AN IMPROVED PROCESS FOR PREPARATION OF AMORPHOUS

NELFINAVIR MESYLATE

FIELD OF THE INVENTION

The invention relates to a process to prepare amorphous form of [3S- (3R ^* , 4aR ^* , 2'S\ 3 ¹ S ^* )]-2'-[2 ¹ -hydroxy-3 ^> -phenylthiomethyl-4'-aza-5 ^l -oxo-5 ¹ -(2"-methyl- 3"-hydroxyphenyl)pentyl]decahydroisoquinoline-3-N-tert-butyl carboxamide methanesulfonate, also known as nelfmavir mesylate, of the following Formula I

Formula I

BACKGROUND OF THE INVENTION

Treatment of HIV-infected individuals is one of the most pressing biomedical problems of recent times. A promising new therapy has emerged as an important method for preventing or inhibiting the rapid proliferation of the virus in human tissue. HIV-protease inhibitors block a key enzymatic pathway in the virus resulting in substantially decreased viral loads, which slows the steady decay of the immune system and its resulting deleterious effects on human health.

The HIV-protease inhibitor nelfϊnavir mesylate of Formula I has been shown to be an effective treatment for HIV-infected individuals.

Nelfϊnavir mesylate is disclosed in US 5,484,926, the process of making mesylate salt comprising:

i) dissolving the base in a mixture of methanol and anhydrous methylenechloride with methanesulfonic acid; ii) concentrating the reaction mass to obtain white foam; iii) dissolving the white foam in tetrahydrofuran; and iv) addition of mixture of ethyl ether and hexanes to isolate the salt.

The above mentioned process has substantial drawbacks in that the solvent and solvent mixtures employed are highly inflammable.

US 5,962,725 describes the preparation of intermediate compounds, which can be used in several ways for the preparation of nelfinavir mesylate and also methods for making nelfinavir mesylate from nelfinavir base. One of the procedures disclosed involves the conversion of nelfinavir base to nelfinavir mesylate by spray drying in which the nelfinavir base in organic solvent is mixed with an equivalent amount of methanesulfonic acid till nelfinavir mesylate is formed and the resultant slurry or solution is pumped through spray drier with controlled settings. US '725 further discloses that nelfinavir mesylate is prepared by dissolving the nelfinavir base in a suitable solvent such as tetrahydrofuran, methanol or ethanol, adding a molar equivalent of methanesulfonic acid, mixing to get a uniform solution and adding this solution rapidly to several volumes of an anti solvent (such as methyl tert-butyl ether, diethyl ether, hexanes, heptane with rapid stirring.

Journal of Medicinal Chemistry 1997, 40, 3979-3985 describes the preparation of nelfinavir mesylate from base in methylene chloride by adding methanesulfonic acid and evaporating overnight under high vacuum to yield an off-white foam. The nelfinavir obtained in this process is impractical for filtration.

The Journal of Pharmaceutical Sciences, Vol. 84 (1995) pp. 1090-1093 discloses the XRD, DSC and TGA studies along with other physiochemical properties of nelfinavir mesylate to establish a preformulation database. This publication discloses that nelfinavir mesylate is substantially amorphous with no evidence of

long-range periodicity. It also further reveals that there is no evidence of crystallinity by XRD and no birefringence on polarized light microscopy after repeated heating and cooling cycles. In addition the marketed form is amorphous as evidenced in the Summary Basis of Approval.

However, recently WO 2006/021964 A2 described novel crystalline forms of nelfinavir mesylate designated as Forms A, Form B, Form C and Form D. This publication discloses a process for their preparation avoiding the use of highly flammable solvents such as ethers. The various crystalline forms can be tailored with the selection of the appropriate anti solvent to precipitate the product. However, this publication does not provide a process for preparation of amorphous form of nelfinavir mesylate.

The prior-art process for the preparation of amorphous nelfinavir mesylate suffers from the following disadvantages

1) use of spray drying that involves critical temperature maintenance.

2) requirement of specialized equipment for spray drying.

3) use of highly flammable solvents is risky at commercial level and often requiring special design for ensuring safety.

