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WO2015157360A1 - Procédés pour produire des inhibiteurs de protéine kinase - Google Patents

Procédés pour produire des inhibiteurs de protéine kinase Download PDF

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Publication number
WO2015157360A1
WO2015157360A1 PCT/US2015/024820 US2015024820W WO2015157360A1 WO 2015157360 A1 WO2015157360 A1 WO 2015157360A1 US 2015024820 W US2015024820 W US 2015024820W WO 2015157360 A1 WO2015157360 A1 WO 2015157360A1
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isolating
pyridin
amino
phenyl
reacting
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Jeff M. KALLEMEYN
Yi-Yin Ku
Mathew M. Mulhern
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AbbVie Inc
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AbbVie Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • This invention pertains to processes to prepare compounds that inhibit protein kinases such as Aurora-kinases and the VEGFR and PDGFR families of kinases.
  • Novel compounds that inhibit protein kinases such as Aurora-kinases and the VEGFR and PDGFR families of kinases are described in, for example, U. S. Patent Publications 20050020619A1, 20050043347A1, 20050026944A1, 20070155776A1, 20100069371A1, 20070135387A1,
  • the present invention provides, among other things, a safe, efficient and cost-effective process for making compounds that inhibit protein kinases such as Aurora-kinases and the VEGFR and PDGFR families of kinases.
  • One aspect of this invention pertains to a process for making 2-(2-amino-5-bromopyridin-4- ylthio)-l -(4-aminophenyl)ethanone, comprising:
  • Another aspect of this invention pertains to 2-(2-amino-5-bromopyridin-4-ylthio)-l-(4- aminophenyl)ethanone, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • Another aspect of this invention pertains to a process for making l-(4-(4-amino-7- bromothieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea, comprising:
  • Another aspect of this invention pertains to l-(4-(4-amino-7-bromothieno[3,2-c]pyridin-3- yl)phenyl)-3-(3-fluorophenyl)urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • Another aspect of this invention pertains to a process for making A ⁇ -(4- ⁇ 4-amino-7-[l-(2- hydroxyethyl)-li7-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)urea, comprising:
  • Another aspect of this invention pertains to A ⁇ -(4- ⁇ 4-amino-7-[l-(2-hydroxyethyl)-li7- pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • Another aspect of this invention pertains to a process for making 2-(2-amino-5-bromopyridin- 4-ylthio)-l -(4-aminophenyl)ethanone, comprising:
  • Another aspect of this invention pertains to 2-(2-amino-5-bromopyridin-4-ylthio)-l-(4- aminophenyl)ethanone, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • Another aspect of this invention pertains to a process for making l-(4-(4-amino-7- bromothieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea, comprising:
  • Another aspect of this invention pertains to l-(4-(4-amino-7-bromothieno[3,2-c]pyridin-3- yl)phenyl)-3-(3-fluorophenyl)urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • Another aspect of this invention pertains to a process for making A ⁇ -(4- ⁇ 4-amino-7-[l-(2- hydroxyethyl)-li7-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)urea, comprising:
  • Another aspect of this invention pertains to A ⁇ -(4- ⁇ 4-amino-7-[l -(2-hydroxyethyl)-li7- pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • Another aspect of this invention pertains to a process for making 2-(2-aminopyridin-4-ylthio)-
  • Another aspect of this invention pertains to 2-(2-aminopyridin-4-ylthio)-l-(4- bromophenyl)ethanone, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • Another aspect of this invention pertains to a process for making (E)-N'-(3-(4-(3-(3- fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridin-4-yl)-N,N-dimethylformimidamide, comprising:
  • Another aspect of this invention pertains to (E)-N'-(3-(4-(3-(3- fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridm or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • Another aspect of this invention pertains to a process for making N-(4- ⁇ 4-amino-7-[l-(2- hydroxyethyl)-li7-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)iirea, comprising:
  • Another aspect of this invention pertains to A ⁇ -(4- ⁇ 4-amino-7-[l-(2-hydroxyethyl)-li7- pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • Another aspect of this invention pertains to a process for making 2-(2-aminopyridin-4-ylthio)- 1 -(4-bromophenyl)ethanone, comprising:
  • Another aspect of this invention pertains to 2-(2-aminopyridin-4-ylthio)-l-(4- bromophenyl)ethanone, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • Another aspect of this invention pertains to a process for making (E)-N'-(3-(4-(3-(3- fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridin-4-yl)-N,N-dimethylformimidamide, comprising:
  • Another aspect of this invention pertains to (E)-N'-(3-(4-(3-(3- fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridm ⁇ or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • Another aspect of this invention pertains to a process for making N-(4- ⁇ 4-amino-7-[l-(2- hydroxyethyl)-li7-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)urea, comprising:
  • Another aspect of this invention pertains to A ⁇ -(4- ⁇ 4-amino-7-[l -(2-hydroxyethyl)-li7- pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • Another aspect of this invention pertains to a compound selected from the group consisting of 2-(2-amino-5-bromopyridin-4-ylthio)-l -(4-aminophenyl)ethanone;
  • Compounds of this invention can have one or more than one asymmetrically substituted carbon atoms in the R or S configuration.
  • Compounds having asymmetrically substituted carbon atoms enriched with one configuration over the other are assigned the configuration which is present in the higher amount, preferably 85% to 95% enrichment, more preferably 95% to 99% enrichment, and still more preferably greater than 99% enrichment.
  • compounds of this invention can exist as enantiomers, mixtures of enantiomers, diastereomers having relative stereochemistry, diastereomers having absolute stereochemistry, diastereomers having at least one asymmetrically substituted carbon atom which is enriched in one configuration and at least one asymmetrically substituted carbon atom which is not enriched, and mixtures of the preceding.
  • Compounds of this invention can also have one or more than one carbon-carbon double bond or carbon-nitrogen double bond. Accordingly, compounds of this invention can exist as geometric isomers of either Z or E configuration or as mixtures of geometric isomers.
  • Acid addition salts of compounds are prepared by reaction with acid.
  • acid addition salts of compounds are prepared by reaction with acid.
  • acid for example, the acetate, adipate, alginate, bicarbonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, citrate, digluconate, formate, fumarate, glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate, propionate, succinate,
  • Base addition salts of compounds of this invention may be prepared by reaction with a base such as the hydroxide, carbonate, bicarbonate, phosphate, hydrogen phosphate, or dihydrogen phosphate of cations such as calcium, iron, lithium, potassium, sodium or magnesium.
