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WO2003080621A1 - Procede de preparation et produits intermediaires d'imidazopyrimidines substituees - Google Patents

Procede de preparation et produits intermediaires d'imidazopyrimidines substituees Download PDF

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Publication number
WO2003080621A1
WO2003080621A1 PCT/US2003/008301 US0308301W WO03080621A1 WO 2003080621 A1 WO2003080621 A1 WO 2003080621A1 US 0308301 W US0308301 W US 0308301W WO 03080621 A1 WO03080621 A1 WO 03080621A1
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WO
WIPO (PCT)
Prior art keywords
fluoro
compound
reaction
trifluoromethyl
represents hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2003/008301
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English (en)
Inventor
Wenjie Li
Dongwei Cai
R. Scott Hoerrner
Mark S. Jensen
Robert D. Larsen
Nicos A. Petasis
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Priority to AU2003223295A priority Critical patent/AU2003223295A1/en
Publication of WO2003080621A1 publication Critical patent/WO2003080621A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/05—Cyclic compounds having at least one ring containing boron but no carbon in the ring

Definitions

  • the present invention discloses a novel process for the preparation of imidazo[l,2- ⁇ ]pyrimidines which are substituted at the 3-position of the bicyclic ring system with a substituted chlorophenyl group. These compounds represent useful intermediates in the synthesis of ligands for GABA A receptors for the treatment of a variety of deleterious mental disorders.
  • the present invention provides an efficient process for the preparation of irmdazo[l,2- ⁇ ]pyrimidines of structural formula I,
  • R 1 represents hydrogen, 2-hydroxyprop-2-yl, or trifluoromethyl
  • X 1 represents fluoro, methyl, trifluoromethyl, or methoxy
  • X 2 represents hydrogen or fluoro.
  • the compounds are intermediates in the synthesis of ligands for GABA A receptors which are useful in the treatment of a variety of deleterious mental disorders, such as anxiety disorders.
  • the present invention also provides novel intermediates which are derived from the instant process.
  • the compounds of formula I are produced in an efficient manner via a palladium-catalyzed coupling (Heck) of a compound of structural formula II with a substituted bromochlorobenzene or chloroiodobenzene of structural formula III:
  • the derived 3-(3-chlorophenyl)-imidazo[l,2- ]pyrimidines of formula I can be further elaborated into the desired GABA A ligands of structural formula IV via a Suzuki cross-coupling reaction with an aryl or heteroarylboronic acid Z-B(OH)2 or a Stille cross-coupling reaction with an aryl or heteroarylstannane Z-SnR3,
  • Z represents 2-cyanophenyl, 2-cyano-4-fluorophenyl, pyridin-2-yl, pyridin-3- yl, or 3-cyanopyridin-2-yl.
  • This invention is concerned with a process for the preparation of 3-(3- chlorophenyl)-imidazo[l,2 ⁇ ]pyrimidines of formula I and useful intermediates obtained from that process.
  • the process utilizes a regioselective palladium-catalyzed Heck-type phenylation of the C-3 position of a 7-substituted imidazo[l,2- ⁇ ]pyrimidine of structural formula II with an optionally substituted bromochlorobenzene or chloroiodobenzene of structural formula III to generate the compounds of formula I:
  • Compounds of formula I are useful intermediates in the synthesis of ligands of GABA A receptors which can be used to treat a variety of deleterious mental disorders, such as anxiety disorders.
  • R 1 represents hydrogen, 2-hydroxyprop-2-yl, or trifluoromethyl
  • X 1 represents fluoro, methyl, trifluoromethyl, or methoxy
  • X" represents hydrogen or fluoro
  • R 1 represents 2-hydroxyprop-2-yl
  • X 1 represents fluoro
  • X 2 represents hydrogen
  • the process of the present invention features a regioselective C-3 phenylation of a 7-substituted imidazo[l,2- ⁇ ]pyrimidine with an optionally substituted bromochlorobenzene or chloroiodobenzene.
  • a chloro substituent on the C-3 phenyl group provides a reactive handle for further chemical manipulation which allows for the introduction of an optionally substituted phenyl or heteroaryl group via a palladium-catalyzed cross-coupling reaction with a phenyl- or heteroarylboronic acid (Suzuki raction) or with a phenyl- or heteroarylstannane (Stille reaction).
