PREPARATION OF BOCCORE

INTRODUCTION

The present application relates a process for the preparation of Boccore or a salt thereof. The present application also provides processes for the preparation of ritonavir Form I and Form II.

Boc-core is an abbreviation for a compound having a chemical name (2S,3S,5S)-2-amino-3-hydroxy-5-(t-butyloxycarbonyl)amino)-1,6-diphenylhexane, and represented by structural formula (I).

Compounds of formula (I), and salts thereof, are useful as intermediates for the manufacture of HIV protease inhibitors, such as lopinavir and ritonavir.

Ritonavir, the active ingredient in products sold as NORVIR™ by Abbott Laboratories, has a chemical name 10-hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]3-6-dioxo-8,11 -bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)], and the following structural formula:
Lopinavir, an active ingredient (in combination with ritonavir) in products sold as KALETRA™ by Abbott Laboratories, has a chemical name [1S-[1R*,(R*),3R*,4R*]]-/V-[4-[[(2,6-dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]tetrahydro-alpha-(1-methylethyl)-2-oxo-1(2H)-pyrimidineacetamide, and the following structural formula:

U.S. Patent No. 5,616,776 discloses a process for the preparation of a substituted 2,5-diamino-3-hydroxyhexane, such as Boc-core, by reducing (S)-2-t-butyloxycarbonylamino-5-N,N-dibenzylamino-1,6-diphenyl-4-oxo-2-hexene, followed by deprotecting the resultant intermediate to give Boc-core.

International Application Publication No. WO 2006/096264 A1 discloses an in situ process for the preparation of 2-amino-5-protectedamino-3-hydroxy-1,6-diphenylhexane compounds or acid addition salts thereof.

There remains a need to provide simple, cost effective and commercially viable processes for the preparation of Boc-core.

U.S. Patent No. 6,894,171 discloses crystalline Form II of ritonavir. The patent also discloses a process for the preparation of crystalline Form II of ritonavir by a solvent-anti solvent method using a mixture of solvents. The patent also discloses the processes for preparing ritonavir disclosed in U.S. Patent No. 5,541,206, which produces a crystalline polymorph of ritonavir termed crystalline Form I. The process disclosed in U.S. Patent No. 5,541,206 also involves a solvent-antisolvent method using a mixture of solvents.

There remains a need for simple, robust, cost effective and eco-friendly processes for the preparation of ritonavir Form I and Form II.

SUMMARY

In an aspect, the present application provides processes for the preparation of a compound of formula (I) or a salt thereof, an embodiment including one or more of the following steps, individually or in the sequence recited:

a) reacting L-phenylalanine of formula (II) with a reagent to provide the aminoalcohol of formula (III), or a salt thereof, where Ph is a phenyl group;

b) converting the amino alcohol of formula (III) into a compound of formula (IV), or a salt thereof,

wherein X is a halogen such as chlorine, bromine, fluorine and iodine, or a leaving group such as p-toluenesulfonyloxy, methanesulfonyloxy, and the like;

c) reacting a compound of formula (IV) with a reagent to provide the aminonitrile of formula (V), or a salt thereof;

d) converting the aminonitrile of formula (V) into an N-protected aminonitrile of formula (VI);

wherein R is a N-protecting group such as formyl, acetyl, t-butylacetyl, pivaloyl, benzoyl, trifluoroacetyl, 4-nitrobenzoyl, benzyl, benzyloxymethyl, benzyloxycarbonyl, t-butyloxycarbonyl (Boc), fluorenyl-9-methoxycarbonyl, or any other suitable protecting group;

e) reacting a compound of formula (VI) with a suitable reagent to provide an aminoaldehyde of formula (VII);

wherein R is as described previously;

f) reacting a compound of formula (VII) with the compound of formula (VIII) to provide the nitroaldol derivative of formula (IX); and

g) reacting the nitroaldol derivative of formula (IX) with a suitable reagent to provide the compound of formula (I), or a salt thereof.

The compound of formula (I), or a salt thereof, prepared according to a process described in the present application is useful as an intermediate for the manufacture of HIV protease inhibitors, such as lopinavir and ritonavir.

Crystalline Form I of ritonavir prepared according to the process described in Example 22 (A) of the present application may be characterized by its powder X-ray diffraction pattern substantially as illustrated by Figure 1.

Crystalline Form II of ritonavir prepared according to the process described in Example 20 (A) of the present application may be characterized by its powder X-ray diffraction pattern substantially as illustrated by Figure 2.

In embodiments, ritonavir Form I and Form II may be prepared by crystallization of ritonavir from a solution of ritonavir in a single solvent.

In embodiments, the present application provides processes for the preparation of ritonavir Form I and Form II, which include:

i) providing a solution of ritonavir in an organic solvent; and

ii) forming crystals of ritonavir Form I or Form II.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an illustration of a powder X-ray diffraction (PXRD) pattern of ritonavir Form I prepared according to Example 22 (A).

Figure 2 is an illustration of a PXRD pattern of ritonavir Form II prepared
according to Example 20 (A).

DETAILED DESCRIPTION

In an embodiment, the present application provides a process for the preparation of a compound of formula (I), or a salt thereof, which includes one or more of the following steps, individually or in the sequence recited:

a) reacting L-phenylalanine of formula (II) with a reagent to provide the
aminoalcohol of formula (III), or a salt thereof, where Ph is a phenyl group;

b) converting the aminoalcohol of formula (III) into a compound of formula
(IV), or a salt thereof; where X is a halogen such as chlorine, bromine, fluorine and iodine, or any leaving group such as p-toluenesulfonyloxy, methanesulfonyloxy, and the like;

c) reacting a compound of formula (IV) with a suitable reagent to provide
the aminonitrile of formula (V), or a salt thereof;

d) converting the aminonitrile of formula (V) into an N-protected aminonitrile of formula where R is a N-protecting group such as formyl, acetyl, t-butylacetyl, pivaloyl, benzoyl, trifluoroacetyl, 4-nitrobenzoyl, benzyl, benzyloxymethyl, benzyloxycarbonyl, t-butyloxycarbonyl ("Boc"), fluorenyl-9-methoxycarbonyl, or any other suitable protecting group;

e) reacting a compound of formula (VI) with a suitable reagent to provide
an aminoaldehyde of formula (VII), wherein R is as described previously;

f) reacting a compound of formula (VII) with the compound of formula (VIII) to provide the nitroaldol derivative of formula (IX); and

g) reacting the nitroaldol derivative of formula (IX) with a suitable reagent to provide the compound of formula (I), or a salt thereof.

Step a) involves reacting L-phenylalanine of formula (II) with a reagent to provide the amino alcohol of formula (III), or a salt thereof.

Step a) may be carried out in presence of a reagent. Suitable reagents that may be used include, but are not limited to: boron-containing reducing agents such as sodium borohydride; lithium borohydride, potassium borohydride, NaCNBH3, and the like; lithium aluminum hydride and the like; and any other suitable reagents.

Step a) may be optionally carried out in the presence of iodine.