  • a base such as the hydroxide, carbonate, bicarbonate, phosphate, hydrogen phosphate, or dihydrogen phosphate of cations such as calcium, iron, lithium, potassium, sodium or magnesium.
  • Isolating means separating a compound from a solvent, anti-solvent, or a mixture of solvent and anti-solvent to provide a solid, semisolid or syrup. This is typically accomplished by means such as centrifugation, filtration with or without vacuum, filtration under positive pressure, distillation, evaporation or a combination thereof. Isolating may or may not include purifying during which the chemical, chiral or chemical and chiral purity of the isolate is increased.
  • Purifying is typically conducted by means such as precipitation, crystallization, distillation, extraction, filtration through acidic, basic or neutral alumina, filtration through acidic, basic or neutral charcoal, column chromatography on a column packed with a chiral stationary phase, filtration through a porous paper, plastic or glass barrier, column chromatography on silica gel, ion exchange chromatography, recrystallization, normal-phase high performance liquid chromatography, reverse-phase high performance liquid chromatography, trituration and the like.
  • isolation or not isolating means that during the practice of this invention, it is optional to isolate a particular compound after each step prior to the next step. Such a decision can easily be made by one of ordinary skill in the art, based on stability, purity, solvent conditions of the next step, etc.
  • ABT-348 (A ⁇ -(4- ⁇ 4-amino-7-[l-(2-hydroxyethyl)-li7-pyrazol-4-yl]thieno[3,2-c]pyridin-3- yl ⁇ phenyl)-A ⁇ -(3-fluorophenyl)urea) is an orally bioavailable pan-Aurora/KDR inhibitor.
  • ABT-348 potently inhibits the tumor growth of a broad range of tumor models spanning both hematological malignancies and solid tumors (Bioorganic & Medicinal Chemistry Letters. 22. (2012): 3208-3212; Journal of Pharmacology and Experimental Therapeutics. 343.3 (2012): 617-27).
  • aminopyridinethiophene core which involves five chemical steps to prepare and requires harsh reaction conditions.
  • the starting material, 2,3-dibromothiophene is expensive and not readily available. Consequently, the cost of the core is very high, which contributes to the high cost and lengthy inefficient synthesis of ABT-348 and related compounds.
  • Process A reduces the number of steps from the current 9-step process to just 6 steps and more than doubles the overall yield (from 26% to 56%).
  • Another new process reduces the number of steps from the current 9-step process to just 8 steps overall and significantly increases the yield (from 26% to 45%).
  • One embodiment pertains to a process for making 2-(2-amino-5-bromopyridin-4-ylthio)-l-(4- aminophenyl)ethanone, comprising:
  • Another embodiment pertains to 2-(2-amino-5-bromopyridin-4-ylthio)-l-(4- aminophenyl)ethanone, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • Another embodiment pertains to the compound 2-(2-amino-5-bromopyridin-4-ylthio)-l -(4- aminophenyl)ethanone, or a pharmaceutically acceptable salt thereof.
  • Another embodiment pertains to 2-(2-amino-5-bromopyridin-4-ylthio)-l-(4- aminophenyl)ethanone, or a pharmaceutically acceptable salt thereof, for use in making ⁇ -(4- ⁇ 4- amino-7-[l-(2-hydroxyethyl)-li7-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3- fluorophenyl)urea, or a pharmaceutically acceptable salt thereof.
  • Another embodiment pertains to 2-(2-amino-5-bromopyridin-4-ylthio)-l-(4- aminophenyl)ethanone, or a pharmaceutically acceptable salt thereof, for use in making compounds such as those described in, for example, U. S. Patent Publications 20050020619A1, 20050043347A1, 20050026944A1, 20070155776A1, 20100069371A1, 20070135387A1, 20100144783A1, and 20120309783A1, and PCT Patent Publications WO2005/010009, WO2007/067781, and
  • One embodiment pertains to a process for making l-(4-(4-amino-7-bromothieno[3,2- c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea, comprising:
  • Another embodiment pertains to l-(4-(4-amino-7-bromothieno[3,2-c]pyridin-3-yl)phenyl)-3- (3-fluorophenyl)urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • Another embodiment pertains to the compound l-(4-(4-amino-7-bromothieno[3,2-c]pyridin- 3-yl)phenyl)-3-(3-fluorophenyl)urea, or a pharmaceutically acceptable salt thereof.
  • Another embodiment pertains to l-(4-(4-amino-7-bromothieno[3,2-c]pyridin-3-yl)phenyl)-3- (3-fluorophenyl)urea, or a pharmaceutically acceptable salt thereof, for use in making N-(4- ⁇ 4-amino- 7-[l-(2-hydroxyethyl)-l//-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)urea, or a pharmaceutically acceptable salt thereof.
  • Another embodiment pertains to l-(4-(4-amino-7-bromothieno[3,2-c]pyridin-3-yl)phenyl)-3- (3-fluorophenyl)urea, or a pharmaceutically acceptable salt thereof, for use in making compounds such as those described in, for example, U. S. Patent Publications 20050020619A1, 20050043347A1, 20050026944A1, 20070155776A1, 20100069371A1, 20070135387A1, 20100144783A1, and 20120309783A1, and PCT Patent Publications WO2005/010009, WO2007/067781, and
  • One embodiment pertains to a process for making N-(4- ⁇ 4-amino-7-[l-(24iydroxyethyl)-li7- pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)urea, comprising:
  • Another embodiment pertains to A ⁇ -(4- ⁇ 4-amino-7-[l-(2-hydroxyethyl)-li7-pyrazol-4- ylJthienofS ⁇ -cJpyridin-S-yllpheny ⁇ -A ⁇ -iS-fluoropheny ⁇ urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • Another embodiment pertains to the compound A ⁇ -(4- ⁇ 4-amino-7-[l-(2-hydroxyethyl)-li7- pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)urea, or a pharmaceutically acceptable salt thereof.
