WO2013011485A1

WO2013011485A1 - Process for the preparation of sulfonamides useful as retroviral protease inhibitors

Info

Publication number: WO2013011485A1
Application number: PCT/IB2012/053700
Authority: WO
Inventors: Suresh Babu Jayachandra; Ruchika Yogesh; Devendra Prakash NAGDA; Chandra Has Khanduri
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2011-07-20
Filing date: 2012-07-19
Publication date: 2013-01-24

Abstract

The present invention relates to a process for the preparation of sulfonamides useful as retroviral protease inhibitors.

Description

PROCESS FOR THE PREPARATION OF SULFONAMIDES USEFUL AS RETROVIRAL PROTEASE INHIBITORS

Field of the Invention

Background of the Invention

Sulfonamides of Formula I or their salts, solvates and prodrugs thereof, are known for inhibiting retroviral proteases and for treating retroviral infections, for example, human immunodeficiency virus (HIV) infection,

FORMULA I

wherein Ri is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocycloalkyl or heteroaryl. A large number of sulfonamides have been prepared and investigated for clinical efficacy. Darunavir, amprenavir and fosamprenavir are some of the sulfonamides useful as retroviral protease inhibitors and they are available in the market for treating HIV infection.

Darunavir is chemically [(lS,2R)-3-[[(4-aminophenyl)sulfonyl](2- methylpropyl)amino]-2-hydroxy- l-(phenylmethyl)propyl]-carbamic acid (3R,3aS,6aR)- hexahydrofuro[2,3-b]furan-3-yl ester of Formula la.

FORMULA la

Amprenavir is chemically (3S)-tetrahydro-3-furyl N-[(lS,2R)-3-(4-amino-N- isobutylbenzenesulfonamido)- 1 -benzyl-2-hydroxypropyl]carbamate of Formula lb.

FORMULA lb

Fosamprenavir is a prodrug of amprenavir and is chemically (3S)-tetrahydrofuran- 3-yl[(2S,3R)-4- {[(4-aminophenyl)sulfonyl](2-methylpropyl)amino}-l-phenyl-3- (phosphonooxy)butan-2-yl]carbamate of Formula Ic.

FORMULA Ic Fosamprenavir is marketed as a calcium salt. Darunavir, amprenavir and fosamprenavir calcium, individually or in combination with other antiretroviral agents, are indicated for the treatment of HIV infection.

4-Amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl) benzenesulfonamide of Formula II is an important intermediate for the preparation of sulfonamides of Formula I.

FORMULA II

There are several processes available in the prior art for obtaining the compound of Formula II. Bioorg. Med. Chem. Lett., 8, p. 687-690 (1998), provides the following process for preparing the compound of Formula II.

FORMULA III FORMULA IV

FORMULA V

FORMULA II

Similar processes involving above intermediates are also provided in WO 99/67254, WO 99/67417 and JP 2002-518063 A2.

Org. Process Res. Dev., 1, p. 45-54 (1997), and J. Med. Chem., 48, p. 1813- 1822 (2005) provide the following process for preparing the compound of Formula II.

FORMULA VI FORMULA VII

J. Med. Chem., 48, p. 1813-1822 (2005) also provides another process, wherein t- butoxycarbonyl group is used as a protecting group for the amino groups of the compounds of Formulae VI, VII and VIII instead of benzyl group. U.S. Patent No. 6,248,775 also provides a similar process, wherein benzyloxycarbonyl group is used as a protecting group for the amino groups of the compounds of Formulae VI, VII and VIII. The above processes involve simultaneous reduction of nitro group and deprotection at the final step to obtain the compound of Formula II. U.S. Publication No. 2007/0060642 says that said simultaneous reduction and deprotection is highly exothermic and it poses problems in controlling the reaction temperature. The U.S. '642 publication also says that the catalyst employed in reduction and deprotection is poisoned with the sulfur from 4- nitrobenzenesulfonyl chloride and it decreases product selectivity and results into the appearance of side products. The U.S. '642 publication provides a modified process for the preparation of the compound of Formula II, wherein the nitro group of the compound of Formula Villa is reduced using palladium-carbon to obtain the compound of Formula VHIb, which is subsequently deprotected by acid or base treatment to obtain the compound of Formula II.

FORMULA Villa

FORMULA VHIb

WO 2010/023322 provides a multistep process for the preparation of darunavir using N-benzyl protected derivative of the compound of Formula II. The above process requires starting with N-benzylisobutylamine, therefore requiring the debenzylation step at later stages to finally obtain darunavir.

WO 201 1/048604 provides a process for the preparation of darunavir wherein 4- amino-N-(2R,3S)-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylbenzenesulfonamide is coupled with (3R,3aS,6aR)-hexahydrofuro[2,3-Z?]furan-3-ol in N-methyl-2-pyrrolidinone.

The prior art processes for the preparation of compound of Formula II involve exothermic reactions and catalyst poisoning or the use of azide intermediates, which are difficult to handle at industrial scale. The modified process provided in U.S. Publication 2007/0060642 and WO 2010/023322 increases the number of steps. These processes require the amino group to be protected while the nitro group is reduced and therefore, involve additional benzylation/debenzylation steps.

Summary of the Invention

The present inventors have developed a simple process for the preparation of sulfonamides of Formula I using 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]- N-(2-methylpropyl)benzenesulfonamide of Formula II as an intermediate. The present process minimizes the number of steps involved in the preparation of the compound of Formula II. Further, the present process avoids the disadvantages associated with the prior art methods, including the use of any azide intermediate, exothermic reactions, etc. The present process does not require the amino group to be protected while the nitro group is reduced. The present process also provides the compound of Formula II and sulfonamides of Formula I with better yield. The present inventors have also found that the compound of Formula II can be directly obtained from the corresponding protected intermediate, in which both the amino functions are protected, in a single step by a simultaneous deprotection of both the amino functions using a hydrohalic acid. The deprotection method of the present invention also facilitates the isolation of the compound of Formula II as an acid addition salt with a hydrohalic acid, which helps in obtaining the compound of Formula II with higher purity. Thus, the present invention provides a simple, efficient and industrially preferable process for the preparation of the compound of Formula II and sulfonamides of Formula I.

The term "alkyl" in the present invention, alone or in combination, means a straight-chain or branched-chain alkyl radical containing from 1 carbon atom to about 10 carbon atoms, preferably from 1 carbon atom to about 8 carbon atoms, more preferably 1 carbon atom to about 5 carbon atoms. Examples of alkyl radicals include methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, and the like.

The term "alkenyl", alone or in combination, means a straight-chain or branched- chain hydrocarbon radical having one or more double bonds and containing from 2 carbon atoms to about 18 carbon atoms, preferably from 2 carbon atoms to about 8 carbon atoms, more preferably from 2 carbon atoms to about 5 carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, 1 ,4-butadienyl, and the like.

The term "alkynyl", alone or in combination, means a straight-chain or branched chain hydrocarbon radical having one or more triple bonds and containing from 2 carbon atoms to about 10 carbon atoms, more preferably from 2 carbon atoms to about 5 carbon atoms. Examples of alkynyl radicals include ethynyl, propynyl, butynyl, and the like.

The term "cycloalkyl", alone or in combination, means a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical wherein each cyclic moiety contains from 3 carbon atoms to about 8 carbon atoms, more preferably from 3 carbon atoms to about 6 carbon atoms. Examples of cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "cycloalkylalkyl" means an alkyl radical as defined above which is substituted by a cycloalkyl radical as defined above. Examples of cycloalkylalkyl radicals include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1 - cyclopentylethyl, 1 -cyclohexylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl,

cyclobutylpropyl, cyclopentylpropyl, cyclohexylbutyl, and the like.

The term "aryl", alone or in combination, means a phenyl or naphthyl radical which optionally carries one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, heterocycloalkyl, amido, mono and dialkyl substituted amino, mono and dialkyl substituted amido, and the like. Examples of aryl radicals include phenyl, p-tolyl, 4- methoxyphenyl, 4-(tert-butoxy)phenyl, 3-methyl-4-methoxyphenyl, 4-fluorophenyl, 4- chlorophenyl, 3-nitrophenyl, 3-aminophenyl, 3-acetamidophenyl, 4-acetamidophenyl, 2- methyl-3-acetamidophenyl, 2-methyl-3-aminophenyl, 3-methyl-4-aminophenyl, 2-amino- 3-methylphenyl, 2,4-dimethyl-3-aminophenyl, 4-hydroxyphenyl, 3-methyl-4- hydroxyphenyl, 1 -naphthyl, 2-naphthyl, 3-amino-l-naphthyl, 2-methyl-3 -amino- 1 - naphthyl, 6-amino-2-naphthyl, 4,6-dimethoxy-2-naphthyl, and the like.

