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WO2018015929A1 - Nouveau procédé de préparation des inhibiteurs de la protéase du vih et de leurs intermédiaires - Google Patents

Nouveau procédé de préparation des inhibiteurs de la protéase du vih et de leurs intermédiaires Download PDF

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Publication number
WO2018015929A1
WO2018015929A1 PCT/IB2017/054420 IB2017054420W WO2018015929A1 WO 2018015929 A1 WO2018015929 A1 WO 2018015929A1 IB 2017054420 W IB2017054420 W IB 2017054420W WO 2018015929 A1 WO2018015929 A1 WO 2018015929A1
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Prior art keywords
formula
compound
preparation
darunavir
solvate
Prior art date
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Ceased
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PCT/IB2017/054420
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English (en)
Inventor
Krishna Prasad CHIGURUPATI
Srinivas Areveli
Goverdhan Gilla
Rajesh Kumar Rapolu
Prasada Raju Vnkv VETUKURI
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GRANULES INDIA Ltd
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GRANULES INDIA Ltd
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Publication of WO2018015929A1 publication Critical patent/WO2018015929A1/fr
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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

Definitions

  • the present invention relates to a novel process for the preparation of HIV protease inhibitor compound and intermediates thereof.
  • the present invention relates to a novel process for the preparation of Darunavir or a solvate thereof.
  • the present invention also to the process for the preparation of novel intermediates (3R,3aS,6aR)-hcxahydrofuro[2,3-b]furan-3-yl (2S,3R)-4-(4-( 1 ,3- dioxoisoindolin-2-yl)-N-isobutylphenylsulfonamido)-3-hydroxy-l-phenylbutan-2- ylcarbamate Compound of formula (II) of Darunavir or a solvate thereof.
  • Darunavir is a new generation of non-peptide protease inhibitor that exhibits potent antiviral activity with low toxicity in vitro and in vivo. The agent retains activity against resistant strains and has lower probability for the development of resistance.
  • Darunavir was approved by the FDA under the name PREZISTATM, and is administered in combination with a low-dose of ritonavir and other active anti-HIV agents.
  • Vazquez et. al. in U.S. patent 5,843,946 discloses generically Darunavir and specifically disclosed in US patent 6,248,775.
  • Vazquez et. al. in patent US 6,248,775 B2 does not provide any enabling disclosure for preparation of Darunavir or solvate thereof, however a related process
  • the process involves simultaneous reduction of nitro moiety and CBz dcprotcction in the intermediate nitro compound results in various unwanted side reactions leading to poor product selectivity.
  • the process disclosed is not suitable for large scale production because it involves hazardous azide compounds.
  • PCT Publication No. WO 201 1 /051978 discloses an alternative process of darunavir by introducing furanyl compound before the nitro group reduction.
  • Darunavir synthetic procedures as described in the art contained relatively large amounts of impurities, for example, when replicating the processes of the '41 1, '978 patent resulted in the elevation of impurities such as bisfuranyl impurities. Extensive purification procedures are required in order to limit the impurities to meet the requirements as per regulatory guidelines and this may results low product yield thereby making the process quite expensive. Hence there remains a need for an improved process to prepare darunavir, particularly amorphous form of darunavir, which is cost effective, industrially viable, and provide darunavir substantially free of impurities.
  • aspects of the present invention relates to the commercially viable process for the preparation of Darunavir and its intermediates.
  • the present invention relates a novel intermediate compound of formula (II):
  • embodiments of the present invention provide a process for the preparation of Darunavir or a solvate thereof of Formula I comprising the steps of: a. reacting the compound of Formula VI or a salt thereof with a compound of Formula VII in an organic solvent to afford the compound of Formula V and treating the compound of Formula V or a salt thereof with acid to get the compound of Formula IV or a salt thereof;
  • the compounds having Formula (V) is generally synthesized under alkaline conditions.
  • Suitable alkaline conditions include inorganic or organic bases and/or acid scavengers.
  • Conventional inorganic or organic bases include hydroxides, carbonates, or hydrogen carbonates of alkaline earth metals; metal amides, such as sodium amide, potassium amide, lithium diisopropylamide or potassium hexamethyl di s i 1 a/ i d e, and sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium acetate, potassium acetate, calcium acetate, ammonium acetate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, or ammonium carbonate, and also basic organic nitrogen compounds such as, irialkylarnines, like triethylamine, tributylamine, N.N-diisopropylelhylamine, pyridine,