  • One embodiment pertains to a process for making 2-(2-amino-5-bromopyridin-4-ylthio)-l-(4- aminophenyl)ethanone, comprising:
  • Another embodiment pertains to 2-(2-amino-5-bromopyridin-4-ylthio)-l-(4- aminophenyl)ethanone, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making 3-(4-aminophenyl)-7-bromothieno[3,2- c]pyridin-4-amine, comprising:
  • Another embodiment pertains to 3-(4-aminophenyl)-7-bromothieno[3,2-c]pyridin-4-amine, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making l-(4-(4-amino-7-bromothieno[3,2- c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea, comprising:
  • Another embodiment pertains to l-(4-(4-amino-7-bromothieno[3,2-c]pyridin-3-yl)phenyl)-3- (3-fluorophenyl)urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making A ⁇ -(4- ⁇ 4-amino-7-[l-(2-hydroxyethyl)-li7- pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)urea, comprising:
  • Another embodiment pertains to A ⁇ -(4- ⁇ 4-amino-7-[l -(2-hydroxyethyl)-li7-pyrazol-4- yl]thieno[3,2-c]pyridin-3-yl ⁇ plienyl)-N-(3-fluoroplienyl)urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making A ⁇ -(4- ⁇ 4-amino-7-[l-(2-hydroxyethyl)-li7- pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)urea, comprising:
  • Another embodiment pertains to A ⁇ -(4- ⁇ 4-amino-7-[l -(2-hydroxyethyl)-li7-pyrazol-4- yl]thieno[3,2-c]pyridin-3-yl ⁇ plienyl)-N-(3-fluoroplienyl)urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • first bases useful for the practice of this invention are selected from the group consisting of potassium carbonate, sodium carbonate, sodium ethoxide, sodium hydroxide, triethylamine, and the like.
  • the first base useful for the practice of this invention is potassium carbonate.
  • second bases useful for the practice of this invention are selected from the group consisting of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, cesium flouride, sodium acetate, potassium acetate, triethylamine, potassium phosphate tribasic and the like.
  • second bases useful for the practice of this invention are selected from the group consisting of potassium hydroxide, potassium carbonate, sodium carbonate, and potassium phosphate tribasic.
  • the second base useful for the practice of this invention is potassium hydroxide.
  • first acids useful for the practice of this invention are selected from the group consisting of sulfuric acid, perchloric acid, hydrochloric acid, polyphosphoric acid, phosphoric acid, and the like. In another embodiment, first acids useful for the practice of this invention are selected from the group consisting of polyphosphoric acid, phosphoric acid, and the like. In another embodiment, the first acid useful for the practice of this invention is polyphosphoric acid.
  • first catalysts useful for the practice of this invention are selected from the group consisting of tetrakis(triphenylphosphine)palladium(0),
  • first catalysts useful for the practice of this invention are selected from the group consisting of tris(dibenzylideneacetone)dipalladium(0), bis(triphenylphosphine)palladium(II) dichloride, and palladium(II)acetate.
  • the first catalyst useful for the practice of this invention is palladium(II)acetate.
  • first ligands useful the practice of this invention are selected from the group consisting of 2-(dicyclohexylphosphino)biphenyl, l,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6- phosphaadamante, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), 1,1 '- bis( diphenylphosphanyl) ferrocene, and the like.
  • first ligands useful the practice of this invention are selected from the group consisting of l ,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa- 6-phosphaadamante and 1 ,1 '- bis( diphenylphosphanyl) ferrocene.
  • the first ligand useful the practice of this invention is l ,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8- pho sphaadamantane .
  • Step (a) is conducted for about 2 to about 6 hours in a solvent such as tetrahydrofuran, acetic acid, dichloromethane, acetonitrile, ⁇ , ⁇ -dimethylformamide, and the like or mixtures thereof. In one embodiment, Step (a) is conducted for about 2 to about 6 hours in N,N- dimethylformamide. In another embodiment, N-bromosuccinimide is added slowly to 4- chloropyridin-2-amine in Step (a).
  • a solvent such as tetrahydrofuran, acetic acid, dichloromethane, acetonitrile, ⁇ , ⁇ -dimethylformamide, and the like or mixtures thereof.
  • Step (a) is conducted for about 2 to about 6 hours in N,N- dimethylformamide.
  • N-bromosuccinimide is added slowly to 4- chloropyridin-2-amine in Step (a).
  • Step (b) is conducted for about 5 to about 25 hours in a solvent such as 7V-methyl-2-pyrrolidone, ethanol, water, and the like or mixtures thereof. In another embodiment, Step (b) is conducted for about 5 to about 25 hours in a solvent such as ethanol, water, or mixtures thereof.
  • Step (c) is conducted for about 2 to about 5 hours in a solvent such as ethanol, methanol, A ⁇ -methyl-2-pyrrolidone, water, tetrahydrofuran, and the like or mixtures thereof. In another embodiment, Step (c) is conducted for about 2 to about 5 hours in a solvent such as N- methyl-2-pyrrolidone, water, tetrahydrofuran, or mixtures thereof. In another embodiment, 2-amino- 5-bromopyridine-4-thiol is added slowly to l-(4-aminophenyl)-2-chloroethanone and, optionally, a first base in Step (c).
  • a solvent such as ethanol, methanol, A ⁇ -methyl-2-pyrrolidone, water, tetrahydrofuran, and the like or mixtures thereof.
  • Step (c) is conducted for about 2 to about 5 hours in a solvent such as N- methyl-2-pyrrolidone, water, tetrahydrofur
  • Step (d) is conducted for about 10 to about 30 hours, and may be conducted without a solvent.
  • Step (e) is conducted for about 0.5 to about 6 hours in a solvent such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl teri-butylether, ⁇ , ⁇ -dimethylformamide, and the like or mixtures thereof.
  • a solvent such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl teri-butylether, ⁇ , ⁇ -dimethylformamide, and the like or mixtures thereof.
  • 3-fluoroisocyanate is added slowly to 3-(4- aminophenyl)-7-bromothieno[3,2-c]pyridin-4-amine in Step (e).
  • 3- fluoroisocyanate is added slowly to a cooled solution of 3-(4-aminophenyl)-7-bromothieno[3,2- c]pyridin-4-amine in Step (e).
  • Step (f) is conducted for about 1 to about 8 hours in a solvent such as methanol, ethanol, benzene, ⁇ , ⁇ -dimethylformamide, tetrahydrofuran, toluene, dioxane, water, t- butanol, isopropyl alcohol, 1, 2 -dimethoxy ethane, and the like or mixtures thereof.