The term "aralkyl", alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom is replaced by an aryl radical as defined above. Examples of aralkyl radicals include benzyl, 2-phenylethyl, dibenzylmethyl,

hydroxyphenylmethyl, methylphenylmethyl, and the like.

The term "heterocyclyl" and "heterocycloalkyl", alone or in combination, mean a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having preferably 3 ring members to 12 ring members, more preferably 5 ring members to 10 ring members and most preferably 5 ring members to 8 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen and sulphur, and which is optionally substituted on one or more carbon atoms by halogen, alkyl, alkoxy, hydroxy, oxo, aryl, aralkyl and the like, and/or on a secondary nitrogen atom (i.e., -NH-) by hydroxy, alkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl and/or on a tertiary nitrogen atom (i.e., =N-) by oxido. Heterocycloalkyl and heterocyclyl also includes benz- fused monocyclic cycloalkyl groups having at least one such heteroatom.

Heterocycloalkyl and heterocyclyl, in addition to sulfur and nitrogen, also include sulfones, sulfoxides and N-oxides of tertiary nitrogen containing heterocycloalkyl groups.

The term "heteroaryl", alone or in combination, means an aromatic monocyclic, bicyclic, or tricyclic heterocyclyl or heterocycloalkyl radical as defined above and is optionally substituted as defined above with respect to the definitions of aryl and heterocyclyl or heterocycloalkyl. Examples of heterocyclyl, heterocycloalkyl and heteroaryl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,

thiamorpholinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, furyl, tetrahydrofuranyl, bis-tetrahydrofuranyl, bis-tetrahydrofuropyranyl, thienyl,

tetrahydrothiophenyl, triazolyl, oxazolyl, thiazolyl, indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, quinoxalinyl, 1-, 2-,4- or 5- benzimidazolyl, and the like.

The term "amino-protecting group" in the present invention refers to one or more selectively removable substituents on the amino group commonly employed to block or protect the amino functionality against undesirable side reactions during synthetic procedures and includes all conventional amino protecting groups. Examples of amino protecting groups include alkoxycarbonyl groups, alkylsilyl groups, alkoxymethyl groups, aralkyl groups, acyl groups, alkenyloxycarbonyl groups and aralkyloxycarbonyl groups. The preferred amino-protecting group is alkoxycarbonyl.

The term "leaving group" in the present invention refers to an atom or a group readily displaceable by a nucleophile, for example, an amine. Examples of leaving groups include halides, inflates, tosylates, and the like.

Detailed Description of the Invention

A first aspect of the invention provides a process for the preparation of a compound of Formula IX,

FORMULA IX

wherein R2 is NO2 or Ν(¾4)₂, R3 is an amino protecting group, and R4 is hydrogen or an amino protecting group,

wherein the process comprises a step of reacting a compound of Formula X with a compound of Formula XI,

FORMULA XI

FORMULA X wherein R2 is NO2 or Ν(¾4)₂, R3 is an amino protecting group, and R4 is hydrogen or an amino protecting group, to obtain the compound of Formula IX.

A second aspect of the invention provides a process for the preparation of 4-amino- N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)benzene sulfonamide of Formula II or an acid addition salt thereof,

FORMULA II

wherein the process comprises:

a) reacting a compound of Formula X with a compound of Formula XI,

FORMULA XI

FORMULA X wherein R2 is NO2 or Ν(¾4)₂, R₃ is an amino protecting group, and R4 is hydrogen or an amino protecting group, to obtain the compound of Formula IX,

wherein R2 is NO2 or Ν(¾4)₂, R₃ is an amino protecting group, and R4 is hydrogen or an amino protecting group; and

b) deprotecting and optionally reducing the compound of Formula IX to obtain the compound of Formula II or an acid addition salt thereof. A third aspect of the invention provides a process for the preparation of a sulfonamide of Formula I;

FORMULA I

or salts, solvates or prodrugs thereof,

wherein Ri is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocycloalkyl or heteroaryl;

wherein the process comprises: a) reacting a compound of Formula X with a compound of Formula XI,

FORMULA XI

FORMULA IX

wherein R2 is NO2 or Ν(¾4)₂, R3 is an amino protecting group, and R4 is hydrogen or an amino protecting group;

b) deprotecting and optionally reducing the compound of Formula IX to obtain the compound of Formula II or an acid addition salt thereof; and

FORMULA II

c) carbamoylating the compound of Formula II or an acid addition salt thereof with an active derivative of a compound of Formula XII,

R-i— OH

FORMULA XII

wherein Ri is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocycloalkyl or heteroaryl, to obtain the sulfonamide of Formula I or its salts, solvates or prodrugs thereof.

The compound of Formula X may be prepared by reacting isobutylamine and a compound of Formula XIII,

FORMULA XIII

wherein L is a leaving group, I¾ is NO2 or Ν(¾4)₂, and R4 is hydrogen or an amino protecting group. The leaving group is preferably a chloro, bromo or iodo. The reaction is carried out in the presence of an organic solvent. The organic solvent may be selected from the group consisting of alcohols, hydrocarbons, halogenated hydrocarbons, ethers, cyclic ethers and esters. The organic solvent is, for example, 1,4-dioxane. The reaction may be carried out at a temperature of about 0°C to about 50°C. The reaction may be accompanied by stirring to obtain the compound of Formula X.

The compound of Formula X need not be isolated from the reaction mixture and it is reacted with the compound of Formula XL The compound of Formula XI may be prepared according to the methods provided in U.S. Publication 2002/0072621,

Tetrahedron Letters, 36(19), p. 3317-3320 (1995), and Tetrahedron Letters, 36(31), p. 5453-5456 (1995). The reaction is carried out in the presence of a base and a quaternary ammonium halide, for example, benzyl triethylammonium chloride. The base may be an organic or inorganic base. The base may be, for example, an alkali metal carbonate, an alkali metal hydroxide, an alkylamine, or an alkali metal hydride. The reaction is carried out at a temperature of about 20°C to about 135°C for about 1 hour to about 100 hours, for example, at a temperature of about 80°C to about 90°C for about 6 hours to about 10 hours. The reaction may be facilitated by stirring the reaction mixture. The compound of Formula IX may be isolated by filtration, extraction, distillation, pH adjustment, concentration, decantation, column chromatography, or a combination thereof.

The compound of Formula IX is deprotected in the presence of an organic solvent to obtain the compound of Formula II or an acid addition salt thereof. The organic solvent may be a water-miscible organic solvent. The water-miscible organic solvent may be a C1-C3 alcohol, for example, methanol, ethanol, isopropanol, denatured spirit, or a mixture thereof. The deprotection may be carried out by treating with acids, for example, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, methanesulfonic acid or trifluoroacetic acid. The deprotection is followed by a reduction step for the compounds of Formula IX, wherein I¾ is NO2. The reduction is carried out using a reducing agent and a source of hydrogen. The reducing agent may be transition metals, for example, palladium-carbon, platinum oxide, Raney-nickel, rhodium or ruthenium. The reduction may be carried out in the presence of an organic solvent. The organic solvent may be alcohols, esters, amides, aromatic hydrocarbons, aliphatic hydrocarbons, ethers, cyclic ethers, or a mixture thereof. The compound of Formula II or an acid addition salt thereof may be isolated by filtration, extraction, distillation, pH adjustment, concentration, decantation, column chromatography, or a combination thereof. The compound of Formula II is isolated, for example, as a free base or as a hydrochloride, hydroiodide or hydrofluoride salt.

The compound of Formula II or an acid addition salt thereof is carbamoylated with the active derivative of the compound of Formula XII to obtain the sulfonamide of

Formula I. The active derivative of the compound of Formula XII is prepared by reacting the compound of Formula XII with a coupling agent. The coupling agent may be carbonates, for example bis-(4-nitrophenyl)carbonate, disuccinimidyl carbonate (DSC) and carbonyl diimidazole (CDI), chloroformates, for example p-nitrophenylchloro- formate, or phosgenes, for example phosgene and triphosgene.

