WO2012170647A1 - Procédé pour la préparation d'étravirine et intermédiaires dans la synthèse de celle-ci - Google Patents

Procédé pour la préparation d'étravirine et intermédiaires dans la synthèse de celle-ci Download PDF

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Publication number
WO2012170647A1
WO2012170647A1 PCT/US2012/041277 US2012041277W WO2012170647A1 WO 2012170647 A1 WO2012170647 A1 WO 2012170647A1 US 2012041277 W US2012041277 W US 2012041277W WO 2012170647 A1 WO2012170647 A1 WO 2012170647A1
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Prior art keywords
etravirine
compound
formula
salt
yloxy
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PCT/US2012/041277
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English (en)
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Maja ŠEPELJ MAJER
Irena Krizmanic
Dragan ŠEPAC
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Assia Chemical Industriew Ltd.
Teva Pharmaceuticals Usa, Inc.
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Publication of WO2012170647A1 publication Critical patent/WO2012170647A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms

Definitions

  • the present invention relates to novel processes for preparing Etravirine and synthetic intermediates in these processes.
  • ETV Etravirine
  • Etravirine was formerly known as TMC-125, and has the brand name INTELENCE ® .
  • Etravirine certain analogs of Etravirine, and their synthesis are described in US patent No. 7,037,917.
  • Etravirine is prepared by reacting a tetra halogenated pyrimidine derivative and an aminobenzene derivative, and optionally brominating the obtained product of that reaction, to obtain Etravirine.
  • This process includes two steps that require chromatographic purification of intermediates, and the final product is obtained in very poor overall yield.
  • EP 945443 discloses a general process for preparing anilinopyrimidine derivatives, and salts thereof, e.g., by aminolysis reactions of pyrimidine compounds containing leaving groups.
  • WO 01/85700 describes a preparation of Etravirine analogues, which do not include an NH 2 group.
  • the Etravirine analogues in this process were purified by column chromatography, and were obtained in very poor overall yield of about 2-5%.
  • WO 2006/094930, WO 2008/071587 and WO 2000/027825 describe different processes for preparing different Etravirine intermediates and derivatives, all of which require at least one chromatographic purification step.
  • WO 2008/068299 discloses that Etravirine has very poor solubility in water, and describes a hydrobromide salt of Etravirine, which is prepared by dissolving Etravirine in dichioromethane and reacting this solution with hydrobromic acid.
  • WO201 1/017079 and WO2010/150279 disclose additional processes for preparation of Etravirine and Etravirine intermediates.
  • the present invention provides a novel process for preparing Etravirine.
  • the present invention encompasses the compound 4-(6-(acetyl- amino)-2-chloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile ("CAPE-Ac”), and salts thereof (structure shown below), which may alternatively be named as N-(2-chloro-6-(4-cyano-2,6- dimethylphenoxy)pyrimidin-4-yl)acetamide:
  • the present invention encompasses the use of CAPE-Ac and salts thereof to prepare Etravirine and Etravirine intermediates, and salts thereof.
  • the present invention encompasses a process for preparing Etravirine and salts thereof comprising preparing CAPE-Ac by the process of the present invention, and converting it to Etravirine and salts thereof.
  • the present invention encompasses a process for preparing CAPE-Ac comprising acetylating 2,6-dichloropyrimidin-4-amine (“DCAP”) of the following structure:
  • DCAP Acetylating 2,6-dichloropyrimidin-4-amine
  • DCAP-Ac acetyl-N-(2,6-dichloropyrimidin-4-yl)amine
  • DCAP-Ac b) Reacting DCAP-Ac and 4-hydroxy-3,5-dimethylbenzonitrile (“DMHB”) of the following structure:
  • CAPE-Ac c Reacting CAPE-Ac and 4-aminobenzonitrile (“ABN”) of the following structure:
  • DEBETV-Ac De-protecting the DEBETV-Ac to obtain 4-(6-amino-2-(4 cyanophenylamino)- pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (DEBETV) of the following structure:
  • the present invention encompasses a compound of the following formula 1 , and salts thereof:
  • X is a halogen, e.g., -Cl, -Br,-I or -F (preferably Cl); or a tosyl group.
  • BDCAP 5-bromo-2,6-dichloropyrimidin-4- amine
  • the present invention encompasses the use of BDCAP and salts thereof to prepare Etravirine and Etravirine intermediates, and salts thereof.