4) also the use of highly flammable solvents in spray drying makes the process all the more dangerous thus making the process commercially unsafe in industry.

5) high residual solvent content in the finished product and its associated smell affecting the organoleptic properties of the API/Formulation.

OBJECTIVES OF INVENTION

The objective of the present invention is to provide an improved process for the preparation of nelfinavir mesylate in amorphous form.

Another objective of the present invention is to provide an improved process for the preparation of amorphous nelfinavir mesylate in high purity and high yield.

Another objective of the present invention is to provide a process for producing amorphous nelfinavir mesylate by avoiding spray drying thereby making the process simple and easy to scale up for commercial quantities that does not require dedicated/specialized equipment.

SUMMARY OF INVENTION

Accordingly, the present invention provides a process for the preparation of amorphous nelfinavir mesylate of Formula I

Formula I

comprising: i) providing a solution of nelfinavir mesylate in a suitable solvent such as methanol or ethanol and evaporation of the solvent completely at a temperature in the range up to 80° C under reduced pressure, preferably at

50-60 ⁰ C; ii) precipitating the product by the addition of a suitable solvent such as cyclohexane, methyl tert.butyl ether, heptanes, hexanes; and iii) isolating nelfinavir mesylate by filtration in amorphous form.

Another embodiment of the present invention provides a process for the preparation of crystalline nelfinavir mesylate from nelfinavir base in a variety of solvents and mixture of solvents like acetone or acetone/ethanol.

DETAILED DESCRIPTION OF INVENTION

The aim of the present invention is to provide processes for the preparation of both amorphous and crystalline nelfinavir mesylate of Formula I

Formula I

The process for preparing amorphous nelfinavir mesylate comprises of treating a suspension of nelfinavir base in methanol or ethanol with methanesulfonic acid and subsequently stirring for 10 minutes at ambient temperature. The resulting clear solution was charcolized and washed with methanol or ethanol. The methanol or ethanol from filtrate was concentrated at < 80 °C under reduced pressure leaving a foamy residue. The distillation was continued till no more solvent distills out. To this residue was added a suitable solvent such as cyclohexane, methyl tert-butyl ether, heptanes, hexanes and stirred for 15 minutes to result into a free flowing amorphous powder which was filtered and washed again with the precipitated solvent of choice. Aliphatic hydrocarbons, ethers etc in which nelfinavir mesylate is insoluble are the solvents of choice.

The process for preparing crystalline nelfinavir mesylate comprises of treating the nelfinavir base with methanesulfonic acid in acetone or in a mixture of acetone and ethanol at 20-35°C resulting in a clear solution. The resulting solution is stirred for 2 hrs at 20-25°C during which the product precipitates out, which is collected by filtration and washed with acetone or mixtures thereof. The filtered product is dried at 70-75 ⁰ C to obtain mesylate salt as a crystalline product.

This crystalline nelfϊnavir mesylate is then dissolved in a suitable solvent such as methanol, ethanol to get a clear solution. Alternatively nelfinavir mesylate amorphous obtained by any of the prior art procedures may be used. Evaporation of the solvents under reduced pressure gives a foamy residue. The foamy residue is precipitated by the addition of inert solvents such as cyclohexane, heptanes, hexanes and methyl t-butyl ether and dried as white to off white amorphous powder that is filtered.

The purity of the amorphous nelfinavir mesylate obtained by the process of the present invention > 99.5% by HPLC.

The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

EXAMPLE 1

PREPARATION OF CRYSTALLINE [3S-(3R*,4AR*,8AR*,2'S*,3'S*)]-2- [2'-HYDROXY-3 ^t -PHENYLTHIOMETHYL-4'-AZA-5'-OXO-5'-(2"-MET- HYL-3"-HYDROXYPHENYL)- PENTYL]DECAHYDROISOQUINOLINE- 3-N-TERT-BUTYLCARBOXAMIDE METHANESULFONATE

Methanesulfonic acid (8.46 g, 88 mmol) was added to a suspension of nelfinavir base (50 g, 88 mmol) in acetone (400 ml) at 25-35°C, and stirred to obtain a clear solution. Stirred the reaction mixture for ~2 h at 20-25°C, and the precipitated product was collected by filtration and washed with acetone (100 ml). This was dried at 70-75°C under reduced pressure till LOD was -8% w/w to yield 57.5 g (98%) of the title compound having the purity > 99.5% (HPLC) and the product is crystalline by XRD.