The reaction is carried out in the presence of an organic solvent and optionally a base. The base may be an organic or inorganic base. Alkali metal hydroxide, alkylamine, alkali metal hydride, alkali metal bicarbonate or alkali metal carbonate may be used as a base. The organic solvent may be selected from the group consisting of dichloromethane, tetrahydrofuran, dimethylformamide, acetonitrile, dioxane, chloroform and ethyl acetate. The reaction may be carried out at a temperature of about 5°C to about 75°C for about 1 hour to about 20 hours. The reaction may be facilitated by stirring the reaction mixture.

The compound of Formula I may be converted into its salt, solvate or prodrug forms. The solvate of the compound of Formula I may be prepared by treating with a suitable solvent, for example ethanol, isopropanol, water, methanol, acetone,

dichloromethane, ethylacetate, 1 -ethoxy-2-propanol, anisole, tetrahydrofuran or methanesulfonic acid. The prodrug of the compound of Formula I may be prepared by the methods provided in U.S. Patent Nos. 6,436,989 and 6,514,953. The compound of Formula I or its salts, solvates or prodrugs thereof is isolated from the reaction mixture by filtration, extraction, distillation, pH adjustment, concentration, decantation, column chromatography, or a combination thereof.

A fourth aspect of present invention provides a process for the preparation of 4- amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)benzene sulfonamide of Formula II or an acid addition salt thereof;

FORMULA II wherein the process comprises deprotecting compound of Formula IXa,

FORMULA IXa

wherein R3 is an amino protecting group, and R4 is hydrogen or an amino protecting group with a hydrohalic acid to obtain 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]- N-(2-methylpropyl)benzenesulfonamide of Formula II or an acid addition salt thereof.

A fifth aspect of present invention provides a process for the preparation of a sulfonamide of Formula I,

FORMULA I

or salts, solvates or prodrugs thereof,

wherein Ri is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocycloalkyl or heteroaryl,

wherein the process comprises:

a) deprotecting compound of Formula IXa,

FORMULA IXa

wherein R3 is an amino protecting group, and R4 is hydrogen or an amino protecting group with a hydrohalic acid to obtain 4-amino-N-[(2R,3S)-3-amino- 2-hydroxy-4-phenylbutyl] -N-(2-methylpropyl)benzenesulfonamide of Formula II or an acid addition salt thereof: and

FORMULA II

b) carbamoylating the compound of Formula II or an acid addition salt thereof with an active derivative of a compound of Formula XII,

R-i— OH FORMULA XII

The starting compound of Formula IXa may be prepared according to the methods described in the previous aspects of the present invention. The compound of Formula IXa may also be prepared by reacting a compound of Formula XI,

FORMULA XI

wherein R₃ is an amino protecting group, and R4 is hydrogen or an amino protecting group, with isobutylamine in the presence or absence of any additional solvent, to obtain a compound of Formula XIV,

FORMULA XIV

wherein R₃ is an amino protecting group, and R4 is hydrogen or an amino protecting group, and reacting the compound of Formula XIV with a compound of Formula XHIa,

FORMULA XHIa

wherein L is a leaving group, R3 is an amino protecting group, and R4 is hydrogen or an amino protecting group in the presence of a solvent and optionally a base to obtain the compound of Formula IXa, for example, as described in U.S. Patent No. 5,585,397. The compound of Formula IXa may be isolated from the reaction mixture or the reaction mixture containing the compound of Formula IXa may be used as such for the next deprotection step.

The compound of Formula IXa is deprotected in the presence of an organic solvent to obtain the compound of Formula II or an acid addition salt thereof. The deprotection at both the amino functions of the compound of Formula IXa may be carried out by treating with a hydrohalic acid, for example, hydrochloric acid, hydrobromic acid or hydriodic acid in the presence of an organic solvent or water, or a mixture thereof. The organic solvent may be a water-miscible organic solvent. The water-miscible organic solvent may be a C1-C3 alcohol, for example, methanol, ethanol, isopropanol, denatured spirit or a mixture thereof. The normality of the hydrohalic acid may be from about 8 N to about 12 N, for example, about IO N. The treatment with hydrohalic acid may be carried out by stirring the reaction mixture for about 1 minute to about 50 hours, for example, about 2 hours to about 10 hours. The stirring may be carried out at about 10°C to about 80°C, for example, at about 50°C to about 75°C. The compound of Formula II or an acid addition salt thereof, for example a hydrohalic acid addition salt, may be isolated by filtration, extraction, distillation, pH adjustment, concentration, decantation, column

chromatography, or a combination thereof.

Formula I. The active derivative of the compound of Formula XII is prepared by reacting the compound of Formula XII with a coupling agent. The coupling agent may be carbonates, for example bis-(4-nitrophenyl)carbonate, disuccinimidyl carbonate (DSC) and carbonyl diimidazole (CDI), chloroformates, for example, p-nitrophenylchloro- formate, or phosgenes, for example phosgene and triphosgene.

The reaction is carried out in the presence of an organic solvent and optionally a base. The base may be an organic or inorganic base. Alkali metal hydroxide, alkylamine, alkali metal hydride, alkali metal bicarbonate or alkali metal carbonate may be used as a base. The organic solvent may be selected from the group consisting of dichloromethane, tetrahydrofuran, dimethylformamide, acetonitrile, dioxane, chloroform and ethyl acetate. The reaction may be carried out at a temperature of about 5°C to about 75°C for about 1 hour to about 20 hours. The reaction may be facilitated by stirring the reaction mixture. The compound of Formula I may be converted into its salt, solvate or prodrug forms. The solvate of the compound of Formula I may be prepared by treating with a suitable solvent, for example, ethanol, isopropanol, water, methanol, acetone, dichloromethane, ethylacetate, 1 -ethoxy-2-propanol, anisole, tetrahydrofuran or methanesulfonic acid. The prodrug of the compound of Formula I may be prepared by the methods provided in U.S. Patent Nos. 6,436,989 and 6,514,953. The compound of Formula I or its salts, solvates or prodrugs thereof is isolated from the reaction mixture by filtration, extraction, distillation, pH adjustment, concentration, decantation, column chromatography, or a combination thereof.

The sulfonamide of Formula I includes amprenavir, fosamprenavir and darunavir.

While the present invention has been described in terms of its specific

embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1 : Preparation of l-Benzyl-2-Hvdroxy-3-risobutyl-(4-

Nitrobenzenesulfonylamino)Propyl1-Carbamic Acid Tert-Butyl Ester

Step A) Isobutylamine (3.79 mL, 50.7 mmol) was added dropwise to a stirred solution of 4-nitrobenzenesulfonyl chloride (5 g, 22.5 mmol) and 1,4-dioxane (10 mL) at 10°C to 15°C in 30 minutes and stirring was continued for further 30 minutes at 20°C to 25°C.

Step B) Potassium carbonate (0.31 g, 2.24 mmol) and benzyl triethylammonium chloride (0.53 g, 2.3 mmol) were added to the reaction mixture of step A) at 20°C to 25°C followed by the addition of tert-butyl[S-(R*,R*)]-(-)-(l-oxiranyl-2-phenylethyl)carbamate (5.94 g, 22.5 mmol). The reaction mixture was heated up to 80°C and stirred at 80°C to 85°C for 6 hours. Dichloromethane (80 mL) and water (50 mL) were added to the reaction mixture at 20°C to 25°C. The aqueous layer was extracted with dichloromethane (80 mL). The combined organic layer was washed with water (3 x 40 mL), dried over sodium sulfate and concentrated under vacuum to obtain a light yellow residue. Hexanes (25 mL) were added to the residue and the mixture was stirred at 20°C to 25°C for 1 hour. The yellow solid obtained was filtered off and washed with hexanes to obtain the title compound.