Step a) may be optionally carried out in the presence of a suitable acid such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, periodic acid, sulphuric acid, phosphoric acid, polyphosphoric acid, phosphorous acid, nitric acid, nitrous acid, and the like.

Step a) may be optionally carried out in a suitable solvent. Suitable solvents that may be used include, but are not limited to: alcohols such as methanol, ethanol, isopropanol, n-butanol, and the like; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, and the like; aliphatic or alicyclic hydrocarbons such as hexanes, n-heptane, n-pentane, cyclohexane, and the like; halogenated hydrocarbons such as dichloromethane, chloroform, and the like; aromatic hydrocarbons such as toluene, xylenes, and the like; polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, and the like; and any mixtures thereof.

Suitable temperatures that may be used in step a) may be less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, or any other suitable temperatures.

The salt of compound of formula (III) include, but are not limited to: inorganic acid addition salts such as hydrochloride, hydrobromide, sulphate and phosphate; and the like; organic acid addition salts such as formate, acetate, fumarate, oxalate, maleate, succinate, citrate, tartarate, glutarate, and the like.

Optionally, the reaction mixture containing the compound of formula (III) obtained in step a), before or after conventional work-up, may be carried forward to step b) without isolating the compound.

Step b) involves converting the aminoalcohol of formula (III) into a compound of formula (IV), or a salt thereof.

Step b) may optionally be carried out in a suitable solvent. Suitable solvents that may be used in step b) include, but are not limited to: ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dimethoxyethane, and the like; aliphatic or alicyclic hydrocarbons such as hexanes, n-heptane, n-pentane, cyclohexane, and the like; halogenated hydrocarbons such as dichloromethane, chloroform, and the like; aromatic hydrocarbons such as toluene, xylenes, and the like; polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, and the like; and any mixtures thereof.

Step b) may be carried out in the presence of a reagent. Suitable reagents that may be used in step b) include, but are not limited to: halogenating agents such as thionyl chloride and the like; a combination of triphenylphosphine (PPh3) and CCl4, a combination of PPh3 and CBr4, a combination of PPh3 and CCI4, and the like; cyanuric trichloride; a combination of isocyanuric chloride and PPh3; and any other suitable reagents.

Suitable temperatures that may be used in step b) may be less than about 200°C, less than about 150°C, less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures.

The salt of compound of formula (IV) include, but are not limited to: inorganic acid addition salts such as hydrochloride, hydrobromide, sulphate and phosphate; and the like; organic acid addition salts such as formate, acetate, fumarate, oxalate, maleate, succinate, citrate, tartarate, glutarate, and the like.

Optionally, the mixture containing a compound of formula (IV) obtained in step b), before or after conventional work-up, may be carried forward to step c) without isolating the compound.

Step c) involves reacting the compound of formula (IV) with a suitable reagent to provide an aminonitrile of formula (V) or a salt thereof.

Step c) may be optionally carried out in a suitable solvent. Suitable solvents that may be used in step c) include, but are not limited to: polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, and the like; and mixtures thereof.

Step c) may be carried out in the presence of a reagent. Suitable reagents that may be used in step c) include, but are not limited to: metal cyanides such as sodium cyanide, potassium cyanide, and the like; any other suitable reagents.
Suitable temperatures that may be used in step c) may be less than about 200°C, less than about 150°C, less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures.

The salt of compound of formula (V) include, but are not limited to: inorganic acid addition salts such as hydrochloride, hydrobromide, sulphate and phosphate; and the like; organic acid addition salts such as formate, acetate, fumarate, oxalate, maleate, succinate, citrate, tartarate, glutarate, and the like.

Optionally the reaction mixture containing a compound of formula (V) obtained in step c), before or after conventional work-up, may be carried forward to step d) without isolating the compound.

Step d) involves converting the aminonitrile of formula (V) into the N-protected aminonitrile of formula (VI).

Step d) may be optionally carried out in a suitable solvent. Suitable solvents that may be used in step d) include, but are not limited to: water; alcohols such as methanol, ethanol, 1-propanol, 1-butanol, t-butyl alcohol, ethylene glycol, and the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, iso-butyl acetate, and the like; ethers such as diethyl ether, dnsopropyi ether, t-butyl methyl ether, tetrahydrofuran, methyl t-butyl ether, cyclopentyl methyl ether, and the like; aliphatic or alicyclic hydrocarbons such as hexanes, n-heptane, n-pentane, cyclohexane, and the like; halogenated hydrocarbons such as dichloromethane, chloroform, and the like; aromatic hydrocarbons such as toluene, xylenes, and the like; nitriles such as acetonitrile, propionitrile, and the like; polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, and the like; and any mixtures thereof.

The term "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid, or to protect an amino group, against undesirable reactions during synthesis procedures. Suitable N-protecting groups that may be used include, but are not limited to: acyl groups such as formyl, acetyl, t-butyl acetyl, pivaloyl, benzoyl, trifluoroacetyl, 4-nitrobenzoyl, and the like; alkyl groups such as benzyl, benzyloxymethyl, and the like; carbamate forming groups such as benzyloxycarbonyl, t-butyloxycarbonyl, fluorenyl-9-methoxycarbonyl, and the like; and any other suitable protecting groups.

Step d) may be carried out in the presence of a reagent. Suitable reagents that may be used in step a) include, but are not limited to: Boc anhydride [di-t-butyl dicarbonate or (Boc)20]; benzyl chloride; mixtures of t-butanol and ethyl chloroformate; and any other suitable reagents.

Step d) may be carried out in the presence of a base. Suitable bases that may be used in step d) include, but are not limited to: organic bases such as triethylamine, tributylamine, N-methylmorpholine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, and the like; inorganic bases such as alkali metal hydrides including sodium hydride, potassium hydride, and the like; sodamide; n-butyl lithium; lithium diisopropylamide; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; alkaline metal hydroxides such as aluminum hydroxide, magnesium hydroxide, calcium hydroxide, and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, and the like; alkaline earth metal carbonates such as magnesium carbonate, calcium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, and the like; and ion exchange resins including resins bound to ions such as sodium, potassium, lithium, calcium, and magnesium; substituted or unsubstituted ammonium and the like; and any other suitable bases.

Suitable temperatures that may be used in step d) may be less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -20°C, less than about -30°C, or any other suitable temperatures.

Optionally the reaction mixture containing a compound of formula (VI) obtained in step d), before or after conventional work-up, may be carried forward to step e) without isolating the compound.

Step e) involves reacting the compound of formula (VI) with a suitable reagent to provide the aminoaldehyde of formula (VII).

Step e) may be carried out in the presence of a reagent. Suitable reagents that may be used in step e) include, but are not limited to: diisobutyl aluminum hydride, Raney nickel, sodium hypophosphate, palladium, and the like; any mixtures thereof; and any other suitable reagents.