  • the intermediates of structural formula II may be prepared by reacting a compound of formula VII with 2-aminoimidazole VUI, in particular, the sulfate salt thereof: wherein R 1 is as defined above and Alk represents Ci-6 alkyl.
  • the reaction to form intermediates II is conveniently effected by heating the reactants VII and VIII under basic conditions in a suitable solvent B, for example, a lower alkoxide such as sodium methoxide or ethoxide in a lower alkanol, such as methanol or ethanol, typically at the reflux temperature of the solvent.
  • a suitable solvent B for example, a lower alkoxide such as sodium methoxide or ethoxide in a lower alkanol, such as methanol or ethanol, typically at the reflux temperature of the solvent.
  • the phenylation of II with in is effected in a suitable reaction solvent in the presence of a palladium catalyst, a base, and a phosphine ligand.
  • the phosphine ligand is selected from the group consisting of DPPF, triphenylphosphine, tri( ⁇ ?-tolyl)phosphine, tri-tert-butyl- phosphine, DPPE, and DPPP.
  • the phosphine ligand is triphenylphosphine.
  • Palladium catalysts which may be used in the phenylation reaction include a palladium alkanoate, a palladium acetonate, a palladium halide, a palladium halide complex, a palladium-dibenzylidene acetone complex, and a triarylphosphine palladium complex.
  • the palladium catalyst is selected from the group consisting of Pd(II) acetate, Pd(II) acetylacetonate, Pd(II) bromide, Pd(II) chloride, Pd(II) iodide, Pd(II) sulfate, Pd(II) trifluoroacetate, Pd(II) Cl2(CH3CN)2, Pd2(dba)3, Pd(dba)2, Pd(dppf)Cl2, PdCl2(PPh3)2, Pd(PPh3)4, and Pd(II)Cl2(PhCN)2.
  • the palladium catalyst is Pd(H) acetate.
  • the phenylation reaction is carried out in a suitable solvent, such as THF, benzene, toluene, 1,4-dioxane, DME, DMSO, DMF, DMAC, and NMP, or a mixture of these solvents, such as TBDF/DMF.
  • a suitable solvent such as THF, benzene, toluene, 1,4-dioxane, DME, DMSO, DMF, DMAC, and NMP, or a mixture of these solvents, such as TBDF/DMF.
  • the reaction solvent is anhydrous.
  • the reaction solvent is anhydrous DMF or anhydrous 1,4-dioxane. Exclusion of water from the reaction mixture minimizes contamination with the C-2 phenyl regioisomer V.
  • the reaction is carried out in the presence of a base.
  • the base is an inorganic base selected from the group consisting of sodium carbonate, potassium carbonate, and cesium carbonate In one embodiment, the base is powdered cesium carbonate.
  • the reaction is performed at a temperature of about 50 °C to about 125 °C. In one embodiment of the process, the reaction is performed at a temperature of about 60 °C to about 100 °C.
  • Another aspect of the present invention is concerned with novel compounds of structural formula I which are derived from the instant process:
  • R 1 represents hydrogen, 2-hydroxyprop-2-yl, or trifluoromethyl
  • X 1 represents fluoro, methyl, trifluoromethyl, or methoxy
  • X 2 represents hydrogen or fluoro.
  • the derived 3-(3-chlorophenyl)-imidazo[l,2- ]pyrimidines of formula I can be further chemically elaborated into the desired GABA A ligands of structural formula IV via a palladium-catalyzed Suzuki cross-coupling reaction with an aryl or heteroarylboronic acid Z-B(OH) 2 or a Stille cross-coupling reaction with an aryl or heteroarylstannane Z-SnR 3 .
  • compound IX (IV wherein R 1 represents 2- hydroxyprop-2-yl, X 1 represents fluoro, X 2 represents hydrogen, and Z represents pyridin-3 -yl) can be prepared as shown below by Suzuki cross-coupling of the compound of formula VI with 3-pyridine boronic acid:
  • the 3-pyridineboronic acid may be prepared by a novel "in situ quench” procedure in high yield and purity from commercially available 3- bromopyridine.
  • This approach consists of addition of an alkyl lithium, such as n- butyl lithium, to a solution of 3-bromopyridine and trialkyl borate, such as triisopropyl borate.
  • This method is superior to that wherein the alkyllithium is added to a solution of the aryl halide and the resulting aryllithium is quenched with the trialkyl borate or the "reverse" addition procedure wherein the aryl halide is added to a solution of the alkyl lithium followed by addition of the alkyl borate.