  • the present invention encompasses a process for preparing Etravirine and salts thereof comprising preparing BDCAP by the process of the present invention, and converting it to Etravirine and salts thereof.
  • the present invention encompasses a process for preparing a compound of Formula 1 and salts thereof comprising brominating a compound of Formula 2:
  • X is a halogen, e.g., -CI, -Br, -I or -F; or a tosyl group, to obtain a compound of Formula 1 .
  • the present invention encompasses a process for preparing Etravirine and salts thereof comprising:
  • Figure 1 provides a ⁇ NMR spectrum of 4-(6-amino-5-bromo-2-chloropyrimidin-4- yloxy)-3,5-dimethylbenzonitrile ("BCAPE”)
  • Figure 2 provides a l 3 C NMR spectrum of 4-(6-amino-5-bromo-2-chloropyrimidin-4- yloxy)-3,5-dimethylbenzonitrile ("BCAPE”)
  • Figure 3 provides a l 5 N NMR spectrum of 4-(6-amino-5-bromo-2-chloropyrimidin-4- yloxy)-3,5-dimethylbenzonitrile ("BCAPE”)
  • the present invention provides novel processes for preparing Etravirine, as well as novel intermediates in these processes.
  • room temperature refers to a temperature from about 20°C to about 30 °C. Usually, room temperature ranges from about 20°C to about 25°C.
  • the term “overnight” refers to a period of between about 15 hours and about 20 hours, typically between about 16 hours to about 20 hours.
  • Etravirine and Etravirine intermediates corresponds to Etravirine, or an Etravirine intermediate, that is physically separated from the reaction mixture in which it is formed.
  • tosyl refers to a 4- methylbenzenesulfonate substituent on an aromatic ring, i.e., having the structure -0-S0 2 - C6H4CH3.
  • examples include 6-amino-5-bromopyrimidine-2,4-diyl bis(4-methylbenzene- sulfonate), shown in the structure below:
  • the present invention provides a novel process for preparing Etravirine or a salt thereof via a novel intermediate: 4-(6-(acetylamino)-2-chloropyrimidin-4-yloxy)-3,5- dimethylbenzonitrile ("CAPE-Ac").
  • This process provides Etravirine in high purity, and in good overall yield, preferably of about 30%.
  • the bromination reaction which is performed in the last step, can be carried out under mild conditions.
  • the crude product is obtained in a high purity, which purity can be further increased using simple methods, such as crystallization.
  • the present invention encompasses the compound, 4-(6-(acetyl- amino)-2-chloropyrimidin-4-yloxy)-3, 5-dimethylbenzonitrile (“CAPE-Ac”), and salts thereof of the following structure:
  • the intermediate CAPE-Ac can be isolated, and, according to some embodiments, this intermediate is crystalline.
  • the intermediate CAPE-Ac can be prepared by a process comprising acetylating 2,6- dichloropyrimidin-4-amine (“DCAP") of the following structure:
  • Suitable acetylating agents for step a) include, for example, acetyl chloride or acetic anhydride.
  • the acetylation can optionally be done in the presence of a suitable base.
  • Suitable bases include, for example, a carbonate base such as sodium or potassium carbonate or sodium or potassium bicarbonate.
  • the acetylation can optionally be done in the presence of a suitable solvent.
  • Suitable solvents include organic solvents that are inert to the acetylation reagent.
  • the acetylation reaction can be performed neat, for example by mixing the DECAP with neat acetic anhydride.
  • the acetylation can be carried out at a suitable temperature, for example from about room temperature up to about the reflux temperature of the solvent, if a solvent is used, or of acetic anhydride, if the reaction is carried out in acetic anhydride with no additional solvent.
  • the above described CAPE-Ac can be used to prepare Etravirine and salts thereof.
  • the present invention provides a process for preparing Etravirine and salts thereof comprising preparing CAPE-Ac by the process of the present invention, and converting it to Etravirine or a salt thereof.
  • the conversion can be done, for example, by a) reacting CAPE-Ac and ABN to obtain DEBETV-Ac; b) de-protecting DEBETV-Ac to obtain DEBETV; and c) brominating DEBETV to obtain Etravirine.
  • the process can further include converting the Etravirine produced in step c) to an Etravirine salt, for example by reacting the Etravirine product with a suitable acid.