Step e) may be optionally carried out in a suitable solvent. Suitable solvents that may be used in step e) include, but are not limited to: water; alcohols such as methanol, ethanol, 1-propanol, 1-butanol, t-butyl alcohol, ethylene glycol, and the like; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, and the like; aliphatic or alicyclic hydrocarbons such as hexanes, n-heptane, n-pentane, cyclohexane, and the like; halogenated hydrocarbons such as dichloromethane, chloroform, and the like; aromatic hydrocarbons such as toluene, xylenes, and the like; polar aprotic solvents such as pyridine, dimethylsulphoxide, sulpholane, formamide, and the like; acids such as formic acid, acetic acid, propionic acid, valeric acid, and the like; and any mixtures thereof.
Optionally the reaction mixture containing a compound of formula (VII) obtained in step e), before or after conventional work-up, may be carried forward to step f) without isolating the compound.

The aminoaldehyde of formula (VII) may also be prepared by any process known in the art.

Step f) involves reacting the compound of formula (VII) with a compound of formula (VIII), to provide the nitroaldol derivative of formula (IX).

Step f) may be optionally carried out in a suitable solvent. Suitable solvents that may be used in step f) include, but are not limited to: water; alcohols such as methanol, ethanol, 1-propanol, 1-butanol, t-butyl alcohol, ethylene glycol, and the like; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, methyl t-butyl ether, cyclopentyl methyl ether, and the like; aliphatic or alicyclic hydrocarbons such as hexanes, n-heptane, n-pentane, cyclohexane, and the like; halogenated hydrocarbons such as dichloromethane, chloroform, and the like; aromatic hydrocarbons such as toluene, xylenes, and the like; polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, and the like; and anymixtures thereof.

Step f) may be carried out in the presence of a catalyst. Suitable catalysts that may be used in step f) include, but are not limited to: tetra-n-butylammonium fluoride; chiral phase transfer catalysts such as cinchona based phase transfer catalysts; zinc (II) based catalysts such as zinc complexes of proline, lysine, arginine, (+)-N-methylephedrine, (-)-N-methylephedrine, and the like; chiral complexes of metals such as bis(oxazoline)-metal complexes; aza(bisoxazoline) metal complexes; thio bis(oxazoline) metal complexes; oxy bis(oxazoline) metal complexes; polymer based bis(oxazoline) complexes; guanidine based catalysts; lanthanum binol complexes; cobalt (II) based catalysts; other metal-based catalysts; and any other suitable reagents.

In an embodiment, a lanthanum binol complex of the present application may be prepared by processes known in the art. For example, it may be prepared by treating lanthanum (III) tri-isopropoxide [La(OiPr)3] with chiral binol derivatives.

In an embodiment, bis(oxazoline) ligands such as (-)-(S,S)-bis(4-isopropyloxazoline) may be prepared by processes known in the art. For example, one may be prepared by reacting acetone with nitromethane to provide 2,2-diemthylmalonic acid, converting the 2,2-dimethylmalonic acid to 2,2-dimethylpropanedioyl dichloride by following the process described in Journal of Organic Chemistry (1998) 63, 4541, and reacting the obtained 2,2-dimethylpropanedioyl dichloride with (L)-valinol, following the process described in Organic Synthesis (2006), 83, 97-102.

Step g) involves reacting the nitroaldol derivative of formula (IX) with a suitable reagent to provide the compound of formula (I), or a salt thereof.

Step g) may be optionally carried out in a suitable solvent. Suitable solvents that may be used in step g) include, but are not limited to: water; alcohols such as methanol, ethanol, 1-propanol, 1-butanol, t-butyl alcohol, and the like; aliphatic or alicyclic hydrocarbons such as hexanes, n-heptane, n-pentane, cyclohexane, and the like; halogenated hydrocarbons such as dichloromethane, chloroform, and the like; aromatic hydrocarbons such as toluene, xylenes, and the like; pyridine and the like; and any mixtures thereof.

Step g) may be carried out in presence of a reagent. Suitable reagents that may be used in step g) include, but are not limited to, zinc, ammonium formate, ammonium acetate, Raney nickel, palladium, iron, and the like, and any other suitable reagents.

The salt of compound of formula (I) include, but are not limited to: inorganic acid addition salts such as hydrochloride, hydrobromide, sulphate and phosphate; and the like; organic acid addition salts such as formate, acetate, fumarate, oxalate, maleate, succinate, citrate, tartarate, glutarate, and the like.

The compound of formula (I), or a salt thereof, prepared according to the processes described in the present application is useful as an intermediate for the manufacture of HIV protease inhibitors such as lopinavir and ritonavir.

For example, lopinavir may be prepared from the compound of formula (I) or a salt thereof by any process known in the art. For example, lopinavir may be prepared from the compound of formula (I) or a salt thereof by a process as described in India Patent Application No. 2974/CHE/2008.

Similarly, ritonavir may be prepared from the compound of formula (I) or a salt thereof by any process known in the art. For example, ritonavir may be prepared from the compound of formula (I) or a salt thereof according to the process described in the present application.

Crystalline Form I of ritonavir prepared according to the process described in Example 22 (A) of the present application may be characterized by its powder X-ray diffraction pattern, substantially as illustrated in Figure 1.

Crystalline Form II of ritonavir prepared according to the process described in Example 20 (A) of the present application may be characterized by its powder X-ray diffraction pattern, substantially as illustrated in Fig. 2.

In embodiments, ritonavir Form I and Form II may be prepared by crystallization of ritonavir from solutions of ritonavir in a single solvent.

In embodiments, the present application provides processes for the preparation of ritonavir Form I and Form II, which include:

i) providing a solution of ritonavir in an organic solvent; and

ii) forming crystals of ritonavir Form I or Form II.

Providing a solution of ritonavir in an organic solvent includes direct use of a reaction mixture containing ritonavir that is obtained in the course of its synthesis, or dissolving ritonavir in an organic solvent.

Any physical forms of ritonavir, such as crystalline, amorphous or their mixtures may be utilized for providing the solution of ritonavir in step i).

Suitable solvents that may be used in step i) include, but are not limited to, esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, n-butyl acetate, t-butyl acetate, isobutyl acetate, methyl propanoate, ethyl proponoate, methyl butanoate, ethyl butanoate, and the like, and mixtures thereof.

In embodiments, solvents that may be used for the preparation of ritonavir Form I include, but are not limited to, isopropyl acetate and isobutyl acetate.
In embodiments, a solvent that may be used for the preparation of ritonavir Form II includes, but is not limited to, ethyl acetate.

The dissolution temperatures may range from about -20°C to about the reflux temperature of the solvent, depending on the solvent used for dissolution, as long as a clear solution of ritonavir is obtained without affecting its quality.

The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove colour and/or to improve clarity of the solution.

Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

The crystal formation in step ii) may be effected by any method including cooling the solution and seeding the solution with a small amount of the desired polymorph of ritonavir.

Suitable temperatures for crystal formation may be less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 5°C, less than about 0°C, less than about -10°C, less than about -20°C, or any other suitable temperatures. Suitable times for isolation may be less than about 25 hours, less than about 15 hours, less than about 10 hours, less than about 5 hours, or longer times may be used.

The cystallized ritonavir Form I and Form II may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the separation of solids from liquids.