  • the present "in situ quench" procedure proved to be temperature- tolerant with yields of 90-95% at -40 °C and about 80% at 0 °C.
  • the product was isolated in the form of the crystalline boroxine 1-8.
  • ACN is acetonitrile
  • AcOH is acetic acid
  • BuLi is n- butyl lithium
  • CH2CI dichloromethane
  • CS2CO3 is cesium carbonate
  • dba is dibenzylideneacetone
  • DIEA is diisopropylethylamine
  • DMAC is N,N- dimethylacetamide
  • DMAP is 4-dimethylaminopyridine
  • DME is 1,2- dimethoxyethane
  • DMF is N,N-dimethylformamide
  • DMPU is 1, 3-dimethyl-3, 4,5,6- tetrahydro-2(lH)-pyrimidinone
  • DMSO is dimethyl sulfoxide
  • DPPE is diphenylphosphinoethane
  • DPPF is diphenylphosphinoferrocene
  • DPPP is diphenylphosphinopropane
  • EtOAc is ethyl acetate
  • the filtrate was concentrated to about 200 mL by rotary evaporation, then 300 mL of EtOAc was added and the mixture was concentrated to about 300 mL. This was repeated three times with crystals forming during the process.
  • the final slurry was diluted to 600 mL with EtOAc and then cooled to 5 °C with stirring. The solids were collected on a frit, rinsed with cold EtOAc (50 mL) and dried overnight under vacuum at 22 °C to provide 1 ⁇ 5 (79 g) as a crystalline solid.
  • the mixture was cooled to 60 °C then water (150 mL) and EtOAc (150 mL) were added to the crude reaction mixture and the slurry was stirred at 45 °C until all of the solids were dissolved.
  • the layers were partitioned and the aqueous phase was extracted again with EtOAc (50 mL).
  • the organic phases were combined and extracted twice with 2N HC1 (100 mL then 30 mL).
  • the phases were separated and the organic phase was concentrated to about 200 mL to provide a slurry.
  • the warm catalyst solution was cannulated to the 5 L flask and the resulting mixture was stirred at 70 °C for 16 h. At the end of reaction, most of the product had crystallized out to provide a grey slurry.
  • the reaction mixture was partitioned between 2N HCl (1.8 L) and toluene (0.9 L). The clear yellow aqueous phase was transferred to a stirred 4 L Erlenmeyer flask with a nitrogen sweep and borane trimethylamine complex (1.87 g) was added. After 90 min the resulting black solids were removed by filtration through a l.O ⁇ filter. The filtrate was transferred to a mechanically stirred 5L flask equipped with a pH probe.
  • the pH was adjusted to 3.8 by slow addition of 50 wt% NaOH (about 130 mL).
  • the mixture self nucleated to provide a slurry.
  • Additional 50 wt% NaOH (about 36 mL) was added over 30 min to pH 7.1 to provide a cream colored slurry.
  • the solids were collected on a frit, washed with water (250 mL) and air dried to give the free base L9 as an off-white crystalline solid (117.38 g, 94.5 wt% pure); m.p. 234 - 236 °C.
  • the resulting clear solution was transferred to a mechanically stirred 3 L round-bottomed-flask equipped with a reflux condenser. The solution was warmed to 75 °C and isopropyl acetate (1.00 L) was added. During the isopropyl acetate addition, the solution self-nucleated to provide a white suspension which was cooled over several hours to room temperature. The solids were collected on a frit, rinsed with 1:1 EtOH/isopropyl acetate (100 mL) then dried in a 60 °C vacuum oven to provide the bis HCl salt as colorless crystals (26.76 g); m.p. 241- 250 °C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne un nouveau procédé de préparation d'imidazo[1,2-a]pyrimidines, substituées en position 3 par un groupe chlorophényle substitué. Ces composés s'utilisent dans la synthèse de ligands du récepteur GABAA dans le traitement de troubles mentaux délétères. Ladite invention concerne également des produits intermédiaires obtenus à partir dudit procédé et utilisés dans la synthèse de ligands du récepteur GABAA.
PCT/US2003/008301 2002-03-19 2003-03-17 Procede de preparation et produits intermediaires d'imidazopyrimidines substituees Ceased WO2003080621A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003223295A AU2003223295A1 (en) 2002-03-19 2003-03-17 Process and intermediates to substituted imidazopyrimidines