  • DCAP Acetylating 2,6-dichloropyrimidin-4-amine
  • DCAP-Ac acetyl-N-(2,6-dichloropyrimidin-4-yl)amine
  • DCAP-Ac b) Reacting the DCAP-Ac and 4-hydroxy-3,5-dimethylbenzonitrile (“DMHB”) of the following structure:
  • CAPE - Ac c Reacting the CAPE-Ac and 4-aminobenzonitrile (“ABN”) of the following
  • DEBETV-Ac De-protecting the DEBETV-Ac to obtain 4-(6-amino-2-(4 cyanophenylamino)- pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (DEBETV) of the following structure:
  • Suitable acetylating agents for step a) include, for example, acetyl chloride or acetic anhydride.
  • the acetylation can optionally be done in the presence of a suitable base, and optionally in the presence of a suitable solvent, as described above.
  • reaction in step b) can typically be done in the presence of a suitable base.
  • Suitable bases include: metal hydrides such as, for example, sodium hydride; non- nucleophilic bases, such as, for example, lithium diisopropylamide ("LDA"); alkoxide bases, such as, for example sodium methoxide or potassium methoxide; and carbonate bases, such as, for example, potassium carbonate or sodium carbonate. This step can also be done in the presence of a suitable solvent.
  • metal hydrides such as, for example, sodium hydride
  • non- nucleophilic bases such as, for example, lithium diisopropylamide (“LDA"
  • alkoxide bases such as, for example sodium methoxide or potassium methoxide
  • carbonate bases such as, for example, potassium carbonate or sodium carbonate.
  • Suitable solvents include amide solvents, such as N- methyl- pyrrolidone (“NMP”), DMF, dimethylacetamide (“DMA”), 2-pyrrolidone, l ,3-dimethyl-2- imidazolidinone (“DMI”) and imidazolidinone; sulfoxide and sulfone solvents, such as dimethylsulfoxide (“DMSO”), and methylsulfonylmethane (“MSM”).
  • NMP N- methyl- pyrrolidone
  • DMA dimethylacetamide
  • 2-pyrrolidone 2-pyrrolidone
  • l ,3-dimethyl-2- imidazolidinone l ,3-dimethyl-2- imidazolidinone
  • imidazolidinone imidazolidinone
  • sulfoxide and sulfone solvents such as dimethylsulfoxide (“DMSO”), and methylsulfonylmethane (“MSM”
  • the reaction is done at a temperature from about 0°C to about 130°C, or from about 30°C to 130°C, or from about 60°C to about 120°C, or from about 80°C to about 120°C, or from about 100°C to about 120 o C.jDne suitable reaction temperature is about 100°C.
  • the reaction is continued for a period of time sufficient to complete the reaction, for instance from about 1 hour to about 20 hours, or from about 1 hour to about 10 hours, or from about 1 hour to about 5 hours. In some instances, the reaction is complete in about 1 hour.
  • Step c) can be done in the presence of a suitable solvent.
  • suitable solvents include polar aprotic solvents, such as acetonitrile; DMF (or other amide solvents); DMSO or DMA, ether solvents, such as dioxane; ester solvents, such as ethyl acetate; or ketone solvents, such as acetone.
  • polar aprotic solvents such as acetonitrile
  • DMF or other amide solvents
  • DMSO or DMA DMSO or DMA
  • ether solvents such as dioxane
  • ester solvents such as ethyl acetate
  • ketone solvents such as acetone
  • the process in step c) can be performed at a suitable temperature, for example, from about from about 0°C to about 130°C, or from about 30°C to about 130°C, or from about 60°C to about 120°C, or from about 80°C to about 120°C or from about 100°C to about 120°C.
  • a suitable temperature is about 100°C.
  • the reaction is continued for a period of time sufficient to complete the reaction, for instance from about 1 hour to about 20 hours, from about 1 hour to about 10 hours, or from about 1 hour to about 5 hours. In some instances, the reaction is complete in about 1 hour.
  • the deprotection reaction in step d) is typically done in the presence of a suitable base.
  • suitable bases include inorganic bases, such as metal hydroxides, e.g., sodium hydroxide or potassium hydroxide, alkoxide bases, such as sodium methoxide or potassium methoxide, and hydrazine bases.
  • the deprotection can be accomplished with a reducing agent, such as sodium borohydride, or by enzymatic hydrolysis.