The recovered crystals may be optionally further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at temperatures less than about 150°C, less than about 120°C, less than about 100°C, less than about 80°C, less than about 60°C, or any other suitable temperatures, as long as the ritonavir is not degraded in quality, at atmospheric pressure or under a reduced pressure.

It is normally beneficial to use a single solvent, rather than a mixture of solvents, for crystallization of a particular compound - especially for commercial scale processing - to make the process simple, robust, cost effective and ecologically friendly. Hence, the present processes for preparation of ritonavir Form I and Form II are advantageous, when compared with prior processes where mixtures of solvents were used for the crystallization of ritonavir Forms I and II.

All PXRD data reported herein are obtained using a Bruker Axe D8 Advance Powder X-ray Diffractometer with copper Ka radiation.

Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided for the purpose of illustration only, and should not be construed as limiting the scope of the application in any manner.

Examples EXAMPLE 1: Preparation of N-((t-butoxy)carbonyl)-L-phenylalanine.

L-phenylalanine (100 g), tetrahydrofuran (1000 mL) and a solution of sodium hydroxide (56 g) in water (1000 mL) are charged into a round bottom flask and stirred for 5 minutes. The mixture is cooled to 0°C and (BOC)20 (132 g) is added slowly at 0°C. The temperature is slowly raised to 30°C and maintained for 21-22 hours. The mixture is acidified with 2.8 N HCI (600 ml_). Ethyl acetate (2000 mL) is charged to the mass and the mixture is stirred at 30°C for 20 minutes. The layers are separated and the organic layer is dried over sodium sulphate (120 g). The solvent from the organic layer is evaporated at 50°C under reduced pressure to afford 174 g of the title compound. Purity by HPLC: 99.95%.

EXAMPLE 2: Preparation of N-((t-butoxy)carbonyl)-L-phenylalanol.

N-((t-butyloxy)carbonyl)-L-phenylalanine (20 g) and tetrahydrofuran (250 mL) are charged into a round bottom flask and stirred for 5 minutes. The mixture is cooled to -15°C and N-methylmorpholine (8.3 mL) is added. Isobutylchloroformate (9.77 mL) is added at -10°C and stirred for 30 minutes. The mixture is filtered and the obtained white precipitate washed with tetrahydrofuran (30 mL). The filtrate is charged into a round bottom flask under a nitrogen atmosphere, and a solution of sodium borohydride (4.3 g) in water (10 mL) is slowly added at 0°C. The mixture is poured into another flask containing water (500 mL) at 28°C and stirred for 45 minutes. The solid is filtered under reduced pressure at 28°C and dried under reduced pressure at 28°C to afford 12.0 g of the title compound. Purity by HPLC: 95.8%.

EXAMPLE 3: Preparation of (S)-2-[(t-butoxycarbonyl)amino]-3-phenylpropan-1-tosylate.

N-((t-butoxy)carbonyl)-L-phenylalanol (7.5 g) and dichloromethane (120 mL) are charged into a round bottom flask at 28°C under a nitrogen atmosphere and stirred for 10 minutes. The mixture is cooled to 0°C and triethylamine (5.1 mL) is added at 0°C, followed by adding dimethylaminopyridine (370 mg). p-Toluenesulphonyl chloride (6.5 g) is added at 0°C and the mixture is maintained at 28°C for 1-2 hours. 1M potassium carbonate solution (50 mL) is added to the reaction mixture, the layers are separated, and the organic layer is washed with 1N HCI (50 mL). The solvent from the organic layer is evaporated completely at 50°C under reduced pressure to afford 12.0 g of the title compound.

EXAMPLE 4: Preparation of (S)-2-[(t-butoxycarbonyl)amino]-3-phenylpropan-1-mesylate.

N-((t-butoxy)carbonyl)-L-phenylalanol (140 g), dichloromethane (1000 mL) and triethylamine (230 mL) are charged into a round bottom flask under a nitrogen atmosphere at 28°C. The mixture is cooled to 0°C and methanesulfonyl chloride (108 mL) is added. The mixture is stirred for 20 minutes at 0°C and further maintained at 28°C for 2 hours. 1N HCI solution (500 mL) is added and the mixture is stirred for 20 minutes. The organic layer is washed with 5% sodium bicarbonate solution (500 mL), then is washed with a solution of sodium chloride (50 g) in water (100 mL). The organic layer is dried over sodium sulphate (50 g) and the solvent is evaporated at 45-50°C under reduced pressure. Ethyl acetate (500 mL) is added to the residue and stirred at 28°C for 20 minutes. Hexane (1500 mL) is added and stirred for 20 minutes. The formed solid is filtered under reduced pressure to afford 138 g of the title compound.

EXAMPLE 5: Preparation of (S)-2-[(t-butoxycarbonyl)amino]-3-phenyl-1-bromopropane.

(S)-2-[(t-butoxycarbonyl)amino]-3-phenylpropan-1-tosylate (5 g) and acetone (200 mL) are charged into a round bottom flask at 25°C under a nitrogen atmosphere and stirred for 5 minutes. LiBr (2.68 g) is added and the mixture is stirred at 25°C for 23-24 hours. The solvent is evaporated at 45°C under reduced pressure. The residue is extracted with ethyl acetate (800 mL) and the organic layer is washed with water (200 mL). The organic layer is dried over sodium sulphate (2 g) and the solvent is evaporated at 50°C under reduced pressure, to afford 2.72 g of the title compound.

EXAMPLE 6: Preparation of (S)-3-[(t-butoxycarbonyl)amino]-4-phenylbutanenitrile.
A). (S)-2-[(t-butoxycarbonyl)amino]-3-phenylpropan-1-tosylate (15 g) is charged into a round bottom flask at 28°C under a nitrogen atmosphere. N,N-dimethylformamide (50 mL) is added and stirred for 15 minutes. NaCN (5.4 g) is added at 28°C and the mixture is maintained at 28°C for 21 hours. The reaction is quenched by adding water (1000 mL) and the mixture is extracted with ethyl acetate (500 mL). The organic layer is washed with water (2x500 mL), then with a solution of sodium chloride (50 g) in water (150 mL), and is dried over sodium sulphate (50 g).

The solvent is evaporated at 55°C to afford a yellow thick liquid. Dichloromethane (30 mL) is added at 28°C and stirred for a period of 5 minutes. Hexane (3x30 mL) is slowly added to the solution and stirred for 45 minutes. The formed solid is filtered and washed with hexane (20 mL), to afford 4.0 g of the title compound. Purity by HPLC: 88.87%.

B). (S)-2-[(t-butoxycarbonyl)amino]-3-phenylpropan-1-mesylate (138 g), N,N-dimethylformamide (500 mL) and sodium cyanide (62 g) are charged into a round bottom flask and stirred for 10-15 minutes. The mixture is heated to 50°C and maintained for a period of 1 hour. The mixture is cooled to 28°C, water (2000 mL) is added, and the mixture is stirred for 20 minutes. Ethyl acetate (1000 mL) is added and stirred for 20 minutes. The organic layer is separated and washed with water (2x500 mL). The organic layer is dried over sodium sulphate (50 g) and the solvent is evaporated at 50°C under reduced pressure. Dichloromethane (200 mL) is added to the residue and stirred at 28°C for 20 minutes. Hexane (600 mL) is added and stirred for 30-45 minutes. The formed solid is filtered under reduced pressure, to afford 75 g of the title compound. Purity by HPLC: 98.55%.