  • Step (f) is conducted for about 1 to about 8 hours in a solvent such as tetrahydrofuran, dioxane, water, 1,2 -dimethoxy ethane, or mixtures thereof.
  • One embodiment pertains to a process for making 2-(2-amino-5-bromopyridin-4-ylthio)-l-(4- aminophenyl)ethanone, comprising:
  • Another embodiment pertains to 2-(2-amino-5-bromopyridin-4-ylthio)-l-(4- aminophenyl)ethanone, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making l-(4-(4-amino-7-bromothieno[3,2- c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea, comprising:
  • Another embodiment pertains to l-(4-(4-amino-7-bromothieno[3,2-c]pyridin-3-yl)phenyl)-3- (3-fluorophenyl)urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making A ⁇ -(4- ⁇ 4-amino-7-[l-(2-hydroxyethyl)-li7- pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)urea, comprising:
  • Another embodiment pertains to A ⁇ -(4- ⁇ 4-amino-7-[l-(2-hydroxyethyl)-li7-pyrazol-4- ylJthienofS ⁇ -clpyridin-S-yllpheny ⁇ -A ⁇ -iS-fluoropheny ⁇ urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making 2-(2-amino-5-bromopyridin-4-ylthio)-l-(4- aminophenyl)ethanone, comprising:
  • Another embodiment pertains to 2-(2-amino-5-bromopyridin-4-ylthio)-l-(4- aminophenyl)ethanone, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making A ⁇ -(4- ⁇ 4-amino-7-[l-(2-hydroxyethyl)-li7- pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)urea, comprising:
  • Another embodiment pertains to A ⁇ -(4- ⁇ 4-amino-7-[l-(2-hydroxyethyl)-li7-pyrazol-4- ylJthienofS ⁇ -cJpyridin-S-yllpheny ⁇ -A ⁇ -iS-fluoropheny ⁇ urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making A ⁇ -(4- ⁇ 4-amino-7-[l-(2-hydroxyethyl)-li7- pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)urea, comprising: (c) reacting 2-amino-5-bromopyridine-4-thiol, l-(4-aminophenyl)-2-chloroethanone, and potassium carbonate to provide 2-(2-amino-5-bromopyridin-4-ylthio)-l-(4-aminophenyl)ethanone, and isolating or not isolating the 2-(2-amino-5-bromopyridin-4-ylthio)-l -(4-aminophenyl)ethanone;
  • Another embodiment pertains to A ⁇ -(4- ⁇ 4-amino-7-[l -(2-hydroxyethyl)-li7-pyrazol-4- ylJthienofS ⁇ -cJpyridin-S-yllpheny ⁇ -A ⁇ -iS-fluoropheny ⁇ urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making 2-(2-amino-5-bromopyridin-4-ylthio)-l-(4- aminophenyl)ethanone, comprising:
  • Another embodiment pertains to 2-(2-amino-5-bromopyridin-4-ylthio)-l-(4- aminophenyl)ethanone, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making l-(4-(4-amino-7-bromothieno[3,2- c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea, comprising: (a) reacting 4-chloropyridin-2 -amine and N-bromosuccinimide at about -10°C to about 30°C to provide 5-bromo-4-chloropyridin-2 -amine and isolating or not isolating the 5-bromo-4- chloropyridin-2-amine;
  • Another embodiment pertains to l-(4-(4-amino-7-bromothieno[3,2-c]pyridin-3-yl)phenyl)-3- (3-fluorophenyl)urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making A ⁇ -(4- ⁇ 4-amino-7-[l-(2-hydroxyethyl)-li7- pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)urea, comprising:
  • Another embodiment pertains to A ⁇ -(4- ⁇ 4-amino-7-[l -(2-hydroxyethyl)-li7-pyrazol-4- yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-N-(3-fluoroplienyl)urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making 2-(2-amino-5-bromopyridin-4-ylthio)-l-(4- aminophenyl)ethanone, comprising:
  • Another embodiment pertains to 2-(2-amino-5-bromopyridin-4-ylthio)-l-(4- aminophenyl)ethanone, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making 3-(4-aminophenyl)-7-bromothieno[3,2- c]pyridin-4-amine, comprising:
  • Another embodiment pertains to 3-(4-aminophenyl)-7-bromothieno[3,2-c]pyridin-4-amine, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making l-(4-(4-amino-7-bromothieno[3,2- c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea, comprising:
  • Another embodiment pertains to l-(4-(4-amino-7-bromothieno[3,2-c]pyridin-3-yl)phenyl)-3- (3-fluorophenyl)urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making A ⁇ -(4- ⁇ 4-amino-7-[l-(2-hydroxyethyl)-li7- pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)urea, comprising:
  • Another embodiment pertains to A ⁇ -(4- ⁇ 4-amino-7-[l -(2-hydroxyethyl)-li7-pyrazol-4- yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-N-(3-fluoroplienyl)urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making A ⁇ -(4- ⁇ 4-amino-7-[l-(2-hydroxyethyl)-li7- pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)urea, comprising:
  • Another embodiment pertains to A ⁇ -(4- ⁇ 4-amino-7-[l-(2-hydroxyethyl)-li7-pyrazol-4- yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-N-(3-fluorophenyl)urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making 2-(2-aminopyridin-4-ylthio)-l-(4- bromophenyl)ethanone, comprising:
  • Another embodiment pertains to 2-(2-aminopyridin-4-ylthio)-l-(4-bromophenyl)ethanone, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • Another embodiment pertains to the compound 2-(2-aminopyridin-4-ylthio)-l-(4- bromophenyl)ethanone, or a pharmaceutically acceptable salt thereof.
  • Another embodiment pertains to 2-(2-aminopyridin-4-ylthio)-l-(4-bromophenyl)ethanone, or a pharmaceutically acceptable salt thereof, for use in making A ⁇ -(4- ⁇ 4-amino-7-[l-(2-hydroxyethyl)- l//-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)urea, or a pharmaceutically acceptable salt thereof.