  • the de-protection is typically done in the presence of a suitable solvent, for example, an alcoholic solvent, such as a Ci-C 6 alcohol, or a C1 -C4 alcohol, such as, for example ethanol, methanol, propanol, isopropanol or butanol.
  • a suitable solvent for example, an alcoholic solvent, such as a Ci-C 6 alcohol, or a C1 -C4 alcohol, such as, for example ethanol, methanol, propanol, isopropanol or butanol.
  • the process in step d) can be performed at a temperature from about 10°C to about 30°C, or from about 15°C to about 30°C, or from about 20°C to about 30°C.
  • the reaction can be continued for a period of time sufficient to complete the reaction, for example, from about 1 hour to about 20 hours, or from about 1 hour to about 10 hours, or from about 1 hour to about 5 hours. In some instances, the reaction is complete in about 1 hour.
  • the obtained DEBETV of step d) is brominated to obtain Etravirine.
  • the bromination can be done in the presence of a suitable solvent.
  • suitable solvents include alcohol solvents, e.g., C]-C 4 alcohol solvents, such as methanol, ethanol, 1 -propanol or 1 -butanol; organic acids, such as acetic acid; amide solvents, such as DMF; ether solvents, such as THF; nitrile solvents, such as acetonitrile, and mixtures thereof.
  • the bromination can be performed at a temperature from about 0°C to about 30°C, from about 10°C to about 30°C, or from about 15°C to about 30°C; preferably from about 5°C to about 15°C.
  • the reaction can be continued for a period of time sufficient to complete the reaction, for instance from about 1 hour to about 4 hours, from about 2 hour to about 4 hours, or from about 1 hour to about 3 hours. In some instances, the reaction is complete in about 1 to 2 hours.
  • Etravirine can be purified, by any suitable method known in the art, for example, by column chromatography or by crystallization.
  • Etravirine can be purified by converting it to an Etravirine salt, which can then be recrystallized. Such a conversion is typically done by reacting the Etravirine with a suitable acid.
  • the present invention also provides an alternative process for preparation of
  • Etravirine via the compound of Formula 1 or salts of said compound, particularly 5-bromo- 2,6-dichloropyrimidin-4-amine ("BDCAP").
  • BDCAP 5-bromo- 2,6-dichloropyrimidin-4-amine
  • This process provides Etravirine in high purity, and in overall yield of more than 36%, via a process that comprises only three synthetic steps.
  • X is a halogen, e.g., -CI, -Br, -I or -F; or a tosyl group.
  • the present invention encompasses a compound of Formula 1 and salts thereof:
  • X is a halogen, e.g., -CI, -Br, -I or -F; or a tosyl group.
  • BDCAP 5-bromo-2,6-dichloropyrimidin-4- amine
  • the compound of Formula 1, particularly the intermediate BDCAP can be isolated, and preferably, it is crystalline.
  • the compound of Formula 1 particularly the intermediate BDCAP, and salts thereof can be prepared by a process comprisi rominating a compound of Formula 2:
  • the above described compound of Formula 1 and salts thereof, particularly BDCAP, can be used to prepare Etravirine, salts thereof and solid state forms thereof.
  • the present invention provides a process for preparing Etravirine, salts thereof and solid state forms thereof comprising preparing compound of Formula 1, e.g., BDCAP, by the process of the present invention, and converting it to Etravirine or a salt thereof.
  • the conversion can be done, for example, by a) reacting the compound of Formula 1 (e.g., BDCAP) and DMHB to obtain BCAPE; b) reacting the BCAPE and ABN to obtain Etravirine; and c) optionally converting the Etravirine to an Etravirine salt, for example by reacting Etravirine with a suitable acid.
  • X is a halogen, e.g., -CI, -Br, -I or -F; or a tosyl group to obtain a compound of formula 1 , particularly BDCAP;
  • Step A) can be done in the presence of a suitable solvent.
  • suitable solvents for step A) include alcohol solvents, e.g., C1 -C4 alcohol solvents, for example, methanol, ethanol, 1- propanol or 1-butanol; organic acid solvents, such as acetic acid; amide solvents, such as dimethylformamide (“DMF”); ether solvents, such as tetrahydrofuran (“THF”); nitrile solvents, such as acetonitrile, and mixtures thereof.