C). (S)-2-[(t-butoxycarbonyl)amino]-3-phenyl-1-bromopropane (2 g), N,N-dimethylformamide (10 mL) and sodium cyanide (0.936 g) are charged into a round bottom flask and stirred for 5 minutes at 25°C under a nitrogen atmosphere. The mixture is heated to 60°C and maintained for 31-32 hours. Ice water (100 mL) is added and the mixture is extracted with ethyl acetate (200 mL). The solvent from the organic layer is evaporated at 45°C under reduced pressure, to afford 1.24 g of the title compound. Purity by HPLC: 99.1%.

EXAMPLE 7: Preparation of (S)-3-[(t-butoxycarbonyl)amino]-4-phenyl butanaldehyde. A). (S)-3-[(t-butoxycarbonyl)amino]-4-phenylbutanenitrile (500 mg) is charged into a round bottom flask at 28°C under a nitrogen atmosphere, toluene (15 mL) is added, and the mixture is stirred for 5-10 minutes. The mixture is cooled to -78°C and diisobutylaluminium hydride (20% by weight, 1.4 M in toluene; 5.4 mL) is added at -78°C over a period of 2 hours. The mixture is maintained at -78°C for 30 minutes, then the reaction is quenched by adding methanol (1 mL). Saturated ammonium chloride solution (50 mL) and ethyl acetate (50 mL) are added and stirred for 20 minutes at -50 to -60°C. A solution of 1M HCI (20 mL) is added, followed by 3M HCI solution (20 mL) until pH of the reaction mixture is 2-3. The layers are separated and the organic layer is washed with 1M HCI solution (100 mL), followed by 10% sodium bicarbonate solution (100 mL), and finally with brine (20 mL). The solvent from the organic layer is evaporated at 45-50°C under reduced pressure to afford 100 mg of the title compound.

B). Pyridine (86.6 mL), water (51.6 mL), acetic acid (51.6 mL), Raney nickel (22.8 g), sodium hypophosphate (13.5 mL) and ((S)-3-[(t-butoxycarbonyl)amino]-4-phenylbutanenitrile (4 g) are charged into a round bottom flask and stirred at 25°C for 22-23 hours. Dichloromethane (100 mL) is added and stirred for 15 minutes. The mixture is filtered through a celite bed. The layers are separated and 15% sodium bicarbonate solution (100 mL) is added to the organic layer. The layers are separated and the organic layer is washed with 10% brine (50 mL), followed by 1% HCI solution (100 mL). The organic layer is dried over sodium sulphate (4 g) and the solvent is evaporated at 35°C under reduced pressure. Pyridine is removed by azeotropic distillation with toluene (20 mL). The residue is purified by column chromatography, using 5% ethyl acetate in hexane as the eluent, to afford 1.198 g of the title compound.

EXAMPLE 8: Preparation of (2S,3S,5S)-2-nitro-3-hydroxy-5-(t-
butyloxycarbonyl)amino)-1,6-diphenylhexane.

A). Tetrabutylammonium fluoride (1.011 mL) is charged into a round bottom flask at 0°C and a solution of 2-nitroethylbenzene (157 mg) in tetrahydrofuran (2 mL) is added at 0°C. A solution of (S)-3-[(t-butoxycarbonyl)amino]-4-phenyl butanaldehyde (250 mg) in tetrahydrofuran (2 mL) is added and stirred at 0°C for 2 hours. A saturated solution of sodium bicarbonate (5 mL) is added, the mixture is extracted with ether (3x15 mL), and the combined organic layer is washed with sodium chloride solution (5 mL). The solvent from the organic layer is evaporated at 24°C under reduced pressure to afford 408 mg of a residue. The residue is purified by column chromatography using a hexane-ethyl acetate mixture (95:5 by volume), to afford 167 mg of the title compound.

B). (S)-3-[(t-butoxycarbonyl) amino]-4-phenylbutanaldehyde (3.2 g) and tetrahydrofuran (60 mL) are charged into a round bottom flask and stirred for 10 minutes. 2-Nitroethylbenzene (2.2 mL) is added. The mixture is cooled to -38°C and lanthanum binol complex "(R)-LLB" (2.8 mL) is added. The mixture is stirred at -38°C for 24-25 hours. The reaction is quenched by adding 2N HCI (5 mL). The temperature is raised to room temperature and the mixture extracted with methyl t-butyl ether (100 mL). The organic layer is washed with water (30 mL), then is washed with aqueous saturated sodium bicarbonate (30 mL). The organic layer is dried over sodium sulphate. The solvent from the organic layer is evaporated at 40°C under reduced pressure. The residue is purified by column chromatography using 8% ethyl acetate in petroleum ether, to afford 2.5 g of the title compound.

EXAMPLE 9: Preparation of (2S,3S,5S)-2-amino-3-hydroxy-5-(t-
butyloxycarbonyl)amino)-1,6-diphenylhexane.

(2S,3S,5S)-2-nitro-3-hydroxy-5-(t-butyloxycarbonyl)amino)-1,6-diphenylhexane (20 mg) in methanol (2 mL) is charged into a round bottom flask at 25°C, followed by adding zinc (6 mg) and ammonium formate (3 mg) at 25°C. The mixture is maintained at 25°C for a period of 4-5 hours and filtered through a celite bed. The solvent from the filtrate is evaporated at 45°C and the residue is extracted with ethyl acetate (5 mL). The organic layer is washed with brine solution (5 mL) and finally washed with water (2 mL). The solvent from the organic layer is evaporated at 45°C and the residue is dried at 24°C under vacuum, to afford 15 mg of the title compound.

EXAMPLE 10: Preparation of nitrostyrene.

Benzaldehyde (20 mL) and methanol (200 mL) are charged into a round bottom flask and stirred at 28°C for 10 minutes. Nitromethane (11.96 g) is added and stirred for 5 minutes. The mixture is cooled to 0°C and a solution of sodium hydroxide (10.19 g) in water (25 mL) is added below 10°C, and the mixture is maintained at 0-5°C for 4 hours. Chilled water (200 mL) is added and stirred for 10 minutes. 4M HCI solution (200 mL) is charged into another round bottom flask and the above mixture is added to the round bottom flask containing 4M HCI solution at 10°C over 30 minutes. The mixture is stirred at 28°C for 16 hours. The formed solid is filtered under reduced pressure to afford 24 g of the title compound. Purity by HPLC: 99.32%.

EXAMPLE 11: Preparation of 2-nitroethylbenzene.