  • Another embodiment pertains to 2-(2-aminopyridin-4-ylthio)-l -(4-bromophenyl)ethanone, or a pharmaceutically acceptable salt thereof, for use in making compounds such as but not limited to those described in, for example, U. S. Patent Publications 20050020619A1, 20050043347A1, 20050026944A1, 20070155776A1, 20100069371A1, 20070135387A1, 20100144783A1, and 20120309783A1, and PCT Patent Publications WO2005/010009, WO2007/067781, and
  • One embodiment pertains to a process for making (E)-N'-(3-(4-(3-(3- fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridin-4-yl)-N,N-dimethylformimidamide, comprising:
  • Another embodiment pertains to (E)-N'-(3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2- c]pyridin-4-yl)-N,N-dimethylformimidamide, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • Another embodiment pertains to the compound (E)-N'-(3-(4-(3-(3- fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridin-4-yl)-N,N-dimethylformimidamide, or a pharmaceutically acceptable salt thereof.
  • Another embodiment pertains to (E)-N'-(3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2- c]pyridin-4-yl)-N,N-dimethylformimidamide, or a pharmaceutically acceptable salt thereof, for use in making A ⁇ -(4- ⁇ 4-amino-7-[l-(2-hydroxyethyl)-li7-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''- (3-fluorophenyl)urea, or a pharmaceutically acceptable salt thereof.
  • Another embodiment pertains to (E)-N'-(3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2- c]pyridin-4-yl)-N,N-dimethylformimidamide, or a pharmaceutically acceptable salt thereof, for use in making compounds such as but not limited to those described in, for example, U. S. Patent
  • One embodiment of this invention pertains to a process for making N-(4- ⁇ 4-amino- 7-[l-(2-hydroxyethyl)-li7-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)urea, comprising:
  • Another embodiment pertains to A ⁇ -(4- ⁇ 4-amino-7-[l-(2-hydroxyethyl)-li7-pyrazol-4- ylJthienofS ⁇ -cJpyridin-S-yllpheny ⁇ -A ⁇ -iS-fluoropheny ⁇ urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making 3-(4-bromophenyl)thieno[3,2-c]pyridin-4- amine, comprising:
  • Another embodiment pertains to 3-(4-bromophenyl)thieno[3,2-c]pyridin-4-amine, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making l-(4-(4-aminothieno[3,2-c]pyridin-3- yl)phenyl)-3 -(3 -fluorophenyl) urea, comprising:
  • Another embodiment pertains to l-(4-(4-aminothieno[3,2-c]pyridin-3-yl)phenyl)-3-(3- fluorophenyl) urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making (E)-N'-(3-(4-(3-(3- fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridin-4-yl)-N,N-dimethylformimidamide, comprising:
  • Another embodiment pertains to (E)-N'-(3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2- c]pyridin-4-yl)-N,N-dimethylformimidamide, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • third bases useful for the practice of this invention are selected from the group consisting of cesium carbonate, potassium hydroxide, sodium t-butoxide, lithium
  • third bases useful for the practice of this invention are selected from the group consisting of potassium phosphate tribasic, potassium carbonate, and the like. In another embodiment, the third base useful for the practice of this invention is cesium carbonate.
  • second catalysts useful for the practice of this invention are selected from the group consisting of tris(dibenzylideneacetone)dipalladium(0), [ ⁇ , - bis(diphenylphosphino)ferrocene]dichloropalladium(II), and palladium(II)acetate, dichloro [ ⁇ , bis(di-tert-butylphosphino)]ferrocene palladium(II), dichlorobis(p-dimethylamino
  • the second catalyst useful for the practice of this invention is tris(dibenzylideneacetone)dipalladium(0).
  • second ligands useful for the practice of this invention are selected from the group consisting of 5-(di-ieri-butylphosphino)-l', 3', 5'-triphenyl-l'i7-[l,4']bipyrazole, (2,2'- bis(diphenylphosphino)- 1 , 1 '-binaphthyl), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X- phos), (9,9-dimethyl-9H-xanthene-4,5-diyl)- bis[diphenyl phosphine], 4,5-bis(diphenylphosphino)- 9,9-dimethylxanthene, 2-dicyclohexylphosphino-2 '-(Af Af-dimethylamino)biphenyl (Davephos), racemic-2-di-t-buty
  • the second ligand useful for the practice of this invention is 5-(di-?er?-butylphosphino)- 1 ', 3', 5'-triphenyl-l'//-[l,4']bipyrazole.
  • second acids useful for the practice of this invention are selected from the group consisting of hydrochloric acid, sulfuric acid, and the like.
  • the second acid useful for the practice of this invention is hydrochloric acid.
  • first iodination agents useful for the practice of this invention are selected from the group consisting of iodine and N-iodosuccinimide. In another embodiment, the first iodination agent useful for the practice of this invention is iodine.
  • fourth bases useful for the practice of this invention are selected from the group consisting of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, cesium flouride, sodium acetate, potassium acetate, triethylamine, and the like.
  • fourth bases useful for the practice of this invention are selected from the group consisting of potassium hydroxide, potassium carbonate, sodium carbonate, potassium phosphate tribasic and the like.
  • the fourth base useful for the practice of this invention is potassium carbonate.
  • third catalysts useful for the practice of this invention are selected from the group consisting of tetrakis(triphenylphosphine)palladium(0),
  • third catalysts useful for the practice of this invention are selected from the group consisting of tris(dibenzylideneacetone)dipalladium(0), bis(triphenylphosphine)palladium(II) dichloride, and palladium(II)acetate, and the like.
  • the third catalyst useful for the practice of this invention is palladium(II) acetate.
  • third ligands useful for the practice of this invention are selected from the group consisting of 2-(dicyclohexylphosphino)biphenyl, l,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8- phosphaadamantane, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), 1,1'- bis( diphenylphosphanyl) ferrocene, and the like.
  • third ligands useful for the practice of this invention are selected from the group consisting of l,3,5,7-tetramethyl-6-phenyl-2,4,8- trioxa-6-phosphaadamante, 1,1'- bis( diphenylphosphanyl) ferrocene, and the like.
  • the third ligand useful for the practice of this invention is l,3,5,7-tetramethyl-8-phenyl- 2,4,6-trioxa-8-phosphaadamantane.
  • step (g) is conducted for about 2 to about 6 hours in a solvent such as but not limited to l-methyl-2-pyrrolidinone, H 2 0, tetrahydrofuran, ethanol, and the like or mixtures thereof. In another embodiment, step (g) is conducted for about 2 to about 6 hours in 1 -methyl-2- pyrrolidinone and H 2 0.