^!H NMR (CDC1₃, 300 MHz): δ 0.87-0.90 (d, J= 6.6, 6H), 1.36 (s, 9H), 1.69-1.78 (m, 1H), 2.82-2.96 (m, 4H), 3.58-3.70 (m, 2H), 3.82-3.90 (m, 2H), 4.70 (bs, 1H, exchangeable with D₂0), 7.20-7.33 (m, 5H), 8.04-8.06 (d, J= 8.7, 2H), 8.35-8.38 (d, J= 8.7, 2H). Yield: 10 g

Example 2: Preparation of l-Benzyl-2-Hvdroxy-3-risobutyl-(4- Aminobenzenesulfonylamino)Propyl1-Carbamic Acid Tert-Butyl Ester

Step A) Isobutylamine (3.7 g, 50.7 mmol) was added dropwise to a stirred solution of 4-aminobenzenesulfonyl chloride (5 g, 26.1 mmol) and 1,4-dioxane (10 mL) at 5°C to 7°C in 30 minutes and stirring was continued for further 20 minutes at 20°C to 25°C.

Step B) Potassium carbonate (3.78 g, 27.4 mmol) and benzyl triethylammonium chloride (0.68 g, 2.61 mmol) were added to the reaction mixture of step A) at 20°C to 25°C followed by the addition of tert-butyl[S-(R*,R*)]-(-)-(l-oxiranyl-2- phenylethyl)carbamate (8.23 g, 31.32 mmol). The reaction mixture was heated up to 80°C and stirred at 80°C to 85°C for 6 hours. Dichloromethane (100 mL) and water (50 mL) were added to the reaction mixture at 20°C to 25°C. The aqueous layer was extracted with dichloromethane (20 mL). The combined organic layer was washed with water (2 x 40 mL), dried over sodium sulfate and concentrated under vacuum to obtain light yellow residue. Hexanes (80 mL) were added to the residue and the mixture was stirred at 20°C to 25°C for 1 hour. The yellow solid obtained was filtered off and purified by column chromatography using chloroform-methanol as eluent to obtain the title compound.

¾ NMR (CDCI3, 300 MHz): δ 0.85-0.87 (d, 6H), 1.33 (s, 9H), 1.7-1.8 (m, 1H), 2.7-2.9 (m, 4H), 3.4-3.8 (m, 4H), 4.63 (bs, 1H), 6.66-6.68 (d, J= 6.47, 2H) (m, 5H), 7.20- 7.61 (m, 5H), 7.61-7.63 (d, J= 6.48, 2H).

Yield: 9 g

Example 3: Preparation of l-Benzyl-2-Hvdroxy-3-risobutyl-(4- Acetylaminobenzenesulfonylamino) Propyll -Carbamic Acid Tert-Butyl Ester

Step A) Isobutylamine (4. 6 mL, 48.1 mmol) was added dropwise to a stirred solution of p-acetylsulfanilyl chloride (5 g, 21.4 mmol) and 1,4-dioxane (10 mL) at 5°C to 7°C in 35 minutes and stirring was continued for further 3 hours at 20°C to 25°C.

Step B) Potassium carbonate (0.3 g, 2.1 mmol) and benzyl triethylammonium chloride (0.5 g, 2.2 mmol) were added to the reaction mixture of step A) at 20°C to 25°C followed by the addition of tert-butyl[S-(R*,R*)]-(-)-(l -oxiranyl-2-phenylethyl)carbamate (5.63 g, 21.4 mmol). The reaction mixture was heated to 85°C and stirred at 85°C to 90°C for 14 hours. Water (40 mL) was added to the reaction mixture at 20°C to 25°C and the suspension obtained was stirred at 20°C to 25°C for 1 hour. The precipitate was filtered and washed with water (3 x 15 mL) to obtain the title compound as a solid.

!H NMR (CDCI3, 300 MHz): δ 0.85-0.88 (d, J= 6.68, 6H), 1.25 (s, 9H), 1.66- 1.75

(m, 1H), 2.26 (s, 3H), 2.73-2.96 (m, 4H), 3.61-3.9 (m, 4H), 4.33 (bs, 1H), 7.23-7.35 (m, 5H), 7.64-7.67 (d, 2H), 7.79-7.82 (d, 2H).

Yield: 8.48 g

Example 4: Preparation of 4-Nitro-N-(2R.3S)-(3-Amino-2-Hvdroxy-4-Phenyl ButvD-N- Isobutylbenzenesulfonamide

A solution of l-benzyl-2-hydroxy-3-[isobutyl-(4- nitrobenzenesulfonylamino)propyl]carbamic acid tert-butyl ester (4 g) in trifluoroacetic acid (3 mL) and dichloromethane (7 mL) was stirred at about 20°C to 25°C for 2 hours. Water was added and the pH of the solution was adjusted to 8.5 to 9.2 using triethylamine (7.5 mL). The aqueous layer was extracted with dichloromethane (10 mL). The organic layer was washed with water (3 x 20 mL), dried over sodium sulfate, concentrated and triturated with hexanes (20 mL) to obtain the title compound as a solid.

^!H NMR (CDCI₃, 300 MHz): δ 0.89-0.91 (d, J= 6.5, 6H), 1.71- 1.79 (m, 1H), 2.52- 2.56 (m, 1H), 2.83-2.86 (m, 2H), 3.02-3.06 (m, 2H), 3.21 (bs, 1H), 3.74-3.79 (m, 2H), 4.64 (bs, 1H, exchangeable with D₂0), 7.2-7.34 (m, 5H), 8.05-8.07 (d, 2H), 8.36-8.39 (d, 2H).

Yield: 2.75 g

Example 5: Preparation of 4-Amino-N-(2R.3S) (3-Amino-2-Hydroxy-4-Phenyl Butyl)-N- Isobutylbenzenesulfonamide

A solution of 1 -benzyl-2-hydroxy-3- [isobutyl-(4- aminobenzenesulfonylamino)propyl]carbamic acid tert-butyl ester (5 g) in trifluoroacetic acid (15 mL) and dichloromethane (10 mL) was stirred at about 20°C to 25°C for 2 hours. Water was added and the pH of the solution was adjusted to 8.5 to 9.0 using triethylamine. The aqueous layer was extracted with dichloromethane (20 mL). The organic layer was washed with water (3 x 20 mL), dried over sodium sulfate and concentrated to obtain the title compound as a solid.

^!H NMR (CDCI3, 300 MHz): δ 0.86-0.89 (d, J= 6.6, 6H), 1.23- 1.27 (m, 1H), 2.48- 2.52 (m, 1H), 2.54-2.62 (m, 2H), 2.71-2.75 (m, 1H), 3.3 (bs, 1H), 3.72-3.77 (m, 3H), 4.12 (bs, 2H, exchangeable with D₂0), 4.34 (bs, 1H, exchangeable with D₂0), 6.68-6.7 (m, 2H), 7.22-7.33 (d, 5H), 7.62-7.65 (d, 2H).

Yield: 2.7 g

Example 6: Preparation of 4-Acetylamino-N-(2R,3S) (3-Amino-2-Hydroxy-4-Phenyl ButvD-N-Isobutylbenzenesulfonamide

A solution of l-benzyl-2-hydroxy-3-[isobutyl-(4- acetylaminobenzenesulfonylamino)propyl]carbamic acid tert-butyl ester (2 g) in trifluoroacetic acid (3 mL) and dichloromethane (7 mL) was stirred at about 20°C to 25°C for 5 hours. Water was added and the pH of the solution was adjusted to 9.1 1 using triethylamine (9 mL). The aqueous layer was extracted with dichloromethane (20 mL). The organic layer was washed with water (3 x 20 mL), dried over sodium sulfate and concentrated to obtain the title compound as a solid.

^!H NMR (CDCI₃, 300 MHz): δ 0.86-0.88 (d, J= 5.95, 6H), 1.66-1.75 (m, 1H), 2.2 (m, 3H), 2.47-2.55 (m, 1H), 2.72-2.77 (m, 2H), 3.02-3.05 (m, 1H), 3.2-3.3 (m, 1H), 3.65- 3.78 (m, 3H), 4.4 (bs, 1H, exchangeable with D₂0), 7.20-7.44 (m, 5H), 7.64-7.67 (m, 2H), 7.78-7.81 (m, 2H).

Yield: 2.9 g

Example 7: Preparation of 4-Amino-N-(2R.3S)-(3-Amino-2-Hvdroxy-4-Phenyl Butyl)-N- Isobutylbenzenesulfonamide

4-Nitro-N-(2R,3S)-(3-amino-2-hydroxy-4-phenylbutyl)-N- isobutylbenzenesulfonamide (1 g) was dissolved in ethanol (10 mL) and hydrogenated

(¾, 40 psi) in the presence of 10% palladium-carbon (50% wet; 0.04 g) for 35 minutes at 20°C to 25°C. The mixture obtained was filtered through Celite and the filtrate was concentrated to obtain the title compound as a residue.

