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WO2013011485A1 - Procédé de préparation de sulfonamides utiles en tant qu'inhibiteurs de protéase rétroviraux - Google Patents

Procédé de préparation de sulfonamides utiles en tant qu'inhibiteurs de protéase rétroviraux Download PDF

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Publication number
WO2013011485A1
WO2013011485A1 PCT/IB2012/053700 IB2012053700W WO2013011485A1 WO 2013011485 A1 WO2013011485 A1 WO 2013011485A1 IB 2012053700 W IB2012053700 W IB 2012053700W WO 2013011485 A1 WO2013011485 A1 WO 2013011485A1
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Prior art keywords
formula
compound
amino
acid
protecting group
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Suresh Babu Jayachandra
Ruchika Yogesh
Devendra Prakash NAGDA
Chandra Has Khanduri
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Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups

Definitions

  • the present invention relates to a process for the preparation of sulfonamides useful as retroviral protease inhibitors.
  • 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,
  • 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.
  • Amprenavir is chemically (3S)-tetrahydro-3-furyl N-[(lS,2R)-3-(4-amino-N- isobutylbenzenesulfonamido)- 1 -benzyl-2-hydroxypropyl]carbamate of 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • alkyl radicals include methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, and the like.
  • 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.
  • alkenyl radicals include ethenyl, propenyl, 1 ,4-butadienyl, and the like.
  • 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.
  • alkynyl radicals include ethynyl, propynyl, butynyl, and the like.
  • 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.
  • cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • 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,
  • 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.
  • 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-n-
  • 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.
  • aralkyl radicals include benzyl, 2-phenylethyl, dibenzylmethyl,
  • Heterocycloalkyl and heterocyclyl mean preferably
  • Heterocycloalkyl and heterocyclyl in addition to sulfur and nitrogen, also include sulfones, sulfoxides and N-oxides of tertiary nitrogen containing heterocycloalkyl groups.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a first aspect of the invention provides a process for the preparation of a compound of Formula IX,
  • R2 is NO2 or ⁇ (3 ⁇ 44) 2
  • R3 is an amino protecting group
  • R4 is hydrogen or an amino protecting group
  • 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,
  • R2 is NO2 or ⁇ (3 ⁇ 44) 2
  • R 3 is an amino protecting group
  • R4 is hydrogen or an amino protecting group
  • a third aspect of the invention provides a process for the preparation of a sulfonamide of Formula I;
  • Ri is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocycloalkyl or heteroaryl;
  • R2 is NO2 or ⁇ (3 ⁇ 44) 2
  • R3 is an amino protecting group
  • R4 is hydrogen or an amino protecting group
  • 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,
  • L is a leaving group
  • I3 ⁇ 4 is NO2 or ⁇ (3 ⁇ 44) 2
  • 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,
  • 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 I3 ⁇ 4 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
  • 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,
  • 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;
  • R3 is an amino protecting group
  • 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,
  • Ri is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocycloalkyl or heteroaryl,
  • R3 is an amino protecting group
  • 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:
  • 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 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,
  • R 3 is an amino protecting group
  • 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,
  • R 3 is an amino protecting group
  • R4 is hydrogen or an amino protecting group
  • L is a leaving group
  • R3 is an amino protecting group
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • reaction mixture was washed with water (2 x 15 mL), dried over sodium sulfate and concentrated to obtain a residue.
  • residue was purified by column chromatography using silica gel as stationary phase and dichloromethane-methanol as eluent to obtain the title compound.
  • 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.
  • 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.
  • Triethylamine (26.48 g, 0.26 moles) was added to a solution of tert-butyl [(2S,3R)-
  • 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.
  • 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.
  • Triethylamine (24.8 mL, 0.178 moles) was added to a solution of tert-butyl
  • 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.
  • Triethylamine (1.98 Ltr, 14.28 moles) was added to a solution of tert-butyl
  • 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.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur un procédé de préparation de sulfonamides utiles en tant qu'inhibiteurs de protéase rétroviraux.
PCT/IB2012/053700 2011-07-20 2012-07-19 Procédé de préparation de sulfonamides utiles en tant qu'inhibiteurs de protéase rétroviraux Ceased WO2013011485A1 (fr)

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EP2998291A1 (fr) 2014-09-16 2016-03-23 ZCL Chemicals Ltd. Nouveau procédé pour préparer des intermédiaires d'inhibiteurs de la protéase du vih
WO2016193481A1 (fr) * 2015-06-05 2016-12-08 Amneal Pharmaceuticals Company Gmbh Procédé pour la préparation de darunavir
US9829185B2 (en) 2013-01-28 2017-11-28 Exposure Illumination Architects, Inc. Intermediate device structure for illumination poles and a method of use thereof
US10215351B2 (en) 2013-01-28 2019-02-26 Daniel S. Spiro Systems and methods for an intermediate device structure
EP3795572A1 (fr) 2012-07-24 2021-03-24 Laurus Labs Limited Solvate de proprionate de darunavir
CN114276280A (zh) * 2021-10-30 2022-04-05 苏州汉酶生物技术有限公司 一种手性苯丁胺醇磺酰胺类化合物的制备方法、制备其的中间体及制备方法

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3795572A1 (fr) 2012-07-24 2021-03-24 Laurus Labs Limited Solvate de proprionate de darunavir
US9829185B2 (en) 2013-01-28 2017-11-28 Exposure Illumination Architects, Inc. Intermediate device structure for illumination poles and a method of use thereof
US10215351B2 (en) 2013-01-28 2019-02-26 Daniel S. Spiro Systems and methods for an intermediate device structure
EP2998291A1 (fr) 2014-09-16 2016-03-23 ZCL Chemicals Ltd. Nouveau procédé pour préparer des intermédiaires d'inhibiteurs de la protéase du vih
WO2016193481A1 (fr) * 2015-06-05 2016-12-08 Amneal Pharmaceuticals Company Gmbh Procédé pour la préparation de darunavir
CN114276280A (zh) * 2021-10-30 2022-04-05 苏州汉酶生物技术有限公司 一种手性苯丁胺醇磺酰胺类化合物的制备方法、制备其的中间体及制备方法
CN114276280B (zh) * 2021-10-30 2023-10-31 苏州汉酶生物技术有限公司 一种手性苯丁胺醇磺酰胺类化合物的制备方法、制备其的中间体及制备方法

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