  • a solvent such as but not limited to l-methyl-2-pyrrolidinone, H 2 0, tetrahydrofuran, ethanol, and the like or mixtures thereof.
  • step (g) is conducted for about 2 to about 6 hours in 1 -methyl-2- pyrrolidinone and H 2 0.
  • step (h) is conducted for about 1 to about 4 hours in a solvent such as but not limited to A ⁇ -methyl-2-pyrrolidone, tetrahydrofuran, ethanol, water, and the like or mixtures thereof. In another embodiment, step (h) is conducted for about 1 to about 4 hours in 1 -methyl-2- pyrrolidinone and H 2 0.
  • a solvent such as but not limited to A ⁇ -methyl-2-pyrrolidone, tetrahydrofuran, ethanol, water, and the like or mixtures thereof.
  • step (h) is conducted for about 1 to about 4 hours in 1 -methyl-2- pyrrolidinone and H 2 0.
  • step (i) is conducted for about 3 to about 20 hours and may be conducted without a solvent. In another embodiment, step (i) is conducted for about 3 to about 20 hours without an additional solvent.
  • step (j) is conducted for about 10 to about 30 hours in a solvent such as but not limited to 1 ,2-dimethoxy ethane, 1 ,4-dioxane, toluene, and the like, or mixtures thereof. In another embodiment, step (j) is conducted for about 10 to about 30 hours in 1 ,2-dimethoxy ethane.
  • a solvent such as but not limited to 1 ,2-dimethoxy ethane, 1 ,4-dioxane, toluene, and the like, or mixtures thereof.
  • step (j) is conducted for about 10 to about 30 hours in 1 ,2-dimethoxy ethane.
  • step (k) is conducted for about 1 to about 4 hours in a solvent such as but not limited to 1,2 -dimethoxy ethane, 1,4-dioxane, toluene, and the like, or mixtures thereof. In another embodiment, step (k) is conducted for about 1 to about 4 hours in 1,2-dimethoxyethane.
  • a solvent such as but not limited to 1,2 -dimethoxy ethane, 1,4-dioxane, toluene, and the like, or mixtures thereof.
  • step (k) is conducted for about 1 to about 4 hours in 1,2-dimethoxyethane.
  • step (1) is conducted for about 2 to about 20 hours in a solvent such as methanol, 1,2-dimethoxyethane, ⁇ , ⁇ -dimethylformamide, water, ethanol, and the like, or mixtures thereof. In another embodiment, step (1) is conducted for about 2 to about 20 hours in methanol.
  • a solvent such as methanol, 1,2-dimethoxyethane, ⁇ , ⁇ -dimethylformamide, water, ethanol, and the like, or mixtures thereof.
  • step (1) is conducted for about 2 to about 20 hours in methanol.
  • step (m) is conducted for about 1 to about 10 hours in a solvent such as tetrahydrofuran, pyridine, N,N-dimethylformamide, ⁇ , ⁇ -dimethylacetamide, 1 -methyl-2- pyrrolidinone, and the like, or mixtures thereof. In another embodiment, step (m) is conducted for about 1 to about 10 hours in tetrahydrofuran and pyridine.
  • a solvent such as tetrahydrofuran, pyridine, N,N-dimethylformamide, ⁇ , ⁇ -dimethylacetamide, 1 -methyl-2- pyrrolidinone, and the like, or mixtures thereof.
  • step (m) is conducted for about 1 to about 10 hours in tetrahydrofuran and pyridine.
  • step (n) is conducted for about 1 to about 8 hours in a solvent such as tetrahydrofuran, water, 1,4-dioxane, 1,2-dimethoxyethane, and the like, or mixtures thereof. In another embodiment, step (n) is conducted for about 1 to about 8 hours in tetrahydrofuran and water.
  • a solvent such as tetrahydrofuran, water, 1,4-dioxane, 1,2-dimethoxyethane, and the like, or mixtures thereof.
  • step (n) is conducted for about 1 to about 8 hours in tetrahydrofuran and water.
  • One embodiment pertains to a process for making (E)-N'-(3-(4-(3-(3- fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridin-4-yl)-N,N-dimethylformimidamide, comprising:
  • [1 ,4']bipyrazole to provide (E)-N'-(3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridin-4-yl)- ⁇ , ⁇ -dimethylformimidamide, and isolating or not isolating the (E)-N'-(3-(4-(3-(3- fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridin-4-yl)-N,N-dimethylformimidamide.
  • Another embodiment pertains to (E)-N'-(3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2- c]pyridin-4-yl)-N,N-dimethylformimidamide, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making A ⁇ -(4- ⁇ 4-amino-7-[l-(2-hydroxyethyl)-li7- pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)urea, comprising:
  • Another embodiment pertains to A ⁇ -(4- ⁇ 4-amino-7-[l-(2-hydroxyethyl)-li7-pyrazol-4- ylJthienofS ⁇ -clpyridin-S-yllpheny ⁇ -A ⁇ -iS-fluoropheny ⁇ urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making l-(4-(4-aminothieno[3,2-c]pyridin-3- yl)phenyl)-3 -(3 -fluorophenyl) urea, comprising:
  • Another embodiment pertains to l-(4-(4-aminothieno[3,2-c]pyridin-3-yl)phenyl)-3-(3- fluorophenyl) urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making (E)-N'-(3-(4-(3-(3- fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridin-4-yl)-N,N-dimethylformimidamide, comprising:
  • Another embodiment pertains to (E)-N'-(3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2- c]pyridin-4-yl)-N,N-dimethylformimidamide, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making 2-(2-aminopyridin-4-ylthio)-l-(4- bromophenyl)ethanone, comprising:
  • Another embodiment pertains to 2-(2-aminopyridin-4-ylthio)-l-(4-bromophenyl)ethanone, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making (E)-N'-(3-(4-(3-(3- fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridin-4-yl)-N,N-dimethylformimidamide, comprising:
  • Another embodiment pertains to (E)-N'-(3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2- c]pyridin-4-yl)-N,N-dimethylformimidamide, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making A ⁇ -(4- ⁇ 4-amino-7-[l-(2-hydroxyethyl)-li7- pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)urea, comprising:
  • Another embodiment pertains to A ⁇ -(4- ⁇ 4-amino-7-[l -(2-hydroxyethyl)-li7-pyrazol-4- yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-N-(3-fluorophenyl)urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making 3-(4-bromophenyl)thieno[3,2-c]pyridin-4- amine, comprising:
  • Another embodiment pertains to 3-(4-bromophenyl)thieno[3,2-c]pyridin-4-amine, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making l-(4-(4-aminothieno[3,2-c]pyridin-3- yl)phenyl)-3 -(3 -fluorophenyl) urea, comprising:
  • Another embodiment pertains to l-(4-(4-aminothieno[3,2-c]pyridin-3-yl)phenyl)-3-(3- fluorophenyl) urea, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • One embodiment pertains to a process for making (E)-N'-(3-(4-(3-(3- fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridin-4-yl)-N,N-dimethylformimidamide, comprising:
  • Another embodiment pertains to (E)-N'-(3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2- c]pyridin-4-yl)-N,N-dimethylformimidamide, or a pharmaceutically acceptable salt thereof, prepared as described in the preceding embodiment.