Yield: 1.0 g Example 8: Preparation of 4-Amino-N-(2R,3S)-(3-Amino-2-Hvdroxy-4-Phenyl ButylVN- Isobutyl Benzenesulfonamide Hydrochloride

7¾rt-butyl {(2S,3R)-4-[{[4-(acetylamino)phenyl]sulfonyl}(propan-2-yl)amino]-3- hydroxy-l-phenylbutan-2-yl} carbamate (5 g, 0.09 moles) was dissolved in denatured spirit (10 mL), and hydrochloric acid (10 N; 5 mL) was added at 25°C to 30°C. The reaction mixture was stirred at 60°C to 65°C for 6.5 hours and was cooled to 30°C. Water (25 mL) and dichloromethane (200 mL) were added at 25°C to 30°C with stirring and the pH of the resulting solution was adjusted to 1 1.5 to 12.5 with sodium hydroxide (10% aqueous solution, 1.5 mL) at 10°C to 15°C. The organic layer was separated at 25°C to 30°C, washed with water and acidified with hydrochloric acid (10 N; 1.5 mL) to pH 0.5 to 1.0 at 10°C to 15°C. The separated solid was filtered, washed with dichloromethane (10 mL) and dried to obtain the title compound as white powder.

Yield: 3.2 g

Purity: 99.35%

Example 9: Preparation of 4-Amino-N-(2R.3S)(3-Amino-2-Hvdroxy-4-Phenylbutyl)-N- Isobutyl-Benzenesulfonamide Hydrochloride

7¾rt-butyl {(2S,3R)-4-[{[4-(acetylamino)phenyl]sulfonyl}(propan-2-yl)amino]-3- hydroxy- 1 -phenylbutan-2-yl} carbamate (5 g, 0.009 moles) was combined with water (50 mL) and hydrochloric acid (10 N; 10 mL) was added at 10°C to 15°C. The reaction mixture was stirred at 70°C to 75°C for 6 hours and cooled to 25°C. Ethyl acetate (25 mL) was added to the reaction mixture and the mixture was stirred for 30 minutes. The upper organic layer was discarded and the lower aqueous layer was concentrated under vacuum to obtain a residue. The residue was treated with ethyl acetate (25 mL) at 25°C to 30°C to obtain a solid. The separated solid was filtered, washed with ethyl acetate (10 mL) and dried to obtain the title compound as white powder.

Yield: 3.86 g

Purity: 98.15% Example 10: Preparation of 4-Amino-N-(2R,3S -(3-Amino-2-Hvdroxy-4-Phenylbutyl -N- Isobutylbenzene Sulfonamide

4-amino-N-(2R,3S)-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylbenzene sulfonamide hydrochloride (15 g, 0.035 moles) was dissolved in dichloromethane (75 mL) at 20°C to 25°C, and aqueous solution of sodium carbonate (120 mL, 10%) was added with stirring. The resulting solution was stirred for 20 minutes at 20°C to 25°C. The organic layer was separated at 25 °C to 30°C, washed with water (15 mL) and concentrated under vacuum to obtain 4-amino-N-(2R,3S)-(3-amino-2-hydroxy-4-phenylbutyl)-N- isobutylbenzene sulfonamide as white solid.

Yield: 1 1.2 g

Example 1 1 : Preparation of Darunavir

Triethylamine (0.85 mL) was added to a stirred solution of 4-amino-N-(2R,3S)-(3- amino-2-hydroxy-4-phenyl butyl)-N-isobutylbenzenesulfonamide (0.2 g, 5.1 1 mmol) and dichloromethane (5 mL). Stirring was continued for further 10 minutes at 20°C to 25°C. (3R,3aS,6aR)-3-Hydroxyhexahydrofuro-[2,3-b]furanylsuccinimyl carbonate (0.42 g, 1.5 mmol) was added to the reaction mixture and the mixture was stirred for 3 hours. The reaction mixture was washed with water (2 x 15 mL), dried over sodium sulfate and concentrated to obtain a residue. The residue was purified by column chromatography using silica gel as stationary phase and dichloromethane-methanol as eluent to obtain the title compound.

Yield: 0.2 g

Example 12: Preparation of Darunavir

4-Amino-N-(2R,3S)-(3-amino-2-hydroxy-4-phenylbutyl)-N- isobutylbenzenesulfonamide hydrochloride (10 g, 0.023 moles) was dissolved in ethyl acetate (100 mL) and triethylamine (4.0 mL, 0.028 moles) was added with stirring. The stirring was continued for 15 minutes at 20°C to 25°C. (3R,3aS,6aR)-3- Hydroxyhexahydrofuro-[2,3-b]furan-3-yl 4-nitrophenyl carbonate (6.21 g, 0.021 moles) was added to the reaction mixture and it was stirred for 1 hour at 60°C to 65°C.

Triethylamine (2.0 mL, 0.014 moles) was added to the reaction mixture and it was stirred for 7 hours at 60°C to 65°C. The reaction mixture was cooled to 25°C to 30°C and washed with sodium carbonate (10% aqueous solution, 3 x 50 mL), hydrochloric acid (5% aqueous solution, 50 mL) and water (50 mL), and concentrated under vacuum to obtain residue, which was stirred with hexanes (100 mL) to obtain the title compound as amorphous product.

Yield: 9.7 g

Purity: 83.2%

Example 13 : Preparation of Darunavir

4-Amino-N-(2R,3S)-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylbenzene sulfonamide hydrochloride (5.5 g, 0.013 moles) was dissolved in dimethylformamide (50 mL), and sodium carbonate (1.85 g, 0.018 moles) was added at 25°C to 30°C. The resulting reaction mixture was stirred for 15 minutes at 25°C to 30°C. (3R,3aS,6aR)-3- Hydroxyhexahydrofuro-[2,3-b]furan-3-yl 4-nitrophenyl carbonate (3.3 g, 0.011 moles) was added and the reaction mixture was stirred for 2 hours at 25°C to 30°C. Water (100 mL) was added to the reaction mixture, followed by ethyl acetate (50 mL) with stirring. The layers were separated and the aqueous layer was extracted with ethyl acetate (25 mL). The combined organic layer was washed with aqueous sodium carbonate solution (10%, 50 mL), aqueous hydrochloric acid solution (5%, 25 mL) and water (25 mL), and concentrated under vacuum to obtain the title compound as amorphous product.

Yield: 5.2 g

Purity: 91.74%

Example 14: Preparation of Darunavir

4-Amino-N-(2R,3S)-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylbenzene sulfonamide hydrochloride (5 g, 0.01 1 moles) was dissolved in dimethylformamide (50 mL), and sodium bicarbonate (2 g, 0.024 moles) was added at 25°C to 30°C. The resulting reaction mixture was stirred for 15 minutes at 25°C to 30°C. (3R,3aS,6aR)-3- Hydroxyhexahydrofuro-[2,3-b]furan-3-yl 4-nitrophenyl carbonate (3.3 g, 0.011 moles) was added at 60°C to 65°C and the reaction mixture was stirred for 2.5 hours at 60°C to 65°C. The reaction mixture was cooled to 25°C. Water (100 mL) was added to the reaction mixture, followed by dichloromethane (50 mL) with stirring. The layers were separated and the aqueous layer was extracted with dichloromethane (25 mL). The combined organic layer was washed with aqueous sodium carbonate solution (10%, 50 mL), aqueous hydrochloric acid solution (5%, 25 mL) and water (25 mL), and

concentrated under vacuum to obtain a residue. The residue was treated with hexanes (100 mL). The solid obtained was filtered and dried under vacuum at 40°C to 45°C to obtain the title compound as amorphous product.