EXAMPLE 2

PREPARATION OF CRYSTALLINE [3S-(3R*,4AR*,8AR*,2 S*,3 S*)]-2- [2'-HYDROXY-3'-PHENYLTHIOMETHYL-4 ^t -AZA-5'-OXO-5 ^t -(2"-MET- HYL-3' -H YDROXYPHEN YL)-PENT YL] DEC AH YDROISOQUINOLINE- 3-N-TERT-BUTYLCARBOXAMIDE METHANESULFONATE

To a suspension of nelfinavir base (1O g, 17.6 m mol) in ethanol (25 ml) added methanesulfonic acid (1.69 g, 17.6 m mol) and stirred for 10 min at 25-35°C. To the resulting clear solution added acetone (125 ml) and stirred for 1 h at 25-30 ⁰ C, where upon product precipitated out, which was collected by filtration, washed with acetone (25 ml) and dried at 75-80°C under reduced pressure to yield 8.1 g (69%) of the title compound.

EXAMPLE 3

PREPARATION OF AMORPHOUS [3S-(3R*,4AR*,8AR*,2'S*,3'S*)]-2-[2'-

HYDROXY-3'-PHENYLTHIOMETHYL-4'-AZA-5 ^f -OXO-5'-(2 ^M -METHYL -3' -HYDROXYPHENYL)-PENTYL]DECAHYDROISOQUINOLINE-S-N- TERT-BUTYLCARBOXAMIDE METHANESULFONATE The product of example (1) (10 g) was dissolved in methanol (30 ml) and treated with carbon (1 g) for 15 min at 25-30°C. The carbon was removed by filtration through hyflo and washed with 10 ml of methanol. The combined filtrate was concentrated at 40-45°C under reduced pressure (150-20 mm Hg) till no more solvent distills out, leaving a foamy residue. This was further kept at 50-55 ⁰ C under reduced pressure (10-20 mm Hg) for 1 h, cooled to 25-30 ⁰ C, added cyclohexane (50 ml) and stirred for 15 min at 25-30 ⁰ C. The resulting free flowing product was filtered and washed with cyclohexane (10 ml). The product was dried at 70-75 ⁰ C for 4 h under reduced pressure (10-20 mm Hg) to obtain 8.8 g (88%), of amorphous nelfinavir mesylate. Purity: > 99.5% (HPLC) Assay: > 99% (HPLC) Total Solvents: < 0.2% w/w (GC); and product is amorphous by XRD.

EXAMPLE 4

PREPARATION OF AMORPHOUS [3S-(3R*,4AR*,8AR*,2'S*,3'S*)]-2-[2 ^t - HYDROXY-3'-PHENYLTHIOMETHYL-4 ^t -AZA-5'-OXO-5'-(2 ^M -METHYL -3"-HYDROXYPHENYL)-PENTYL]DECAHYDROISOQUINOLINE-S-N- TERT-BUTYLCARBOXAMIDE METHANESULFONATE

The product of example (1) (10 g) was dissolved in methanol (30 ml) and treated with carbon (1 g) for 15 min at 25-3O ⁰ C. The carbon was removed by filtration through hyflo and washed with methanol (10 ml). Concentrated the combined filtrate at 45-50°C under reduced pressure (200-20 mm Hg) till no solvent distills out, which leaves a foamy residue. Continued to heat the residue to 50-55 ⁰ C under reduced pressure (10-20 mm Hg) further 1 h. Cooled the residue to 25- 30 ⁰ C, added methyl t-butyl ether (50 ml) and stirred for 15 min. Filtered the product and washed with methyl t-butyl ether (10 ml). After drying 12 h at 80- 85°C under reduced pressure (10-20 mm Hg) yield is 9.3 g (93%).