  • ADDP means
  • AD-mix- ⁇ means a mixture of (DHQD) 2 PHAL, K 3 Fe(CN) 6 , K 2 CO 3 , and K 2 SO 4 ;
  • DIBAL diisobutylaluminum hydride
  • DIEA diisopropylethylamine
  • DMAP N,N-dimethylaminopyridine
  • DMF means
  • dmpe means l,2-bis(dimethylphosphino)ethane
  • DMSO means dimethylsulfoxide
  • dppb means l,4-bis(diphenylphosphino)-butane
  • dppe means 1,2- bis(diphenylphosphino)ethane
  • dppf means l,l'-bis(diphenylphosphino)ferrocene
  • dppm means l,l-bis(diphenylphosphino)methane
  • EDAC HCl means l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride
  • Fmoc means fluorenylmethoxycarbonyl
  • HATU means 0-(7- azabenzotriazol-l-yl)-N,N'N'N'-tetramethyluronium hexafluorophosphate
  • HMPA means he
  • TEA triethylammonium methylpolystyrene cyanoborohydride
  • TFA triethylamine
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • NCS N-chlorosuccinimide
  • NMM N-methylmorpholine
  • NMP N-methylpyrrolidine
  • PPh 3 triphenylphosphine.
  • Scheme 1 shows Process A for preparing A ⁇ -(4- ⁇ 4-amino-7-[l-(2-hydroxyethyl)-li7-pyrazol 4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)urea (10).
  • 5-Bromo-4-chloropyridin-2- amine (2) can be prepared by reacting 4-chloropyridin-2-amine (1) with N-bromosuccinimide, optionally in the presence of an acid such as but not limited to acetic acid. The reaction is typically performed at low temperature in a solvent such as but not limited to tetrahydrofuran.
  • 5-Bromo-4- chloropyridin-2 -amine (2) can be treated with sodium hydrogen sulfide hydrate to provide 2-amino- bromopyridine-4-thiol (3).
  • the reaction is typically performed at elevated temperature in a solvent such as but not limited to 1 -methyl-2-pyrrolidinone.
  • 2-Amino-5-bromopyridine-4-thiol (3) can be reacted with a mixture of l-(4-aminophenyl)-2-chloroethanone (4) and potassium carbonate to provide 2-(2-amino-5-bromopyridin-4-ylthio)-l-(4-aminophenyl)ethanone (5).
  • 3-(4- Aminophenyl)-7-bromothieno[3,2-c]pyridin-4-amine (6) can be prepared by reacting 2-(2-amino-5- bromopyridin-4-ylthio)-l-(4-aminophenyl)ethanone (5) with polyphosphoric acid. The reaction is typically performed at an elevated temperature.
  • 3-(4-Aminophenyl)-7-bromothieno[3,2-c]pyridin-4- amine (6) can be treated with 3-fluoroisocyanate (7) to provide l-(4-(4-amino-7-bromothieno[3,2- c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea (8).
  • the reaction is typically performed at low temperature in a solvent such as but not limited to tetrahydrofuran.
  • the coupling reaction may be conducted in the presence of a palladium catalyst and a base, and optionally in the presence of a ligand, and in a suitable solvent at elevated temperature (about 50°C to about 150°C).
  • the reaction may be facilitated by microwave irradiation.
  • the palladium catalyst include, but are not limited to, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0),
  • Suitable bases include, but are not limited to, carbonates or phosphates of sodium, potassium, and cesium, acetates of sodium or potassium, potassium hydroxide, and cesium fluoride.
  • Suitable ligands include, but are not limited to, 2-(dicyclohexylphosphino)biphenyl, l ,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante, 2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl (X-phos), and 1 ,1'- bis( diphenylphosphanyl) ferrocene.
  • Non-limiting examples of suitable solvent include methanol, ethanol, dimethoxy ethane, N,N-dimethylformamide, dimethylsulfoxide, dioxane, tetrahydropyfuran, and water, or mixtures thereof.
  • Scheme 2 shows Process B for preparing N-(4- ⁇ 4-amino-7-[l -(2 -hy droxy ethyl)- li7-pyrazol- 4-yl]thieno[3,2-c]pyridin-3-yl ⁇ phenyl)-A''-(3-fluorophenyl)urea (10).
  • 2-Aminopyridine-4-thiol (11) can be prepared by reacting 4-chloropyridin-2-amine (1) with sodium hydrogen sulfide. The reaction is typically performed at an elevated temperature in a solvent such as but not limited to l-methyl-2- pyrrolidinone, H 2 0, or mixtures thereof.
  • 2-Aminopyridine-4-thiol (11) can be reacted with 2-bromo- 1 -(4-bromophenyl)ethanone (12) to provide 2-(2-aminopyridin-4-ylthio)-l-(4-bromophenyl)ethanone (13).
  • the reaction is typically performed at an ambient temperature in a solvent such as but not limited to 1 -methyl-2-pyrrolidinone.
  • 3-(4-Bromophenyl)thieno[3,2-c]pyridin-4-amine (14) can be prepared by reacting 2-(2-aminopyridin-4-ylthio)-l-(4-bromophenyl)ethanone (13) with polyphosphoric acid.
  • the reaction is typically performed at an elevated temperature.