Sodium borohydride (13.3 g), dioxane (250 mL) and ethanol (75 mL) are charged into a round bottom flask and stirred for 5 minutes. A solution of nitrostyrene (25 g) in dioxane (250 mL) is slowly added at 28°C over 2 hours, 15 minutes. The reaction is quenched by adding ice water (300 mL) and the mixture is stirred for 15 minutes. 50% acetic acid solution (20 mL) is added slowly to the mixture in portions. The mixture is distilled at 50-55°C under reduced pressure. To the residue is added a mixture of water (250 mL) and chloroform (1000 mL) and the mixture stirred for 10 minutes. The organic layer is separated and washed with water (3*200 mL), followed by washing with brine solution (300 mL), and the organic layer is dried over sodium sulphate (30 g). The solvent from the organic layer is evaporated at 50°C under reduced pressure to afford 24.0 g of the title compound. Purity by HPLC: 90.8%.

EXAMPLE 12: Preparation of 2-amino-3-phenylpropan-1-ol.

Sodium borohydride (65.0 g) and tetrahydrofuran (1000 mL), followed by L-phenylalanine (100 g), are charged into a round bottom flask and stirred for 10 minutes. The mixture is cooled to 0°C and a solution of concentrated H2SO4 (43 mL) in tetrahydrofuran (200 mL) is added drop-wise. The mixture is heated to room temperature and maintained for 17-18 hours at 27°C. The mixture is cooled to 0°C and methanol (100 mL) is added slowly. The mixture is distilled at 50°C under reduced pressure. A solution of sodium hydroxide (5N, 650 mL) is added to the residue, then the mixture is heated to 75°C and maintained for a period of 3 hours. The mixture is cooled to 27-30°C and extracted with dichloromethane (4x500 mL). The total organic layer is dried over sodium sulphate. The solvent from the organic layer is evaporated at 40°C under reduced pressure. The residue is dissolved in dichloromethane (50 mL) and stirred for a period of 10-15 minutes. Dry HCI gas is passed into the mixture for 2 hours at 30°C. The solid is filtered under reduced pressure and dried at 60°C, to afford 68 g of the title compound.

EXAMPLE 13: Preparation of 1-benzyl-2-chloroethylamine hydrochloride.

Dimethoxyethane (165 mL) and thionyl chloride (2.9 mL) are charged into a round bottom flask at 27°C under a nitrogen atmosphere. A solution of 2-amino-3-phenylpropan-1-ol (5 g) in dimethoxyethane (195 mL) is added slowly at 27°C. The mixture is heated to 85°C and maintained for 3-4 hours, then is cooled to 29°C. The mixture is distilled at 55°C under reduced pressure. Ethyl acetate (50 mL) is added to the residue at 30°C and stirred for a period of 40 minutes. The solid is filtered and dried at 55°C under reduced pressure, to afford 5.4 g of the title compound.

EXAMPLE 14: Preparation of 3-amino-4-phenylbutyronitrile.

1-benzyl-2-chloroethylamine hydrochloride (5 g), N,N-dimethylformamide (100 mL) and sodium cyanide (3.56 g) are charged into a round bottom flask under a nitrogen atmosphere at 25°C. The mixture is heated to 40°C and maintained for 9-10 hours. Water (100 mL) is added at 40°C and stirred for 30 minutes. The mixture is extracted with ethyl acetate (75 mL), the ethyl acetate layer is washed with water (2x100 mL), and the solvent from the organic layer is evaporated at 55°C under reduced pressure. Dichloromethane (100 mL) is added to the residue at 20°C and stirred for a period of 5-10 minutes. HCI gas is passed into the mixture for 2 hours to afford 3.57 g of the title compound.

EXAMPLE 15: Preparation of 1-chloro-2-t-butyloxycarbonylamino-3-phenylpropane.
1-benzyl-2-chloroethylamine hydrochloride (18 g), tetrahydrofuran (90 mL) and a solution of sodium hydroxide (7.7 g) in water (90 mL) are charged into a round bottom flask and stirred for 5 minutes. The mixture is cooled to 0-5°C and (Boc)20 (21 g) is added. The temperature is raised to 26°C and the mixture is stirred for 20-21 hours. The mixture is extracted with ethyl acetate (100 mL). The organic layer is dried over sodium sulphate (5 g) and the solvent is evaporated at 55°C under reduced pressure, to afford 23.2 g of the title compound.

EXAMPLE 16: Preparation of (S)-3-[(t-butoxycarbonyl)amino]-4-phenylbutanenitrile.
A). 3-amino-4-phenylbutyronitrile (4 g), tetrahydrofuran (20 mL) and a solution of sodium hydroxide (2.03 g) in water (20 mL) are charged into a round bottom flask and stirred for a period of 5-10 minutes. The mixture is cooled to 0°C and Boc anhydride [(Boc)20] (4.88 g) is added at 0-5°C. The mixture is maintained at 0°C for 5-6 hours, then is maintained at 25°C for 16-17 hours. The pH is adjusted to 2-3 with 1N HCI solution (150 ml_). The mixture is extracted with ethyl acetate (150 mL) and the organic layer is washed with brine (40 mL). The solvent from the organic layer is evaporated at 45°C under reduced pressure, to afford 5.02 g of the title compound.

B). 1-chloro-2-t-butyloxycarbonylamino-3-phenylpropane (2 g), N,N-dimethylformamide (30 mL) and sodium cyanide (1.1 g) are charged into a round bottom flask at 25°C under a nitrogen atmosphere. The mixture is heated to 100-105°C and maintained for 15-30 minutes. The mixture is cooled to 27°C. Water (50 mL) and ethyl acetate (50 mL) are added and stirred for 10 minutes. The layers are separated and aqueous layer is washed with ethyl acetate (20 mL). The combined organic layer is washed with water (50 mL) and further with brine. The solvent from the organic layer is evaporated at 45°C under reduced pressure, to afford 1.71 g of the title compound.

EXAMPLE 17: Preparation of 2,2-dimethyl-1,3-dipropanoic acid.

A). Acetone (50 g), piperidine (187 mL) and nitromethane (46 mL) are charged into a round bottom flask at 29°C. The mixture heated to 48-49°C and maintained at 49° for 4 hours. Nitromethane (46 mL) is added and the mixture is maintained at 49°C for 4 hours. The mixture is cooled to 0°C. Concentrated hydrochloric acid (700 mL) is added, then the mixture is heated to 100-105°C and maintained for 5-6 hours. The mixture is extracted with ethyl acetate (1*500 mL; 1x200 mL). The solvent from the combined organic layer is evaporated at 55°C under reduced pressure. Ethyl acetate (200 mL) is added to the residue at 30°C and stirred for 1 hour. The solid is filtered under vacuum and dried at 45°C, to afford 37 g of the title compound.

B). Concentrated HN03 (600 mL) is charged into a round bottom flask and cooled to 0°C. Neopentyl glycol (100 g) is added and the mixture is stirred at 25°C for 21-22 hours. The mixture is distilled at 60°C under reduced pressure. Water (200 mL) is added to the residue. The mixture is cooled to 8°C and stirred for 20 minutes. The precipitated solid is filtered and washed with water (100 mL) and dried at 60°C, to afford 75 g of the title compound.