Total solvents present in product are < 0.1% w/w (By GC) and product is amorphous by XRD.

EXAMPLE 5

PREPARATION OF AMORPHOUS [3S-(3R*,4AR*,8AR*,2'S*,3'S*)]-2-[2'-

HYDROXY-3 '-PHENYLTHIOMETHYL-4 -AZA-5 -OXO-5 -(2' -METHYL

-3"-HYDROXYPHENYL)-PENTYL]DECAHYDROISOQUINOLINE-S-N-

TERT-BUTYLCARBOXAMIDE METHANESULFONATE The product of example (1) (10 g) was dissolved in absolute alcohol (40 ml) and treated with carbon (1 g) for 15 min at 25-30 ⁰ C. The carbon was removed by filtration through hyflo and washed with 10 ml of absolute alcohol. The combined filtrate was concentrated at 45-50 ⁰ C under reduced pressure (200-20 mm Hg) till no more solvent distills out, leaving a foamy residue. This was further kept at 50-55 ⁰ C under reduced pressure (10-20 mm Hg) for 1 h, cooled to 25-30 ⁰ C, added cyclohexane (50 ml) and stirred for 15 min at 25-30 ⁰ C. The resulting free flowing product was filtered and washed with cyclohexane (10 ml).

The product was dried at 70-75 ⁰ C for 12 h under reduced pressure (10-20 mm Hg) to obtain 9.1 g (91%), of title compound.

EXAMPLE 6

PREPARATION OF AMORPHOUS [3S-(3R*,4AR*,8AR*,2 ^t S*,3'S*)]-2-[2 ^I -

HYDROXY-3'-PHENYLTHIOMETHYL-4'-AZA-5'-OXO-5 ^t -(2"-METHYL -3"-HYDROXYPHENYL)-PENTYL]DECAHYDROISOQUINOLINE-S-N-

TERT-BUTYLCARBOXAMIDE METHANESULFONATE The product of example (1) (10 g) was dissolved in absolute alcohol (40 ml) and treated with carbon (1 g) for 15 min at 25-30 ⁰ C. The carbon was removed by filtration through hyflo and washed with 10 ml of absolute alcohol. The combined filtrate was concentrated at 45-50 ⁰ C under reduced pressure (200-20 mm Hg) till no more solvent distills out, leaving a foamy residue. This was further kept at 50-55 ⁰ C under reduced pressure (10-20 mm Hg) for 1 h, cooled to 25-30 ⁰ C, added methyl t-butyl ether (50 ml) and stirred for 15 min at 25-30 ⁰ C. The resulting free flowing product was filtered and washed with methyl t-butyl ether (10 ml). The product was dried at 70-75 ⁰ C for 12 h under reduced pressure (10-20 mm Hg) to obtain 9.2 g (92%), of title compound.

EXAMPLE 7

PREPARATION OF AMORPHOUS [3S-(3R*,4AR*,8AR*,2'S*,3'S*)]-2-[2'- HYDROXY-3'-PHENYLTHIOMETHYL-4'-AZA-5'-OXO-5'-(2"-METHYL -3 ^M -HYDROXYPHENYL)-PENTYL] DEC AH YDROISOQUINOLINE-3-N- TERT-BUTYLCARBOXAMIDE METHANESULFONATE

The product of example (1) (10 g) was dissolved in methanol (40 ml) and treated with carbon (1 g) for 15 min at 25-30 ⁰ C. The carbon was removed by filtration through hyflo and washed with 10 ml of methanol. The combined filtrate was concentrated at 45-50 under reduced pressure (200-20 mm Hg) till no more solvent distills out, leaving a foamy residue. This was further kept at 5O-55°C under reduced pressure (10-20 mm Hg) for 1 h, added 50 ml of heptanes and stirred for 10 min at 25-3O ⁰ C. The resulting free flowing product was filtered and

washed with heptanes (2 x 10 ml). The product was dried at 70-75°C for 12 h under reduce pressure (10-20 mrn Hg) to obtain 9.2 g (92%).