Yield: 4.95 g

Purity: 96.11%

Example 15: Preparation of Darunavir

4-Amino-N-(2R,3S)-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylbenzene sulfonamide (5 g, 0.013 moles) was dissolved in dimethylformamide (30 mL) and heated to 55°C to obtain a solution. (3R,3aS,6aR)-3-Hydroxyhexahydrofuro-[2,3-b]furan-3-yl 4- nitrophenyl carbonate (3.6 g, 0.012 moles) was added to the reaction mixture at 60°C to 65°C and it was stirred for 3 hours at 60°C to 65°C. The reaction mixture was cooled to 25°C. Water (100 mL) was added to the reaction mixture followed by dichloromethane (50 mL) with stirring. The layers were separated and the aqueous layer was extracted with dichloromethane (25 mL). The combined organic layer was washed with aqueous sodium carbonate solution (10%, 3 x 25 mL), aqueous hydrochloric acid solution (5%, 25 mL) and water (25 mL) and concentrated under vacuum to obtain a residue. The residue was treated with hexanes (100 mL). The solid obtained was filtered and dried under vacuum at 40°C to 45°C to obtain the title compound as amorphous product.

Yield: 6.4 g

Purity: 96%

Example 16: Preparation of Darunavir

4-Amino-N-(2R,3S)-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylbenzene sulfonamide (2 g, 0.0051 moles) was dissolved in dimethylformamide (10 mL), and

(3R,3aS,6aR)-3-hydroxyhexahydrofuro-[2,3-b] furan-3-yl 4-nitrophenyl carbonate (1.41 g, 0.0048 moles) was added at 10°C to 15°C. The resulting reaction mixture was stirred for 4 hours at 10°C to 15°C. Water (50 mL) was added to the reaction mixture at 15°C to 20°C, followed by dichloromethane (10 mL) with stirring. The layers were separated and the organic layer was washed with aqueous sodium carbonate solution (10%, 3 x 10 mL), aqueous hydrochloric acid solution (5%, 10 mL) and water (10 mL), and concentrated under vacuum to obtain a residue. The residue was dissolved in dichloromethane (3 mL) and hexanes (40 mL) were added. The reaction mixture was stirred at 5°C to 10°C for 0.5 hour. The precipitate obtained was filtered, washed with hexanes (10 mL) and dried to obtain the title compound as amorphous product.

Yield: 1.05 g

Purity: 94.27%

Example 17: Preparation of Darunavir

4-Amino-N-(2R,3S)-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylbenzene sulfonamide (10 g, 0.025 moles) was dissolved in dimethylformamide (100 mL), and

(3R,3aS,6aR)-3-hydroxyhexahydrofuro-[2,3-b]furan-3-yl 4-nitrophenyl carbonate (7.55 g, 0.025 moles) was added at 25°C to 30°C. The resulting reaction mixture was stirred for 2 hours at 25°C to 30°C. Aqueous sodium carbonate solution (5%, 250 mL) was added to the reaction mixture, followed by dichloromethane (80 mL) with stirring. The layers were separated and the organic layer was washed with aqueous sodium carbonate solution (80 mL), aqueous hydrochloric acid solution (5%, 50 mL) and water (50 mL) and concentrated under vacuum to obtain a residue. Hexanes (300 mL) were added to the residue and stirred at 25°C to 30°C. The precipitate obtained was filtered, washed with hexanes (25 mL) and dried at 40°C to 45°C to obtain the title compound as amorphous product.

Yield: 1 1.17 g

Purity: 96%

Example 18: Preparation of Darunavir

4-Amino-N-(2R,3S)-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylbenzene sulfonamide hydrochloride (2 g, 0.0047 moles) was combined with dichloromethane (10 mL) at 15°C to 20°C, and aqueous solution of sodium carbonate (10%, 10 mL) was added with stirring. The stirring was carried out for 0.5 hour at 15°C to 20°C. The organic layer was separated at 25°C to 30°C. Dimethylformamide (10 mL) and (3R,3aS,6aR)-3- hydroxyhexahydrofuro-[2,3-b]furan-3-yl 4-nitrophenyl carbonate (1.06 g, 0.0036 moles) were added to the organic layer at 25°C to 30°C and the reaction mixture was stirred for 2.5 hours at 25°C to 30°C. Water (50 mL) was added to the reaction mixture with stirring. The layers were separated and the organic layer was washed with aqueous sodium carbonate solution (10%, 3 x 10 mL), aqueous hydrochloric acid solution (5%, 10 mL) and water (10 mL), and concentrated under vacuum to obtain a residue. The residue was treated with hexanes (40 mL). The solid obtained was filtered, washed with hexanes (5 mL) and dried under vacuum at 40°C to 45°C to obtain the title compound as amorphous product.

Yield: 1.5 g

Purity: 93.6%

Example 19: Purification of Darunavir

A solution of darunavir (2 g; HPLC purity 96.11%) in denatured spirit (20 mL) was heated to 60°C and stirred at 60°C to 65°C for 0.5 hour. The solution was cooled to 15°C. The resultant reaction mixture was stirred at 15°C to 20°C for 0.5 hour. The precipitate obtained was filtered and washed with denatured spirit (5 mL). The precipitate was dissolved in dichloromethane (10 mL) and the resulting solution was subjected to vacuum distillation to remove solvent to obtain a residue. Hexanes (20 mL) were added to the residue and the resultant slurry was stirred for 0.5 hour at 20°C to 25°C. The precipitate was filtered, washed with hexanes and dried under vacuum at 40°C to 45°C to obtain the title compound as amorphous product.

Yield: 1.82 g

HPLC Purity: 99.18%

Example 20: Preparation of Terr-Butyl r(2S.3R)-3-Hydroxy-l-Phenyl-4-(Propan-2-Yl- Amino)Butan-2-YllCarbamate

(2S,3S)- l,2-Epoxy-3-(Boc-amino)-4-phenylbutane (40 g, 0.15 moles) was added to isobutyl amine (80 mL, 0.78 moles) in several portions at 50°C to 60°C. The solution was heated under reflux for 2 hours and isobutyl amine was removed under reduced pressure. Water (200 mL) was added to the residue and the mixture was stirred. The product obtained was filtered, washed with water and dried under vacuum to obtain tert-buiyl [(2S,3R)-3-hydroxy- 1 -phenyl-4-(propan-2-yl-amino)butan-2-yl]carbamate as white powder. Yield: 49.1 g (95.7%)

HPLC Purity: 96%

Example 21 : Preparation of Tert-Butyl |Y2S.3R)-3-Hvdroxy- 1 -Phenyl-4-(Propan-2-Yl- Amino)Butan-2-Y11 Carbamate

(2S,3S)- l,2-Epoxy-3-(Boc-amino)-4-phenylbutane (20 g, 0.076 moles) was added to isobutyl amine (40 mL, 0.39 moles) in several portions at 50°C to 60°C. The solution was heated under reflux for 2 hours and isobutyl amine was removed under reduced pressure. Water (100 mL) was added to the residue and the mixture was stirred.

Dichloromethane (200 mL) was added to stirring mixture and layers were separated. The organic layer was washed with water (100 mL) and concentrated under vacuum to obtain fert-butyl [(2S,3R)-3-hydroxy- 1 -phenyl-4-(propan-2-yl-amino)butan-2-yl]carbamate as white residue which was carried over as such for the next step.

Example 22: Preparation of Tert-Butyl r(2S,3R)-3-Hvdroxy-l-Phenyl-4-(Propan-2-Yl- Amino)Butan-2-Y11 Carbamate

(2S,3S)- l,2-Epoxy-3-(Boc-amino)-4-phenylbutane (20 g, 0.076 moles) was added to a stirred solution of isobutyl amine (40 mL, 0.39 moles) and methanol (60 mL) in several portions at 50°C to 60°C. The solution was heated under reflux for 2 hours.

Water was added to the reaction mixture with stirring. The white precipitate obtained was filtered, washed with water and dried under vacuum to obtain tert-butyl [(2S,3R)-3- hydroxy- 1 -phenyl-4-(propan-2-yl-amino)butan-2-yl]carbamate.