  • the step a is carried out in the presence of a solvent which is selected from solvent used in the present invention is selected from water or "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol and the like or "hydrocarbon solvents” such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents” such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents” such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl a
  • reaction usually performed at from 0°C to a boiling point of an organic solvent used for the reaction for about 30 minutes to 15 hours.
  • process of step a involves the isolation of the compound of formula V optionally as a solid material.
  • process for the preparation of Darunavir or a solvate thereof of Formula I wherein the process step a involves reaction of substantially pure compound of Formula VI with a compound of Formula VII to in an organic solvent to give the compound of Formula V.
  • substantially pure compound of Formula VI obtained by treating the compound of Formula VI in a solvent selected from water, isopropyl alcohol, toluene, diisopropyl ether, ethanol, methanol for 1 - 4 hours. Filtered the compound and washed with solvent and dried to get substantially pure compound of Formula VII.
  • a substantially pure compound formula VI may have purity exceeding 99.0% (by HPLC).
  • substantially pure compound of Formula VI is having dibenzyl impurity of formula (VIII) less than 1.00%.
  • substantially pure compound of Formula VI is having dibenzyl impurity of formula (VIII) less than 0.5% (by HPLC).
  • the mole ratios of reactants and the reagents used therein can be appropriate based on the resultant product and the side products or by products.
  • reaction step of removal of the amino-protecting-group can be achieved using conditions which will not affect the remaining portion of the molecule.
  • These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like, thus using commonly known acids in suitable solvents.
  • acids employed in the removal of the amino-protecting group include inorganic acids such as hydrochloric acid, alcoholic HCl such as Isopropyl alcohol. HCl, methanolic HCl, HCl gas, sulfuric acid and phosphoric acid, organic acids such as acetic acid, trifluoroacetic acid methanesulfonic acid and p-toluenesulfonic acid.
  • the reaction temperature employed depends upon various factors such as the nature of the starting materials, solvents and acids. However it is usually between 30°C and 150°C, or reflux temperatures of the solvents used and is preferably between 35°C and 100°C, even more preferably at a temperature of reflux.
  • the reaction time employed depends on the reaction temperature and the like. It is typically from 30 minutes to 24 hours.
  • removal of boc- protection can be carried using Hydrochloric acid in Isopropyl alcohol at temperature 75-80°C and the reaction carried for 4 - 5 hours.
  • step b reaction of (3R,3aS,6a )-hexahydrofuro[2,3-b]furan-3-yl derivate (IIIA) with compound of Formula (IV) will be performed optionally in the presence of basic organic nitrogen compounds such as trialkylamines, like triethylamine, tributylamine, ⁇ , ⁇ -diisopropylethylamine, pyridine, 1 ,4-diazabicyclo[2.2.2]-oclane (DABCO), l ,5-diazabicyclo[4.3.0]-non-5-ene (DBN). or l ,8-diazabicyclo
  • trialkylamines like triethylamine, tributylamine, ⁇ , ⁇ -diisopropylethylamine, pyridine, 1 ,4-diazabicyclo[2.2.2]-oc
  • step b condensation of Formula IV or its salt with compound of Formula (IIIA) is carried out optionally in the presence of basic organic nitrogen compounds such as, trialkylamines. like triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, l ,4-diazabicyclo[2.2.2]-octane (DABCO), 1 ,5-diazabicyclo[4.3.0]-non-5-ene (DBN), or l ,8-diazabicyclo[5.4.0j-undec-7-ene (DBU), may be used.
  • DBU 1,5-diazabicyclo[4.3.0]-non-5-ene
  • DBU l ,8-diazabicyclo[5.4.0j-undec-7-ene
  • triethylamine is used.
  • the reaction can also be carried out using inorganic bases such as sodium carbonate, Sodium bicarbonate, Potassi
  • Solvent/s in the present invention is selected from water or "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol and the like or "hydrocarbon solvents” such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents” such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents” such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents” such as acctonitrile
  • step b of coupling of (3R,3aS,6aR)-Hydroxyhexahydrofuro[2,3-P]furanyl Succinimidyl Carbonate (IIIA) with compound of Formula (IV), will be performed in the presence of triethylamine in ethyl acetate and water at temperature 25 - 35°C for 1- 2 hours.
  • the suitable agent thai can be used for the conversion of compound of Formula II to the compound of Formula I in step c include but are not limited to alkylamines as methyl amine, n-butylamine.
  • alkali metal hydroxide as sodium hydroxide, potassium hydroxide and the like
  • alkali metal carbonate such as sodium carbonate, potassium carbonate and the like
  • alkali metal bicarbonates such sodium bicarbonate, potassium bicarbonate, Hydrazine hydrate, phenyl hydrazine and sodium sulphide.