EXAMPLE 8

PREPARATION OF AMORPHOUS [3S-(3R*,4AR*,8AR*,2'S*,3'S*)]-2-[2 ⁽ -

HYDROXY-3 -PHENYLTHIOMETHYL-4 -AZA-5 -OXO-5 -(2 ' METHYL

-3"-HYDROXYPHENYL)-PENTYL]DECAHYDROISOQUINOLINE-S-N-

TERT-BUTYLCARBOXAMIDE METHANESULFONATE The product of example (1) (10 g) was dissolved in methanol (40 ml) and treated with carbon (1 g) for 15 min at 25-30°C. The carbon was removed by filtration through hyflo and washed with 10 ml of methanol. The combined filtrate was concentrated at 45-50 ⁰ C under reduced pressure (200-20 mm Hg) till no more solvent distills out, leaving a foamy residue. This was further kept at 50-55°C under reduced pressure (10-20 mm Hg) for 1 h, added 50 ml of hexanes and stirred for 10 min at 25-3O ⁰ C. The resulting free flowing product was filtered and washed with hexanes (2 x 10 ml). The product was dried at 70-75°C for 12 h under reduce pressure (10-20 mm Hg) to obtain 9.15 g (91.5%).

EXAMPLE 9

PREPARATION OF AMORPHOUS [3S-(3R*,4AR*,8AR*,2'S*,3'S*)]-2-[2'- HYDROXY-3 -PHENYLTHIOMETHYL-4 -AZA-5 -OXO-5'-(2 ' METHYL -3"-HYDROXYPHENYL)-PENTYL]DECAHYDROISOQUINOLINE-S-N- TERT-BUTYLCARBOXAMIDE METHANESULFONATE

To a suspension of nelfinavir base (10 g, 17.6 m. mol) in methanol (50 ml) added methanesulfonic acid (1.69 g, 1.76 m mol) was added and stirred for 10 min at 25- 30°C. The resulting clear solution was treated with carbon (1 g) for 15 min at 25- 30 ⁰ C. The carbon was removed by filtration through hyflo and washed with 10 ml of methanol. The combined filtrate was concentrated at 40-45 ⁰ C under reduced pressure (150-20 mm Hg) till no more solvent distills out, leaving a foamy residue. This was further kept at 50-55 ⁰ C under reduced pressure (10-20 mm Hg) for 1 h, cooled to 25-3O ⁰ C, added 50 ml of cyclohexane and stirred for

15 min at 25-3O ⁰ C. The resulting free flowing product was filtered and washed with cyclohexane (10 ml). The product was dried at 70-75°C for 4 h under reduce pressure (10-20 mm Hg) to obtain 1 1.0 g (92%) of the title compound.

Total solvents are < 0.1% w/w (By GC) and the product was amorphous by XRD.

EXAMPLE 10 PREPARATION OF AMORPHOUS [3S-(3R*,4AR*,8AR*,2'S*,3'S*)]-2-[2'- HYDROXY-3'-PHENYLTHIOMETHYL-4'-AZA-5'-OXO-5'-(2"-METHYL -3"-HYDROXYPHENYL)-PENTYL]DECAHYDROISOQUINOLINE-S-N-

TERT-BUTYLCARBOXAMIDE METHANESULFONATE

Nelfinavir mesylate (10 g, obtained by known methods) was dissolved in methanol (30 ml) and treated with carbon (1 g) for 15 min at 25-30°C. The carbon was removed by filtration through hyflo and washed with 10 ml of methanol. The combined filtrate was concentrated at 40-45°C under reduced pressure (150-20 mm Hg) till no more solvent distills out, leaving a foamy residue. This was further kept at 50-55 ⁰ C under reduced pressure (10-20 mm Hg) for 1 h, cooled to 25-30 ⁰ C, added 50 ml of cyclohexane and stirred for 15 min at 25-30 ⁰ C. The resulting slurry product was filtered and washed with cyclohexane (10 ml). The product was dried at 70-75 ⁰ C for 4 h under reduce pressure (10-20 mm Hg) to obtain 9.0 g (90%) of the title compound.

Total residual solvents are < 0.1% w/w (By GC) and the product was amorphous by XRD.