Yield: 79.3%

HPLC Purity: 95.6%

Example 23: Preparation of Tert-Butyl {(2S,3R)-4-r ir4-(Acetylamino)Phenyl1

Sulfonyl} (Propan-2-Yl)Amino1-3-Hydroxy- 1 -Phenylbutan-2-Yl} Carbamate

Triethylamine (26.48 g, 0.26 moles) was added to a solution of tert-butyl [(2S,3R)-

3-hydroxy- l-phenyl-4-(propan-2-yl-amino)butan-2-yl]carbamate (40 g, 0.12 moles) in dichloromethane (400 mL) at 0°C to 5°C. 4-Acetyl sulfanilyl chloride (29.2 g, 0.13 moles) was added to the solution lot-wise at 0°C to 5°C. The solution was stirred for 1 hour at 25°C to 30°C and water (200 mL) was added. The layers were separated. The organic layer was poured over hexanes and the resulting crystals of tert-butyl {(2S,3R)-4- [ { [4-(acetylamino)phenyl] sulfonyl} (propan-2-yl)amino] -3 -hydroxy- 1 -phenylbutan-2- yljcarbamate were filtered. The wet crystals obtained were washed with hexanes and dried under vacuum to obtain white powder.

Yield: 55 g (86.8%)

HPLC Purity: 98.2%

Example 24: Preparation of Tert-Butyl {(2S,3R)-4-r {r4-(Acetylamino)Phenyl1

Sulfonyl} (Propan-2-Yl)Amino^"|-3-Hydroxy- 1 -Phenylbutan-2-Yl} Carbamate

Triethylamine (16 g, 0.16 moles) was added to a solution of tert-butyl [(2S,3R)-3- hydroxy- 1 -phenyl-4-(propan-2-yl-amino)butan-2-yl]carbamate (obtained according to Example 21) in dichloromethane (100 mL). 4-Acetyl sulfanilyl chloride (17.3 g, 0.074 moles) was added lot-wise to the solution at 25°C to 30°C. The solution was stirred for 1 hour at 25°C to 30°C and water (100 mL) was added. The layers were separated and the organic layer was poured over hexanes and the resulting crystals of tert-butyl {(2S,3R)-4- [ { [4-(acetylamino)phenyl] sulfonyl} (propan-2-yl)amino] -3 -hydroxy- 1 -phenylbutan-2- yl}carbamate were filtered. The wet crystals were washed with hexanes and dried under vacuum.

Yield: 33 g

Example 25: Preparation of 4-Amino-N-(2R,3S) (3-Amino-2-Hvdroxy-4-Phenyl Butyl)- N-Isobutyl-Benzenesulfonamide

Triethylamine (26.85 mL, 0.193 moles) was added to a solution of tert-butyl [(2S,3R)-3-hydroxy- l-phenyl-4-(propan-2-yl-amino)butan-2-yl]carbamate (50 g, 0.148 moles) in methyl-tetrahydrofuran (750 mL) at 15°C to 20°C. 4-Acetyl sulfanilyl chloride (43.5 g, 0.186 moles) was added lot- wise to the solution at 15°C to 20°C. The solution was stirred for 1 hour at 25°C to 30°C and water (500 mL) was added. The layers were separated at 35°C to 40°C. Concentrated hydrochloric acid (150 mL) was added to the organic layer at 35°C to 40°C in 20 minutes. The mixture was heated to 65°C and stirred for 10 hours at 62°C to 64°C. Water (250 mL) was added and the mixture was cooled to 20°C. The pH of the mixture was adjusted to 1 1.33 with aqueous sodium hydroxide solution (65 g in 325 mL water) at 15°C to 20°C in 30 minutes and the mixture was stirred at 35°C to 40°C for 30 minutes. The layers were separated. The organic layer was washed with water (500 mL) and concentrated under high vacuum up to maximum extent. Hexane (250 mL) was added to the residue and the mixture was stirred at 28°C to 30°C for 10 minutes. The product was filtered and washed with hexane (50 mL).

Yield: 56.33 g (wet)

Example 26: Preparation of 4-Amino-N-(2R,3S) (3-Amino-2-Hvdroxy-4-Phenyl Butyl)- N-Isobutyl-Benzenesulfonamide

Triethylamine (24.8 mL, 0.178 moles) was added to a solution of tert-butyl

[(2S,3R)-3-hydroxy- l-phenyl-4-(propan-2-yl-amino)butan-2-yl]carbamate (40 g, 0.119 moles) in dichloromethane (400 mL) at 15°C to 20°C. 4-Acetyl sulfanilyl chloride (34.8 g, 0.149 moles) was added lot-wise to the solution at 15°C to 20°C. The solution was stirred for 1 hour at 25°C to 30°C and water (400 mL) was added. The layers were separated at 35°C to 40°C. Methanol (80 mL) was added to the organic layer.

Dichloromethane was recovered completely under high vacuum to obtain a thick slurry. Methanol (40 mL) was added to the slurry. Concentrated hydrochloric acid (120 mL) was added to the mixture at 25°C to 30°C in 40 minutes. The mixture was heated to 55°C and stirred for 2 hours at 45°C to 55°C. The temperature of the mixture was raised to 65°C and the mixture was stirred for 2 hours. The reaction mixture obtained was cooled to 25°C to 30°C. Water (400 mL) and dichloromethane (400 mL) were added to the mixture and the mixture was stirred for 15 minutes. The layers were separated and aqueous layer was washed with dichloromethane (200 mL). Dichloromethane (400 mL) was added to the aqueous layer and the mixture was cooled to 15°C. The pH of the mixture was adjusted to 9.60 with aqueous sodium hydroxide solution (52 g in 400 mL water) at 15°C to 20°C in 30 minutes. The temperature of the mixture was raised to 25°C to 30°C and the mixture was stirred at 25°C to 30°C for 30 minutes. The layers were separated and the aqueous layer was extracted with dichloromethane (200 mL). The organic layers were combined and washed with water (200 mL). The organic layer was concentrated under high vacuum up to maximum extent. Hexane (400 mL) was added to the residue and the mixture was stirred at 28°C to 30°C for 10 minutes. The material was filtered to obtain 45.8 g of wet product. A mixture of methanol and water (400 mL, 2: 1) was added to the wet product and the mixture was heated to 65°C and stirred at 65°C to 70°C to obtain a clear solution. The solution was stirred at 65°C to 70°C for 15 minutes. The mixture was cooled to 25°C to 30°C, stirred for 1 hour and the product obtained was filtered.

Yield: 35.0 g (wet)

Example 27: Preparation of 4-Amino-N-(2R,3S) (3-Amino-2-Hvdroxy-4-Phenyl Butyl)- N-Isobutyl-Benzenesulfonamide

Triethylamine (1.98 Ltr, 14.28 moles) was added to a solution of tert-butyl

[(2S,3R)-3-hydroxy- l-phenyl-4-(propan-2-yl-amino)butan-2-yl]carbamate (3.20 Kg, 9.52 moles) in dichloromethane (32 Ltr) at 15°C to 20°C. 4-Acetyl sulfanilyl chloride (2.784 Kg, 1 1.9 moles) was added lot-wise to the solution at 15°C to 20°C. The solution was stirred for 1 hour at 25°C to 30°C and water (16 Ltr) was added. The layers were separated at 35°C to 40°C. Denatured spirit (9.6 Ltr) was added to the organic layer. Dichloromethane was recovered completely under high vacuum at not more than 60°C and concentrated hydrochloric acid (6.4 Ltr) was added at not more than 55°C. The mixture was heated to 65°C and was stirred for 10 hours at 60°C to 65°C. Water (64 Ltr) was added and the mixture was cooled to 30°C. Dichloromethane (16 Ltr) was added to the mixture and the mixture was stirred for 30 minutes. The layers were separated and the aqueous layer was washed with dichloromethane (16 Ltr). Dichloromethane (32 Ltr) was added to the aqueous layer and the pH of the mixture was adjusted to 1 1.5 to 12.5 with aqueous sodium hydroxide solution (4.16 Kg in 2.08 Ltr water) at 25°C to 30°C. The mixture was stirred at 25°C to 30°C for 30 minutes. The layers were separated and the aqueous layer was extracted with dichloromethane (16 Ltr). The organic layers were combined and washed with water (16 Ltr). The organic layer was heated to 40°C. Hexane (16 Ltr) was added to the organic layer and the mixture was stirred at 38°C to 40°C to obtain a clear solution. The solution was stirred at 38°C to 40°C for 15 minutes. The solution was cooled to 5°C in 2 hours and stirred for 1 hour at 5°C to 10°C. The product was filtered, washed with a mixture of dichloromethane and hexane (3.2 Ltr; 3: 1) and dried under vacuum at 40°C to 45°C.