  • alcohol solvents e.g., C1 -C4 alcohol solvents, for example, methanol, ethanol, 1- propanol or 1-butanol
  • organic acid solvents such as acetic acid
  • amide solvents such as dimethylformamide (“DMF”
  • ether solvents such as tetrahydrofuran (“THF”
  • nitrile solvents such as acetonitrile, and mixtures thereof.
  • Step B) can be done in the presence of a suitable base.
  • Suitable bases for step B) include metal hydrides; such as sodium hydride; non-nucleophilic bases, such as lithium diisopropylamide ("LDA"); alkoxide bases, e.g., sodium methoxide or potassium methoxide; and carbonate bases, e.g., potassium carbonate or sodium carbonate.
  • LDA lithium diisopropylamide
  • alkoxide bases e.g., sodium methoxide or potassium methoxide
  • carbonate bases e.g., potassium carbonate or sodium carbonate.
  • Suitable solvents for this step include, for example, amide solvents, such as N-methylpyrrolidone (“NMP”), DMF, dimethylacetamide (“DMA”), 2-pyrrolidone, l ,3-dimethyl-2-imidazolidinone (“DMI”) or imidazolidinone; and sulfoxide solvents, for example dimethyl sulfoxide (“DMSO”) or methylsulfonylmethane (“MSM”) .
  • NMP N-methylpyrrolidone
  • DMA dimethylacetamide
  • 2-pyrrolidone 2-pyrrolidone
  • l ,3-dimethyl-2-imidazolidinone 2-pyrrolidone
  • DMI 2-pyrrolidone
  • imidazolidinone imidazolidinone
  • sulfoxide solvents for example dimethyl sulfoxide (“DMSO”) or methylsulfony
  • Step C) can be done in the presence of a solvent and a base, as described above.
  • step C) is carried out at a temperature from about 10°C to about 100°C, preferably about 90 to about 100°C, for time period sufficient to complete the reaction, such as from about 1 hour to about 48 hours, preferably from about 40 to about 48 hours.
  • the obtained Etravirine product can be purified by any suitable method known in the art, for example, by column chromatography or by crystallization. Alternatively, the
  • Etravirine product can be purified by converting it to an Etravirine salt, which can then be recrystallized. Such a conversion is typically done by reacting the Etravirine product with a suitable acid.
  • the resulting mixture was stirred at 0-5 °C for 3.5 h, and then at room temperature (25-30 °C) for 18 h, and then at 62 °C for an additional 23 h, and then at 85 °C for l h with addition of an additional 0.275 eq of NaH.
  • the reaction mixture was then cooled to 0-5 °C and water (5 ml) was added, and this mixture was stirred for 2h. A solid precipitated and was separated by filtration. The filtered solid was washed with water (1 ml) and then dried under vacuum 5h/ 40 °C/ 10 mbar, 516 mg (71 %).
  • the product was triturated in methyl isobutyl ketone: 460 mg of crude material was suspended in the solvent (5 ml) and stirred for 20 h at room temperature.
  • Nl or N3 exhibited one signal at ⁇ 229.2 ppm, while one signal could not be observed.
  • the resulting mixture was stirred at 10 °C for 15 minutes, then at room temperature (25-30 °C) for 15 minutes, then at 60 °C for an additional 18 h, and then at 80 °C for lh.
  • the reaction mixture was then cooled to room temperature and water was added (28 ml), and this mixture was stirred for 2h at 0-5 °C. A solid was separated by filtration.
  • the reaction mixture was stirred at 0-5 °C for lh, then at room temperature for 2 h, and then at 100 °C for 44 h.
  • the resulting mixture was then cooled to room temperature and water (3ml) was added dropwise. A solid precipitated. After a few minutes, a solution was obtained.
  • the solution was stirred 1 h at room temperature before additional water (3 ml) was added and crystals began to form. The solution was left for 20 h at 2 °C, then filtered to provide 107 mg (43.5 %) of the crude product.
  • Example 3c Purification of 4-(6-amino-5-bromo-2-(4-cvanophenylamino)-pyrimidin-4- yloxy)-3,5-dimethylbenzonitrile (Etravirine)
  • Acetyl-N-(2,6-dichloropyrimidin-4-yl)hydroxylamine (DCAP-Ac, 1 g, 4.50 mmol) was suspended in DMA (10 mL), and 4-hydroxy-3,5-dimethylbenzonitrile (DMHB, 0.71 g, 4.82 mmol, 1.07 molEq), K 2 C0 3 (1 g, 16.66 mmol, 3.70 molEq) and Nal (0.1 1 g, 0.73 mmol, 0.16 molEq) were added.