Applications Claiming Priority (2)

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US36563002P 2002-03-19 2002-03-19
US60/365,630 2002-03-19

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WO2003080621A1 true WO2003080621A1 (fr) 2003-10-02

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7767675B2 (en) 2006-11-22 2010-08-03 Incyte Corporation Imidazotriazines and imidazopyrimidines as kinase inhibitors
US7915408B2 (en) 2006-08-07 2011-03-29 Incyte Corporation Triazolotriazines as kinase inhibitors
US8420645B2 (en) 2008-05-21 2013-04-16 Incyte Corporation Salts of 2-fluoro-N-methyl-4-[7-(quinolin-6-yl-methyl)-imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same
US8487096B2 (en) 2010-02-03 2013-07-16 Incyte Corporation Imidazo[1,2-B][1,2,4]triazines as C-MET inhibitors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001043978A (ja) * 1999-07-29 2001-02-16 Mitsui Chemicals Inc 有機電界発光素子

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001043978A (ja) * 1999-07-29 2001-02-16 Mitsui Chemicals Inc 有機電界発光素子

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7915408B2 (en) 2006-08-07 2011-03-29 Incyte Corporation Triazolotriazines as kinase inhibitors
US8143251B2 (en) 2006-08-07 2012-03-27 Incyte Corporation Triazolotriazines as kinase inhibitors
US9944645B2 (en) 2006-11-22 2018-04-17 Incyte Corporation Imidazotriazines and imidazopyrimidines as kinase inhibitors
US10738052B2 (en) 2006-11-22 2020-08-11 Incyte Holdings Corporation Imidazotriaines and imidazopyrimidines as kinase inhibitors
US7767675B2 (en) 2006-11-22 2010-08-03 Incyte Corporation Imidazotriazines and imidazopyrimidines as kinase inhibitors
US12084449B2 (en) 2006-11-22 2024-09-10 Incyte Holdings Corporation Imidazotriazines and imidazopyrimidines as kinase inhibitors
US11261191B2 (en) 2006-11-22 2022-03-01 Incyte Holdings Corporation Imidazotriaines and imidazopyrimidines as kinase inhibitors
US12427154B2 (en) 2008-05-21 2025-09-30 Incyte Holdings Corporation Salts of 2-fluoro-n-methyl-4-[7-(quinolin-6-yl-methyl)-imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same
US8901123B2 (en) 2008-05-21 2014-12-02 Incyte Corporation Salts of 2-fluoro-N-methyl-4-[7-(quinolin-6-yl-methyl)-imidazo[1,2-B][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same
US10245265B2 (en) 2008-05-21 2019-04-02 Incyte Incorporation Salts of 2-fluoro-N-methyl-4-[7-(quinolin-6-yl-methyl)-imidazo[1,2-B][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same
US11452726B2 (en) 2008-05-21 2022-09-27 Incyte Corporation Salts of 2-fluoro-N-methyl-4-[7-(quinolin-6-yl-methyl)-imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same
US8420645B2 (en) 2008-05-21 2013-04-16 Incyte Corporation Salts of 2-fluoro-N-methyl-4-[7-(quinolin-6-yl-methyl)-imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same
US10799509B2 (en) 2008-05-21 2020-10-13 Incyte Corporation Salts of 2-fluoro-N-methyl-4-[7-(quinolin-6-yl-methyl)-imidazo[1,2-B][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same
US8487096B2 (en) 2010-02-03 2013-07-16 Incyte Corporation Imidazo[1,2-B][1,2,4]triazines as C-MET inhibitors
US10919901B2 (en) 2010-02-03 2021-02-16 Incyte Holdings Corporation Imidazo[1,2-B][1,2,4]triazines as c-Met inhibitors
US10472367B2 (en) 2010-02-03 2019-11-12 Incyte Incorporation Imidazo[1,2-B][1,2,4]triazines as c-Met inhibitors
US9988387B2 (en) 2010-02-03 2018-06-05 Incyte Holdings Corporation Imidazo[1,2-B][1,2,4]triazines as c-Met inhibitors
US9221824B2 (en) 2010-02-03 2015-12-29 Incyte Holdings Corporation Imidazo[1,2-B][1,2,4]triazines as c-Met inhibitors

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