EXAMPLE 18: Preparation of (2S,3S,5S)-5-amino-2-(N-((5-
thiazolyl)methoxycarbonyl)amino)-3-hydroxy-1,6-diphenylhexane hydrochloride.
Water (500 mL) and sodium bicarbonate (12.8 g) are charged into a round bottom flask and stirred for 5-10 minutes. Ethyl acetate (1000 mL) and (2S,3S,5S)-2-amino-3-hydroxy-5-(t-butyloxycarbonyl)amino)-1,6-diphenylhexane hemisuccinate (50.0 g) are added at 26°C and the mixture is stirred at 26°C for 30 minutes. 5-(p-nitrophenyloxycarbonyloxymethyl)thiazole (30.0 g) is added and the mixture is maintained for 30 minutes at 26°C. The mixture is heated to 70°C and maintained for 3-4 hours. The mixture is cooled to 29°C and the layers are separated. The organic layer is washed with 15% K2CO3 solution (2x250 mL). Aqueous hydrochloric acid (34.5 mL) is slowly added to the organic layer, and then the mixture is heated to 78°C and maintained at reflux at 74°C for 3 hours, 15 minutes. The mixture is cooled to 35°C and maintained at 35°C for 35-40 minutes. The formed solid is filtered, washed with ethyl acetate (200 mL), and dried at 72-74°C under reduced pressure, to afford 50.2 g of the title compound. Purity by HPLC: 99.39%; water content by KF: 4.10%.

EXAMPLE 19: Preparation of ritonavir.

Ethyl acetate (120 mL) and (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl) methoxycarbonyl)amino)-3-hydroxy-1,6-diphenylhexane hydrochloride (20 g) are charged into a round bottom flask at 26°C and stirred for 5-10 minutes at 26°C. Aqueous ammonia solution (19 mL) and water (140 mL) are added and stirred at 26°C for 20 minutes. The layers are separated and the aqueous layer is extracted with ethyl acetate (20 mL). The total organic layer is washed with 25% NaCI solution (100 mL) and the solvent from the organic layer is evaporated below 45°C under reduced pressure, to afford 19.5 g of the free base (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-3-hydroxy-1,6-diphenylhexane.

N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine (13.8 g) and ethyl acetate (180 mL) are charged into a round bottom flask at 26°C under a nitrogen atmosphere and stirred for 10 minutes. N-methylmorpholine (4.9 g) is added and the mixture is cooled to 0 ± 5°C. A solution of ethylchloroformate (4.8 g) in ethyl acetate (20 mL) is slowly added at 0-5°C and the mixture is maintained at 0-5°C for 40 minutes. 1-Hydroxybenzotriazole ("HOBT," 6.0 g) is added and the mixture is maintained at 0-5°C for a period of 40 minutes. A solution of (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-3-hydroxy-1,6-diphenylhexane (19.5 g) in ethyl acetate (80 mL) is added at 0-5°C and maintained at 0-5°C for 40 minutes. The mixture temperature is raised to 26°C and maintained at 26°C for 3-4 hours. The mixture is washed with water (2x100 mL), followed by washing with 10% K2CO3 solution (80 mL), and then by 25% NaCI solution (100 mL). The solvent from the organic layer is evaporated at 45°C under reduced pressure, to afford 30.5 g of a residue. Ethyl acetate (60 mL) is added to the residue, heated to 50°C and maintained at 50° for 45 minutes. Cyclohexane (90 mL) is added, heated to 68°C and maintained at 68°C for 30 minutes. The mixture is cooled to 26°C and maintained for 8 hours. The formed solid is filtered, washed with a mixture of ethyl acetate (20 mL) and cyclohexane (30 mL), and dried at 55°C under reduced pressure, to afford 25.3 g of the title compound. Purity by HPLC: 99.4235%; moisture content: 0.16%; residue on ignition: 0.05%.

EXAMPLE 20: Preparation of ritonavir Form II.

A). Ritonavir (50 g) and ethyl acetate (500 mL) are charged into a round bottom flask and stirred for 5 minutes. The mixture is heated to 66-68°C and maintained under reflux at 66-68°C for 25 minutes. The mixture is filtered at 68°C and the filter is washed with ethyl acetate (50 mL). The filtrate is charged into a round bottom flask and maintained at 29-31°C for 22 hours. The formed solid is filtered, washed with ethyl acetate (50 mL), and dried at 55°C under reduced pressure, to afford 44.7 g of the title compound. Purity by HPLC: 99.86%.

B). Ritonavir (100 g) and ethyl acetate (800 mL) are charged into a round bottom flask and stirred for 5 minutes. The mixture is heated to 74°C and maintained under reflux at 74°C for 15 minutes. The mixture is filtered at 74°C and washed with ethyl acetate (100 mL). The filtrate is charged into a round bottom flask and seeded with ritonavir Form II (1.0 g) at 38°C. The mixture is maintained at 26-27°C for 7-8 hours. The formed solid is filtered, washed with ethyl acetate (100 mL), and dried at 54°C under reduced pressure, to afford 90.2 g of the title compound. Purity by HPLC: 99.70%.

EXAMPLE 21: Preparation of ritonavir Form I.

A) Ritonavir (10 g) and ethyl acetate (40 mL) are charged into a round bottom flask, heated to 72°C, and maintained at 72°C for 30 minutes. The mixture is cooled to 30°C and filtered, followed by washing the filter with ethyl acetate (5 mL). Cyclohexane (100 mL) is placed into another round bottom flask at 25°C and stirred for 5 minutes. The filtrate is added to the round bottom flask containing cyclohexane at 25°C. The mixture is maintained at 25-26°C for 4-5 hours. The formed solid is filtered, washed with cyclohexane (10 mL) and dried at 54°C under reduced pressure, to afford 9.2 g of the title compound. Purity by HPLC: 99.77%.

B) EXAMPLE 22: Purification of ritonavir.

A). Ritonavir (10 g) and isopropyl acetate (70 mL) are charged into a round bottom flask and heated to 65-70°C. The mixture is stirred at 65-70°C for 25 minutes to dissolve ritonavir completely. The solution is filtered at 70°C and the filter is washed with isopropyl acetate (10 mL). The filtrate is charged into a round bottom flask and maintained at 26°C for a period of 4-5 hours. The formed solid is filtered, washed with isopropyl acetate (20 mL), and dried at 55°C, to afford 9.1 g of the title compound. A PXRD pattern for the product is shown in Figure 1.

B). Ritonavir (10 g) and isobutyl acetate (80 mL) are charged into a round bottom flask, and the mixture is heated to 76-78°C and stirred at 76-78°C for 20 minutes to dissolve ritonavir completely. The solution is filtered at 78°C. The filtrate is charged into a round bottom flask and maintained at 26°C for 4-5 hours. The formed solid is filtered, washed with isobutyl acetate (20 mL), and dried at 55°C, to afford 9.2 g of the title compound.
C). Ritonavir (10 g) and n-butyl acetate (80 mL) are charged into a round bottom flask, and the mixture is heated to 7 4°C and stirred at 74°C for 30 minutes to dissolve ritonavir completely. The solution is cooled to 26°C and maintained for a period of 4-5 hours. The formed solid is filtered, washed with n-butyl acetate (20 mL), and dried at 55°C, to afford 9.1 g of the title compound.