  • DMHB 4-hydroxy-3,5-dimethylbenzonitrile
  • K 2 C0 3 (1 g, 16.66 mmol, 3.70 molEq
  • Nal 0.1 1 g, 0.73 mmol, 0.16 molEq
  • the solution was stirred at 100 °C overnight, then cooled to room temperature and diluted with ethyl acetate and salt water. The layers were separated, and the organic layer was washed with saturated NaCl solution. The collected water layers were washed with ethyl acetate, and the collected organic extracts were dried over Na 2 S0 4 , filtered and the filtrate was evaporated to dryness. The resulting residue (43 mg) was triturated with ethyl acetate and filtered. The resulting solid was washed with cold ethyl acetate / diisopropyl ether and dried.
  • Example 6b Preparation of 4-(6-(acetylamino)-2-(4-cvanophenylamino pyrimidin-4-yloxy - 3.5-dimethylbenzonitrile (DEBETV-Ac)
  • the resulting residue was dissolved in ethyl acetate (120 mL) and water (120 mL). The layers were separated, and the organic layer was washed with saturated NaCl solution (40 mL), dried over MgS0 4 , and filtered. The filtrate was evaporated to dryness. The resulting residue was dissolved in DMA (3 mL), and water (2.5 mL) was added dropwise. The resulting suspension was stirred at 0-5 °C for 1 h, and filtered. The collected solid was washed with water and dried 5h / 40 °C / 10 mbar.
  • reaction mixture was then diluted with saturated aqueous NaCl (80 mL), and extracted with ethyl acetate (80 mL). The organic layer was dried over MgS0 4 , and filtered, and the filtrate was evaporated to dryness.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

La présente invention concerne des intermédiaires, par exemple, 4-(6-(acétylamino)-2- chloropyrimidin-4-yloxy)-3,5-diméthylbenzonitrile, pour la préparation d'Étravirine ou des sels d'Étravirine, et des procédés pour la préparation d'Étravirine ou de ses sels selon la présente invention. L'invention concerne également des procédés pour la préparation de 4-(6-(acétylamino)-2- chloropyrimidin-4-yloxy)-3,5-diméthylbenzonitrile.
PCT/US2012/041277 2011-06-09 2012-06-07 Procédé pour la préparation d'étravirine et intermédiaires dans la synthèse de celle-ci WO2012170647A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111362939A (zh) * 2020-04-26 2020-07-03 济南磐石医药科技有限公司 一种帕布昔利布母核结构化合物的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7037917B2 (en) * 1998-11-10 2006-05-02 Janssen Pharmaceutica, N.V. HIV replication inhibiting pyrimidines
WO2010150279A2 (fr) * 2009-06-22 2010-12-29 Emcure Pharmaceuticals Limited Procédé pour la synthèse d'inhibiteur non nucléosidique de la transcriptase inverse diarylpyrimidine
WO2011017079A1 (fr) * 2009-07-27 2011-02-10 Teva Pharmaceutical Industries Ltd. Procédé de préparation et de purification d'etravirine et intermédiaires de celui-ci
WO2011121418A1 (fr) * 2010-03-31 2011-10-06 Palobiofarma, S.L. Dérivés de 4-aminopyrimidine et leur utilisation en tant qu'antagonistes des récepteurs de l'adénosine a2a

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7037917B2 (en) * 1998-11-10 2006-05-02 Janssen Pharmaceutica, N.V. HIV replication inhibiting pyrimidines
WO2010150279A2 (fr) * 2009-06-22 2010-12-29 Emcure Pharmaceuticals Limited Procédé pour la synthèse d'inhibiteur non nucléosidique de la transcriptase inverse diarylpyrimidine
WO2011017079A1 (fr) * 2009-07-27 2011-02-10 Teva Pharmaceutical Industries Ltd. Procédé de préparation et de purification d'etravirine et intermédiaires de celui-ci
WO2011121418A1 (fr) * 2010-03-31 2011-10-06 Palobiofarma, S.L. Dérivés de 4-aminopyrimidine et leur utilisation en tant qu'antagonistes des récepteurs de l'adénosine a2a

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111362939A (zh) * 2020-04-26 2020-07-03 济南磐石医药科技有限公司 一种帕布昔利布母核结构化合物的制备方法

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