  • 3-(4- Bromophenyl)thieno[3,2-c]pyridin-4-amine (14) can be treated with N,N-dimethylformamide dimethyl acetal to provide (E)-N'-(3-(4-bromophenyl)thieno[3,2-c]pyridin-4-yl)-N,N- dimethylformimidamide (15).
  • the reaction is typically performed at an elevated temperature in a solvent such as but not limited to 1 ,2-dimethoxyethane.
  • a mixture of l-(3-fluorophenyl)urea (16), a catalyst such as but not limited to tris(dibenzylideneacetone)dipalladium(0), a ligand such as but not limited to 5-(di-ieri-butylphosphino)-l ', 3', 5'-triphenyl-l'i7-[l,4']bipyrazole, and a base such as but not limited to cesium carbonate can be reacted with (E)-N'-(3-(4-bromophenyl)thieno[3,2-c]pyridin-4- yl)-N,N-dimethylformimidamide (15) to provide (E)-N'-(3-(4-(3-(3- fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridin-4-yl)-N,N-dimethylformimidamide (17).
  • a catalyst such as but not
  • the reaction is typically performed at an elevated temperature in a solvent such as but not limited to 1 ,2- dimethoxyethane.
  • a solvent such as but not limited to 1 ,2- dimethoxyethane.
  • (E)-N'-(3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridin-4-yl)-N,N- dimethylformimidamide (17) can be treated with an acid such as but not limited to hydrochloric acid to provide l-(4-(4-aminothieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl) urea (18).
  • the reaction is typically performed at an elevated temperature in a solvent such as but not limited to methanol.
  • 1- (4-(4-Aminothieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl) urea (18) can be treated with iodine in the presence of a base such as but not limited to pyridine to provide 1 -(4-(4-amino-7- iodothieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea (19).
  • the reaction is typically performed at an elevated temperature in a solvent such as but not limited to tetrahydrofuran.
  • H 2 0 200 mL
  • 50% aqueous NaOH 27 g
  • toluene 200 mL
  • the layers were warmed to room temperature, separated and the aqueous layer was extracted with toluene (200 mL).
  • the combined organic layers were washed with sodium thiosulfate (10 g) dissolved in 8% aqueous NaHC0 3 (200 mL) then with 25% aqueous NaCl (200 mL).
  • the organic layer was concentrated to dryness and chased with toluene (100 mL).
  • N 2 inlet was added 5-bromo-4-chloropyridin-2 -amine (25 g, 121 mmol) and sodium hydrogen sulfide hydrate (26.5 g, 362 mmol).
  • the flask was evacuated and purged with N 2 three times.
  • N 2 sparged l-methyl-2-pyrrolidinone 250 mL was added.
  • the green suspension was heated to 70 °C for 17 hours.
  • the suspension was cooled to room temperature.
  • a cooled bleach scrubber containing 750 mL of bleach was installed and to the suspension concentrated HCl (24.90 mL, 301 mmol) was added. Gas evolution was noted.
  • the resulting dark brown/red suspension was sparged with N 2 for 30 minutes.
  • a solution of 30%o aqueous KOH (500 g) was then added while maintaining the temperature between 50-60 °C.
  • the solution was cooled to 45 °C and tetrahydrofuran (700 mL) and 30% aqueous KOH (450 g) while maintaining an internal temperature below 50 °C.
  • the mixture was cooled to 30 °C.
  • the upper organic layer was stirred with activated carbon (3 g) for 45 minutes. The carbon was removed by filtration through diatomaceous earth and rinsed with tetrahydrofuran (100 mL).
  • the tetrahydrofuran layer was concentrated to 200 g, diluted with methanol (350 mL) and concentrated to 210 g.
  • the flask was equipped with an overhead stirrer, reflux condenser and N 2 inlet and was sparged three times with vacuum/N 2 .
  • a sparged solution of tetrahydrofuran/H 2 0 (5/1 , 400 mL) was added and reaction was heated to reflux under N 2 .
  • Additional palladium(II) acetate 0.035 g, 0.156 mmol
  • 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazol-l-yl)ethanol (3.0 g, 12.6 mmol) was added to bring the reaction to completion.
  • the reaction mixture was cooled to 35 °C and H 2 0 (330 mL) was added. The mixture was cooled to 20 °C and stirred for 30 minutes. The solid was collected by vacuum filtration and was washed with H 2 0 (140 mL). The wet solid was transferred back to the 1L round bottomed flask and methanol (550 mL) was added. The mixture was heated to 55 °C and 1M aqueous KOH (100 mL) was added. The resulting cloudy solution was stirred at 55 °C for 5 minutes and H 2 0 (150 mL) was added. The mixture was cooled to 10 °C for 1 hour.
  • the solid was collected by vacuum filtration and washed with 1/1 1,2- dimethoxyethane/H 2 0 (50 mL).
  • the wet solid was transferred to a 500 mL round bottom flask and diluted with 1,2 -dimethoxy ethane (220 mL) and ethanol (30 mL). This mixture was heated to 70 °C. After 20 minutes, additional 1,2 -dimethoxy ethane (40 mL) was added followed by H 2 0 (150 mL). The mixture was cooled in an ice bath.
  • the flask was equipped with a magnetic stirrer, reflux condenser and N 2 inlet and was sparged three times with vacuum/N 2 .
  • a sparged solution of KOH (1.335 g, 23.80 mmol) in tetrahydrofuran/H 2 0 (5/1 , 120mL) was added.
  • the reaction mixture was heated to reflux under N 2 .
  • the reaction was cooled to room temperature and transferred to a 500 mL separatory funnel with tetrahydrofuran (120 mL).
  • the mixture was washed with an aqueous solution of 7% cysteine and 7%> K 2 C0 3 (2 x 65 g).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention concerne des procédés pour préparer des composés qui inhibent les protéines kinases telles que les kinases d'Aurora et les familles de kinases de des familles VEGFR et PDGFR.
PCT/US2015/024820 2014-04-08 2015-04-08 Procédés pour produire des inhibiteurs de protéine kinase Ceased WO2015157360A1 (fr)

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CN107417625A (zh) * 2017-07-10 2017-12-01 广州博氧医药科技有限公司 高纯度2‑巯基嘧啶的制备方法及其制得的2‑巯基嘧啶

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