  • the solvents that can be used in he said conversion include but are not limited to water; alcohols such as methanol, ethanol, propanol, isopropyl alcohol and the like; esters such as ethyl acetate, isopropyl acetate, butyl acetate and the like; water miscible organic solvent such as acetone, tetrahydrofuran, 1 ,4-dioxan, dimethylsulfoxide and the like; and a mixture of solvents thereof.
  • reaction step c is performed in aqueous methylamine at temperature 0 - 15°C for 12 hours.
  • the obtained compound of Formula I (Darunavir or a solvate thereof) is optionally purified by crystallization or slurry using a suitable organic solvent or mixture of solvents, e.g. acetone, ethyl acetate, dicloromethane, acetonitrile, 2-propanol or methanol.
  • a suitable organic solvent or mixture of solvents e.g. acetone, ethyl acetate, dicloromethane, acetonitrile, 2-propanol or methanol.
  • the obtained Darunavir or a solvate thereof is converted to the corresponding salt by treatment with pharmaceutically acceptable acids.
  • compound of Formula Via is prepared by reacting aniline with Phthalic anhydride in solvent and optionally in the presence of a base and a reagent to give 2-phenylisoindoline-l,3-dione which is further reacted with chlorosulphonic acid in solvent and optionally in the presence of a reagent and base to give compound of Formula VII.
  • compound of Formula Via is prepared by reacting aniline (Vila) with Phthalic anhydride (Vllb) in the absence of a solvent to give 2-phenylisoindoline-l,3-dione (Vile) which is further reacted with chlorosulphonic acid optionally in solvent and optionally in the presence of a reagent and base to give compound of Formula VII.
  • Formula VI is prepared by reacting tert-butyl (S)-l-((S)-oxiran-2-yl)-2- phenylethylcarbamate with isobutylamine in a solvent, optionally in the presence of a base, wherein the solvent used is selected from alcoholic solvents, esters, dichloromethane, chloroform, DMF. DMSO, tetrahydrofuran, methyl THF, aromatic solvents, water or mixture.
  • compound of Formula VI is prepared by reacting tert-butyl (S)-l-((S)-oxiran-2-yl)-2- phenylethylcarbamate with isobutylamine in the absence of a solvent.
  • reaction mixtures especially in order to isolate desired compounds, follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
  • the process of present invention prevents the carrying of dibenyl impurity of formula (VIII) to other steps of the process by using substantially pure compound of formula (VI).
  • the process of present invention does not involve additional purification steps intermittently thus provides the final product Darunavir or a solvate thereof (I) with higher yields and purities.
  • HPLC refers to High-performance liquid chromatography.
  • % area by HPLC refers to the area in an HPLC chromatogram of one or more peaks compared to the total area of all peaks in the HPLC chromatogram expressed in percent of the total area.
  • the term "raccmic mixture” may include mixtures of enantiomers in ratios other than, as well as, a 50:50 mixture of R:S enantiomers (for example from 99: 1 to 1 :99).
  • a particular process of the invention begins with a 50:50 mixture of enantiomers. The process may involve differing mixtures of enantiomers at various stages (including, but not limited to 50:50 mixtures).
  • the term “racemization” covers the conversion of an unresolved enantiomer into a mixture containing the enantiomer to be resolved.
  • the solution obtained is optionally filtered through celite or diatamous earth to separate the extraneous matter present or formed in the solution by using conventional filtration technique known in the art.
  • the precipitation of solid is achieved but not limited to evaporation, cooling, drying, by adding antisolvent and the like.
  • the suitable antisolvent is selected from the group consisting of ethers such as diethyl ether, diisopropyl ether, 1 ,4-dioxane and the like; hydrocarbons such as methyl cyclohexane, cyclohexane, n-hexane, n-heptane and the like; optionally water.
  • the present invention may provide Darunavir or a solvate thereof of Formula 1 having purity greater than 99% as measured by chiral HPLC.
  • the present invention may provide Darunavir or a solvate thereof of Formula I having purity greater than 99.4% as measured by chiral HPLC.
  • stereoisomeric forms as used herein defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three- dimensional structures which are not interchangeable, which the compounds of the present invention may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. Except where specified, all stereoisomeric forms of the compounds employed in the present invention both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.
  • stereoisomeric forms of the compounds mentioned herein i.e. where a particular stereoisomeric form is specified, are defined as isomers substantially free of olher enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates.
  • the term 'stereoisomerically pure' concerns compounds or intermediates having a stereoisomeric x e o f at 1 CHS I. 80% (i. e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e.
  • stereoisomeric forms of the compounds mentioned herein may be obtained by the application of art-known procedures. For instance, enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases.
  • Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereoselectively.
  • said compound will be synthesized by stereoselective methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
  • the desired compounds can be obtained from the reaction mixture by conventional means known in the art.
  • the working-up of reaction mixtures, especially in order to isolate desired compounds follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
  • Crystallization may include in a single solvent or mixture of solvents to facilitate the precipitation of the compound of Formula-I.
  • the resulting crystals are then recovered by conventional techniques, such as filtration. They may be washed with water or an organic solvent.
  • the crystals are then preferably dried. The temperature may be increased or the pressure reduced to accelerate the drying process. Drying may be carried out at a suitable temperature.
  • the purity of the Darunavir samples was measured using Chromatography. Chromatography was performed with Waters Alliance HPLC system (MILD, USA) that consists of quaternary pump equipped with a 2695 separation module with inbuilt auto injector and 2996 photodiode array detector. The output signal was monitored and processed using chromelean software version 6.8.
  • MILD Waters Alliance HPLC system
  • the mass spectrum of sample was measured using Waters SQD-2, Shimadzu- LCMS, Agilent -6120 Quadrupole/LC-MS.
  • NMR of the sample can be predicted using the instrument JEOL 500 MHz NMR Spectrometer with Royal Probe and auto sampler, JEOL 400 MHz NMR Spectrometer with TH5ATFG probe lacility, BRUKER Ascend 400 MHz AVANCE III HD and IR spectroscopy was performed by using Perkin Elmer.
  • Vile (VII) Phosphorus pentachloride (9.3 g, 0.0448 mol) was added to the chlorosulfonic acid(9.0 ml) at room temperature.
  • the reaction mixture was heated to 50-55°C and stirred for 30-45 min.
  • the reaction mass was quenched into water ( 100 mL) and chloroform ( 100 mL) at 5- 10°C. Separated organic layer and extracted aqueous layer with Chloroform.
  • Reaction mass was washed with water (2*90.0 ml) and distilled organic layer completely under vacuum at below 50°C.Charged Isopropyl alcohol (600.0 ml) and concentrated HC1(15.0 ml) at room temperature. Heated the reaction mass to 75-80°C and stirred for 4-5 hours for the completion of reaction. Cooled the reaction mass to room temperature and stirred for 30-60 minutes. Reaction mass was filtered and washed with Isopropyl alcohol (60.0 ml). The above crude material was slurred in Isopropyl alcohol (100.0 ml) for 60-90 minutes at room temperature. Reaction mass was filtered and washed with Isopropyl alcohol (30.0 ml) and dried at 50-55°C.
  • reaction mass was stirred at 25-35°C for 1-2 h. After completion of reaction, filtered the reaction mixture and the obtained solid washed with ethyl acetate (50 mL). The above material was slurred in water at room temperature for 30-60 minutes. Reaction mass was filtered and washed with water (45 ml). The solid was dried at 50-55°C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation de Darunavir ou de son solvate de formule I à l'aide d'un nouvel intermédiaire (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (2S,3R)-4-(4-(1,3-dioxoisoindolin-2-yl)-N-isobutylphenylsulfonamido)-3 -hydroxy- 1 -phenylbutan-2- ylcarbamate composé de la formule (II) : La présente invention concerne également le procédé de préparation de nouveaux intermédiaires (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (2S,3R)-4-(4-(l,3-dioxo iso indolin-2-yl)-N-isobutylphenylsulfonamido)-3 -hydroxy- 1 -phenylbutan-2-ylcarbamate composé de la formule (II). Le Darunavir ou son solvate de formule I sont utiles en tant qu'agent thérapeutique et utilisés dans le traitement de maladies antivirales.
PCT/IB2017/054420 2016-07-22 2017-07-21 Nouveau procédé de préparation des inhibiteurs de la protéase du vih et de leurs intermédiaires Ceased WO2018015929A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108822123A (zh) * 2018-09-06 2018-11-16 南通雅本化学有限公司 一种地瑞那韦的制备方法
CN110698492A (zh) * 2019-09-05 2020-01-17 雅本化学股份有限公司 一种地瑞那韦的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011048604A2 (fr) * 2009-09-17 2011-04-28 Matrix Laboratories Limited Procédé amélioré pour la préparation de darunavir

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011048604A2 (fr) * 2009-09-17 2011-04-28 Matrix Laboratories Limited Procédé amélioré pour la préparation de darunavir

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
AHLAM MAROUF AL-AZZAWI ET AL., SYNTHESIS, CHARACTERIZATION AND ANTIBACTERIAL SCREENING OF NEW SCHIFF BASES LINKED TO PHTHALIMIDE, vol. 3, no. 3, 2013, XP055454837 *
JAN KO I ET AL.: "Solid-phase synthesis and chemical properties of 2-(2-amino/hydroxyethyl)-1-aryl-3, 4-dihydropyrazino[1, 2-b] indazol-2-iums", J COMB CHEM., vol. 12, no. 1, January 2010 (2010-01-01), pages 168 - 175, XP055454838 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108822123A (zh) * 2018-09-06 2018-11-16 南通雅本化学有限公司 一种地瑞那韦的制备方法
CN110698492A (zh) * 2019-09-05 2020-01-17 雅本化学股份有限公司 一种地瑞那韦的制备方法

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