Yield: 2.60 Kg

HPLC Purity: 98.58% Example 28: Preparation of (3R aS,6aR)-3-Hvdroxyhexahvdrofuro 2,3-B1Furan-3-Yl 4- Nitrophenyl Carbonate

4-Nitrophenylchloroformate (38.75 g, 0.19 moles) was added to a solution of (3R,3aS,6aR)-3-hydroxyhexahydrofuro-[2,3-b]furan (20 g, 0.15 moles) in ethyl acetate (300 mL) at 0°C to 5°C. A solution of pyridine (15.5 mL) in ethyl acetate (100 mL) was added at 0°C and the mixture was stirred for 1 hour. Water (200 mL) was added to the mixture and layers were separated at 25°C to 30°C. The organic layer was washed with water (100 mL) and aqueous sodium carbonate solution (10%, 3 x 100 mL). The organic layer was concentrated to dryness under vacuum. The residue was dissolved in ethyl acetate (235 mL) at 45°C to 50°C and hexanes (235 mL) were added slowly to it. The mixture was cooled to 0°C to 5°C with stirring. The white precipitate obtained was filtered, washed with hexanes and dried under vacuum to obtain (3R,3aS,6aR)-3- hydroxyhexahydrofuro-[2,3-b]furan-3-yl 4-nitrophenyl carbonate.

Yield: 23.5 g (51.8%)

HPLC Purity: 96.22%

Example 29: Preparation of Darunavir Ethanolate

A mixture of amorphous darunavir (2 g) and ethyl alcohol (20 mL) was heated to 60°C and stirred at 60°C to 65°C for 0.5 hour. The solution was cooled to 15°C and the resulting mixture was stirred at 15°C to 20°C for 0.5 hour. The precipitate obtained was filtered, washed with ethyl alcohol (5 mL) and dried at 40°C to 45°C to obtain darunavir ethanolate as white powder.

Yield: 1.82 g

HPLC Purity: 98.90%

Example 30: Preparation of Darunavir Ethanolate

A mixture of amorphous darunavir (3 g) and denatured spirit (30 mL) was heated to 65°C and stirred at 65°C to 70°C for 0.5 hour. The solution was cooled to 10°C and the resulting mixture was stirred at 10°C to 15°C for 0.5 hour. The precipitate obtained was filtered, washed with denatured spirit (6 mL) and dried at 40°C to 45°C to obtain darunavir ethanolate as white powder. Yield: 2.8 g

Purity: 99.59%

Example 31 : Preparation of Darunavir Ethanolate

(3R,3aS,6aR)-3-Hydroxyhexahydrofuro-[2,3-b]furan-3-yl 4-nitrophenyl carbonate (6.5 g, 22 mmoles) was added to a solution of 4-amino-N-(2R,3S)-(3-amino-2-hydroxy-4- phenylbutyl)-N-isobutylbenzene sulfonamide (8.7 g, 22.2 mmoles) in dimethylformamide (87 mL) at 25°C to 30°C. The reaction mixture was stirred for 4 hours at 25°C to 30°C. The reaction mixture was added to a mixture of water (220 mL) and dichloromethane (60 mL) at 15°C to 25°C and the resulting mixture was stirred for 30 minutes at 25°C to 30°C. Aqueous sodium bicarbonate solution (5%, 90 mL) was added to the reaction mixture with stirring and layers were separated. The organic layer was washed with aqueous hydrochloric acid solution (2.5%, 45 mL) and water (45 mL). The organic layer was concentrated under vacuum to give an oily residue. Denatured spirit (60 mL) was added to the residue and the resulting mixture was concentrated to give a solid residue.

Denatured spirit (90 mL) was added to the residue. The resulting suspension was heated to 60°C and stirred at 60°C to 62°C for 30 minutes. The solution obtained was cooled slowly to 10°C and stirred for 1 hour at 5°C to 10°C. The product was filtered through suction, washed with denatured spirit (10 mL) and dried at 40°C to 45°C for 12 hours.

Yield: 9.6 g

HPLC Purity: 99.75%

Claims

WE CLAIM:

1. A process for the preparation of a compound of Formula IX,

FORMULA IX

FORMULA XI

FORMULA X wherein R2 is NO2 or Ν(¾4)₂, R₃ is an amino protecting group, and R4 is hydrogen or an amino protecting group, to obtain the compound of Formula IX.

2. A process for the preparation of 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4- phenylbutyl]-N-(2-methylpropyl)benzene sulfonamide of Formula II or an acid addition salt thereof,

FORMULA II

wherein the process comprises:

a) reacting a compound of Formula X with a compound of Formula XI,

FORMULA XI

FORMULA X wherein R2 is NO2 or Ν(¾4)₂, R3 is an amino protecting group, and R4 is hydrogen or an amino protecting group, to obtain the compound of Formula IX,

wherein R2 is NO2 or Ν(¾4)₂, R3 is an amino protecting group, and R4 is hydrogen or an amino protecting group; and b) deprotecting and optionally reducing the compound of Formula IX to obtain the compound of Formula II or an acid addition salt thereof.

3. A process for the preparation of a sulfonamide of Formula I,

FORMULA I

or salts, solvates or prodrugs thereof;

wherein the process comprises:

a) reacting a compound of Formula X with a compound of Formula XI,

FORMULA XI

deprotecting and optionally reducing the compound of Formula IX to obtain the compound of Formula II or an acid addition salt thereof; and

FORMULA II

R-i— OH

FORMULA XII

4. The process according to claims 1 to 3, wherein the compound of Formula XI is added to a reaction mixture in which the compound of Formula X is formed.

5. The process according to claims 1 to 3, wherein the compound of Formula X is reacted with the compound of Formula XI in the presence of a base and a quarternary ammonium halide.

6. The process according to claim 5, wherein a base is selected from the group consisting of an alkali metal carbonate, an alkali metal hydroxide, an alkylamine, or an alkali metal hydride.

7. The process according to claim 5, wherein a quarternary ammonium halide is benzyl triethylammonium chloride.

8. The process according to claims 2 or 3, wherein deprotection of the compound of Formula IX is carried out by treating with an acid.

9. The process according to claim 8, wherein the acid is selected from the group consisting of trifluoroacetic acid, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid and methanesulfonic acid.

10. The process according to claims 2 or 3, wherein optional reduction is carried out using a reducing agent and a source of hydrogen.

11. The process according to claim 10, wherein the reducing agent is selected from the group consisting of palladium carbon, platinum oxide, Raney nickel, rhodium and ruthenium.

12. A process for the preparation of 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4- phenylbutyl]-N-(2-methylpropyl)benzene sulfonamide of Formula II or an acid addition salt thereof,

FORMULA II wherein the process comprises, deprotecting compound of Formula IXa,

FORMULA IXa

13. A process for the preparation of a sulfonamide of Formula I,

FORMULA I

or salts, solvates or prodrugs thereof,

wherein the process comprises:

a) deprotecting a compound of Formula IXa,

FORMULA IXa

wherein R3 is an amino protecting group, and R4 is hydrogen or an amino protecting group, with a hydrohalic acid to obtain 4-amino-N-[(2R,3S)-3- amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)benzenesulfonamide of Formula II or an acid addition salt thereof: and

FORMULA II

R-i— OH FORMULA XII

14. The process according to claims 12 or 13, wherein a hydrohalic acid is added to a mixture in which the compound of Formula IXa is formed.

15. The process according to claims 12 to 13, wherein the hydrohalic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid and hydriodic acid.

16. The process according to claims 12 or 13, wherein deprotection of the compound of Formula IXa is carried out in water or a water-miscible organic solvent or a mixture thereof.

17. The process according to claim 16, wherein the water-miscible organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, denatured spirit or a mixture thereof.

18. The process according to claims 3 or 13, wherein the active derivative of a compound of Formula XII,

R-i— OH FORMULA XII

wherein Ri is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocycloalkyl or heteroaryl, is prepared by reacting the compound of Formula XII with a coupling agent.

19. The process according to claim 18, wherein the coupling agent is selected from the group consisting of bis-(4-nitrophenyl)carbonate, disuccinimidyl carbonate, carbonyl diimidazole, p-nitrophenylchloroformate, phosgene and triphosgene.

20. The process according to claims 3 or 13, wherein the sulfonamide of Formula I is amprenavir or fosamprenavir or darunavir.