EXAMPLE 23: Preparation of (2S,3S,5S)-2-nitro-3-hydroxy-5-(t-
butyloxycarbonyl)amino)-1,6-diphenylhexane.

4, 4'-isopropylbisoxazoline (556 mg) and Cu(OAc)2 (344 mg) are added in to a round bottomed flask at 25°C under nitrogen atmosphere. Ethanol (80 mL) is added to the above contents and the mixture is stirred at room temperature for 1 hour. 2-phenylnitroethane (5.93 g) and (S)-3-[(t-butoxycarbonyl)amino]-4-phenyl butanaldehyde (10 g) are added to the above obtained blue color solution at 25°C and the mixture is stirred for 48 hours. The organic solvent from the mixture evaporated at 45°C under reduced pressure and the obtained crude product is purified by subjecting to column chromatography to afford 12 g of the title compound.

EXAMPLE 24: Preparation of Ritonavir.

Ethyl acetate (125 mL) and (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl) methoxycarbonyl)amino)-3-hydroxy-1,6-diphenylhexane hydrochloride (25 g) are charged into a round bottom flask at 26°C and stirred for 5-10 minutes at 26°C. 25 % of aqueous ammonia solution (25 mL) and water (175 mL) are added and stirred at 26°C for 20 minutes. The layers are separated and the aqueous layer is extracted with ethyl acetate (25 mL). The total organic layer is washed with 25% NaCI solution (125 mL) and the solvent from the organic layer is evaporated below 45°C under reduced pressure, to afford 19.5 g of the free base (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-3-hydroxy-1,6-diphenylhexane.

N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine (17.3 g) and ethyl acetate (100 mL) are charged into a round bottom flask at 26°C under a nitrogen atmosphere and stirred for 10 minutes. N-methylmorpholine (6.0 g) is added and the mixture is cooled to 0 + 5°C. A solution of ethylchloroformate (6.0 g) in ethyl acetate (25 mL) is slowly added at 0-5°C and the mixture is maintained at 0-5°C for 40 minutes. 1-Hydroxybenzotriazole ("HOBT," 7.5 g) is added and the mixture is maintained at 0-5°C for a period of 40 minutes. A solution of (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-3-hydroxy-1,6-diphenylhexane in ethyl acetate (100 mL) is added at 0-5°C and maintained at 0-5°C for 40 minutes. The mixture temperature is raised to 26°C and maintained at 26°C for 2-3 hours. The mixture is washed with water (2x125 mL), followed by washing with 10% K2CO3 solution (1X100 mL; 1X50 mL), then washed with water (2X125 mL), and then by 25% NaCI solution (125 mL). The solvent from the organic layer is evaporated at 45°C under reduced pressure, to afford 30.5 g of a residue. Ethyl acetate (75 mL) is added to the residue, heated to 50°C and maintained at 50° for 30 minutes. Cyclohexane (112.5 mL) is added, heated to 68°C and maintained at 68°C for 30 minutes. The mixture is cooled to 26°C and maintained for 8 hours. The formed solid is filtered, washed with a mixture of ethyl acetate (25 mL) and cyclohexane (37.5 mL). Water (250 mL) is charged to the obtained wet compound at 25-35°C and stirred for 1-2 hours. The resultant solid is filtered, washed with water (50 mL), and dried at 55°C under reduced pressure, to afford 25.3 g of the title compound. Purity by HPLC: 99.31%

EXAMPLE 25: Preparation of ritonavir Form II.

Ritonavir (5.0 g) and ethyl acetate (40 mL) are charged into a round bottom flask and stirred for 5 minutes. The mixture is heated to 64±2°C and maintained at 64±2°C for 15 minutes. The mixture is slowly cooled to 35±2°C, then seeded with ritonavir Form II (0.05 g) at the same temperature and maintained at 35±2°C for 10-12 hours. The formed solid is filtered, washed with ethyl acetate (5 mL), and dried at 54°C under reduced pressure, to afford 4.5 g of the title compound.
Purity by HPLC: 99.9%.

EXAMPLE 26: Preparation of ritonavir Form I.

Ritonavir (20 g) and isopropyl acetate (140 mL) are charged into a round bottom flask and stirred for 5 minutes. The mixture is heated to reflux and maintained at reflux temperature for 5-10 minutes. Carbon (0.2 g) is added to the above mixture and stirred at reflux temperature for 30 minutes. The mixture is filtered, washed with isopropyl acetate (20.0 mL). The resultant filtrate is cooled to 10-15°C, maintained for 6-8 hours at the same temperature. The formed solid is filtered, washed with isopropyl acetate (20 mL), and dried at 55°C under reduced pressure, to afford 19.2 g of the title compound.

Purity by HPLC: 99.96%; ROI (residue on ignition): 0.05%; water content by KF:0.1%w/w;

Residual solvents by Gas chromatography: Methanol content: ND (not detected); Ethanol: ND; Isopropyl alcohol: ND; Ethyl acetate: ND; THF: ND; isopropyl acetate: 1186 ppm; Cyclohexane: ND

We claim:

1. A process for the preparation of a compound of formula (I) or a salt thereof, an embodiment including one or more of the following steps, individually or in the sequence recited:

(a) reacting L-phenylalanine of formula (II) with a reagent to provide the
aminoalcohol of formula (III), or a salt thereof, where Ph is a pnenyl group;

(b) converting the amino alcohol of formula (III) into a compound of formula (IV),
or a salt thereof,

wherein X is a halogen such as chlorine, bromine, fluorine and iodine, or a leaving group such as p-toluenesulfonyloxy, methanesulfonyloxy, and the like;

(c) reacting a compound of formula (IV) with a reagent to provide the aminonitrile
of formula (V), or a salt thereof;

(d) converting the aminonitrile of formula (V) into an N-protected aminonitrile of
formula (VI);

wherein R is a N-protecting group such as formyl, acetyl, t-butylacetyl, pivaloyl, benzoyl, trifluoroacetyl, 4-nitrobenzoyl, benzyl, benzyloxymethyl, benzyloxycarbonyl, t-butyloxycarbonyl (Boc), fluorenyl-9-methoxycarbonyl, or any other suitable protecting group;

(e) reacting a compound of formula (VI) with a suitable reagent to provide an
aminoaldehyde of formula (VII);

wherein R is as described previously;

(f) reacting a compound of formula (VII) with the compound of formula (VIII) to provide the nitroaldol derivative of formula (IX); and

(g) reacting the nitroaldol derivative of formula (IX) with a suitable reagent to provide the compound of formula (I), or a salt thereof.

2. A process for the preparation of ritonavir Form I, which includes:

(a) providing a solution of ritonavir in an organic solvent; and

(b) forming crystals of ritonavir Form I.

3. The process of claim 2, wherein a solvent comprises any one or more of isopropyl acetate and isobutyl acetate.

4. A process for the preparation of ritonavir Form II, which includes:

(a) providing a solution of ritonavir in an organic solvent; and

(b) forming crystals of ritonavir Form II.

5. The process of claim 4, where in the solvent comprises ethyl acetate.