was filtered through Celite bed, and the bed was washed with methanol (12.5 ml). The solvent was distilled off under vacuum at 70°C and cooled to 30°C, followed by the addition of hexanes (200 ml). The precipitated solid was further stirred for 4 h at 25°C to 30°C, filtered and washed with hexanes (25 ml). The solid obtained was dried at 70°C to 75°C under vacuum to obtain the title compound.
Yield: 20.4 g
EXAMPLE 5
PREPARATION OF AMORPHOUS NELFINAVIR MESYLATE:
Nelfinavir mesylate (25 g) was dissolved in methanol (75 ml) at 60°C to 65°C. The solution so obtained was filtered through Celite bed and the bed was washed with methanol (12.5 ml). The solvent was distilled off under vacuum at 70°C to 75°C up to maximum extent and cooled to 25°C to 30°C. The product was scratched from the reaction vessel and dried at 70°C to 75°C under vacuum to obtain the title compound.
Yield: 23.4 g
EXAMPLE 6
PREPARATION OF AMORPHOUS NELFINAVIR MESYLATE:
Nelfinavir mesylate (25 g) was dissolved in THF (62.5 ml) at 60°C to 65°C, and subsequently dispersed into hexanes (200 ml) at 0°C to 5°C under stirring. The precipitated solid was stirred for further 4 h at 0°C to 5°C, filtered and washed with hexanes (25 ml). The solid product was dried at 70°C to 75°C under vacuum to obtain the title compound.
Yield: 22.6 g
EXAMPLE 7
PREPARATION OF AMORPHOUS NELFINAVIR MESYLATE:
Nelfinavir mesylate (25 g) was dissolved in THF (62.5 ml) at 60°C to 65°C, and subsequently dispersed into toluene (200 ml) at 0°C to 5°C under stirring. The precipitated solid was stirred for further 4 h at 0°C to 5°C, filtered and washed with toluene (25 ml). The solid product was dried at 70°C to 75°C under vacuum to obtain the title compound
Yield: 20.1 g
EXAMPLE 8
PREPARATION OF AMORPHOUS NELFINAVIR MESYLATE:
Nelfinavir mesylate (25 g) was dissolved in THF (62.5 ml) at 60°C to 65°C, and subsequently dispersed into cyclohexane (200 ml) at 0°C to 5°C under stirring. The precipitated solid was stirred for further 4 h at 0°C to 5°C, filtered and washed with cyclohexane (25 ml). The solid product was dried at 70°C to 75°C under vacuum to obtain the title compound.
Yield: 20 g
EXAMPLE 9
PREPARATION OF AMORPHOUS NELFINAVIR MESYLATE:
Nelfinavir mesylate (25 g) was dissolved in THF (62.5 ml) at 60°C to 65°C, and subsequently dispersed into diisopropyl ether (200 ml) at 0°C to 5°C under stirring. The precipitated solid was stirred for further 4 h at 0°C to 5°C, filtered and washed with diisopropyl ether (25 ml). The product was dried at 70°C to 75°C under vacuum to obtain the title compound.
Yield: 15.8 g
EXAMPLE 10
PREPARATION OF AMORPHOUS NELFINAVIR MESYLATE:
Nelfinavir mesylate (25 g) was dissolved in THF (62.5 ml) at 60°C to 65°C, and subsequently dispersed into n-heptane (200 ml) at 0°C to 5°C under stirring. The precipitated solid was stirred for further 4 h at 0°C to 5°C, filtered and washed with n-heptane (25 ml).The product was dried at 70°C to 75°C under vacuum to obtain the title compound.
Yield: 21.2 g

WE CLAIM:
1 A process for the preparation of amorphous nelfinavir mesylate, wherein the process comprises,
a) dissolving nelfinavir mesylate in a C1-3 alkanol,
b) removing the solvent from the solution obtained in step a) by distillation,
and
c) isolating amorphous nelfinavir mesylate from the reaction mixture thereof.
2. A process according to claim 1, wherein the C1-3 alkanol is methanol.
3. A process according to claim 1, wherein distillation is carried out at a temperature from about 20°C to about 75°C under vacuum.
4. A process for the preparation of crystalline nelfinavir mesylate, wherein the
process comprises:
a) combining nelfinavir free base, one or more solvents selected from the
group consisting of C-i-3 alkanols and cyclic ethers, and a ketone solvent;
b) treating the reaction mixture obtained in step a) with methane sulfonic
acid,
c) stirring the reaction mixture obtained in step b), and
d) isolating crystalline nelfinavir mesylate from the reaction mixture thereof.
5. A process according to claim 4, wherein the cyclic ether is tetrahydrofuran.
6. A process according to claim 4, wherein the ketone solvent is selected from
the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone,
or 2-pentanone,
7. A process for the purification of nelfinavir mesylate, wherein the process
comprises:
a) adding crude nelfinavir mesylate to a mixture of one or more solvents
selected from the group consisting of C1-3 alkanols and cyclic ethers, and a
ketone solvent;
or adding a mixture of one or more solvents selected from the group consisting of C1-3alkanols and cyclic ethers, and a ketone solvent to crude nelfinavir mesylate,
b) stirring the reaction mixture obtained in step b), and
c) isolating pure nelfinavir mesylate from the reaction mixture thereof.

8. A process according to claim 7, wherein the crude nelfinavir mesylate has a
purity of about 99% or below.
9. A process according to claim 7, wherein the pure nelfinavir mesylate has a
purity of about 99.5% or above.
10. A process according to claim 7, wherein the pure nelfinavir mesylate is
isolated as crystalline Form I.