WO2003000690A1 - Synthese de composes heterocycliques faisant appel a une technologie micro-onde - Google Patents

Synthese de composes heterocycliques faisant appel a une technologie micro-onde Download PDF

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Publication number
WO2003000690A1
WO2003000690A1 PCT/US2002/020206 US0220206W WO03000690A1 WO 2003000690 A1 WO2003000690 A1 WO 2003000690A1 US 0220206 W US0220206 W US 0220206W WO 03000690 A1 WO03000690 A1 WO 03000690A1
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heteroaryl
aryl
halo
formula
substituted
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PCT/US2002/020206
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English (en)
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Tahir Nadeem Majid
Stephanie D. Deprets
Brian L. Pedgrift
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Aventis Pharmaceuticals Inc.
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Priority claimed from GB0119307A external-priority patent/GB0119307D0/en
Application filed by Aventis Pharmaceuticals Inc. filed Critical Aventis Pharmaceuticals Inc.
Publication of WO2003000690A1 publication Critical patent/WO2003000690A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/08—Processes employing the direct application of electric or wave energy, or particle radiation; Apparatus therefor
    • B01J19/12—Processes employing the direct application of electric or wave energy, or particle radiation; Apparatus therefor employing electromagnetic waves
    • B01J19/122—Incoherent waves
    • B01J19/126—Microwaves
    • 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

Definitions

  • the present invention is directed to the microwave mediated synthesis of heterocyclic compounds, more specifically to the microwave mediated synthesis of substituted bicyclic pyrroles which have utility for the treatment of diseases moderated by the inhibition of protein kinases, particularly FAK, KDR , Syk kinase or Aurora2.
  • the present invention provides methods for assisting organic reactions, using microwave energy, to provide good yields of heterocyclic compounds, particularly substituted bicyclic pyrroles of formula (I):
  • Y and Z are each independently selected from CH and CR 3 and W is N; or
  • X represents C-R10, Y and W are both N and Z is C CRK 3J ;
  • CR 12 and X is O, S or NR 1 *, or (b) Y represents a direct bond, W is N, X is CR 10 and Z is O, S, or
  • Y represents a direct bond, W is O, X is CR ⁇ and Z is N or CR* 2 , or (d) Y represents a direct bond, W is O, X is N and Z is CR 12 ;
  • R 4 represents alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, each optionally substituted by one or more groups selected from aryl, cycloalkyl, cyano, halo, heteroaryl, heterocycloalkyl, hydroxy, -CHO (or a 5-, 6- or 7-membered cyclic acetal derivative thereof),
  • R ⁇ represents hydrogen, alkyl, alkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
  • R" represents hydrogen or lower alkyl
  • R 7 represents alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
  • R 8 represents hydrogen or lower alkyl;
  • R ⁇ 2 represents cyano, H, -NY ⁇ Y°, -OR ⁇ , -S0 2 Me or lower alkyl optionally substituted with hydroxy or -NY 5 Y 6 ;
  • R ⁇ represents H, lower alkyl optionally substituted with hydroxy or NY->Y°;
  • Y* and Y 2 are independently hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, or alkyl optionally substituted by one or more groups selected from aryl, halo, heteroaryl, hydroxy,
  • Y 3 and Y 4 are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group -NY Y 4 may form a cyclic amine; ⁇ 5 and Y° are independently hydrogen or lower alkyl; Zl represents O or S(0) n ; and n is zero or an integer 1 or 2.
  • Acyl means an H-CO- or alkyl-CO- group in which the alkyl group is as described herein.
  • acylamino is an acyl-NH- group wherein acyl is as defined herein.
  • Alkenyl means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably 2 to about 6 carbon atoms (e.g. 2 to 4 carbon atoms) in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear chain; here a linear alkenyl chain.
  • “Lower alkenyl” means about 2 to about 4 carbon atoms in the chain, which may be straight or branched.
  • alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methyIbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.
  • alkenyloxy is an alkenyl-O- group wherein alkenyl is as defined above.
  • exemplary alkenyloxy groups include allyloxy.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as described herein.
  • exemplary alkoxy groups include difluoromethoxy, methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.
  • Alkoxycarbonyl means an alkyl-O-CO- group in which the alkyl group is as described herein.
  • exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.
  • Alkyl means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched chain having about 1 to about 15 carbon atoms in the chain, optionally substituted by one or more halogen atoms. Particular alkyl groups have from 1 to about 6 carbon atoms.
  • “Lower alkyl” as a group or part of a lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl group means unless otherwise specified, an aliphatic hydrocarbon group which may be a straight or branched chain having 1 to about 4 carbon atoms in the chain.
  • alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl.
  • exemplary alkyl groups substituted by one or more halogen atoms include trifluoromethyl.
  • Alkylene means an aliphatic bivalent radical derived from a straight or branched alkyl group, in which the alkyl group is as described herein.
  • Exemplary alkylene radicals include methylene, ethylene and trimethylene.
  • Alkylenedioxy means an -O-alkylene-O- group in which alkylene is as defined above.
  • exemplary alkylenedioxy groups include methylenedioxy and ethylenedioxy.
  • Alkylsulfinyl means an alkyl-SO- group in which the alkyl group is as previously described. Preferred alkylsulfinyl groups are those in which the alkyl group is C ⁇ alkyl.
  • Alkylsulfonyl means an alkyl-S0 2 - group in which the alkyl group is as previously described.
  • Preferred alkylsulfonyl groups are those in which the alkyl group is C ⁇ alkyl.
  • Preferred alkylsulfonylcarbamoyl groups are those in which the alkyl group is C ⁇ alkyl.
  • Alkylthio means an alkyl-S- group in which the alkyl group is as previously described.
  • exemplary alkylthio groups include methylthio, ethylthio, isopropylthio and heptylthio.
  • Alkynyl means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which group may be a straight or branched chain having about 2 to about 15 carbon atoms in the chain.
  • Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain; and more preferably 2 to about 6 carbon atoms (e.g. 2 to 4 carbon atoms) in the chain.
  • Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, i-butynyl, 3-methylbut-2-ynyl, and n-pentynyl.
  • Aroyl means an aryl-CO- group in which the aryl group is as described herein.
  • Exemplary aroyl groups include benzoyl and 1- and 2-naphthoyl.
  • Aroylamino is an aroyl-NH- group wherein aroyl is as previously defined.
  • Aryl as a group or part of a group denotes: (i) an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of about 6 to about 14 carbon atoms, such as phenyl or naphthyl; or (ii) an optionally substituted partially saturated multicyclic aromatic carbocyclic moiety in which an aryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure, such as a tetrahydronaphthyl, indenyl or indanyl ring.
  • aryl groups may be substituted with one or more aryl group substituents, which may be the same or different, where "aryl group substituent" includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy (or an acid bioisostere), cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, hydroxy, nitro, trifluoromethyl, -NY 3 Y 4 -CONY
  • Arylalkyl means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a Ci ⁇ alkyl moiety. Exemplary arylalkyl groups include benzyl,
  • Arylalkyloxy means an arylalkyl-0- group in which the arylalkyl groups is as previously described.
  • exemplary arylalkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
  • Arylalkyloxycarbonyl means an arylalkyl-O-CO- group in which the arylalkyl groups is as previously described.
  • An exemplary arylalkyloxycarbonyl group is benzyloxycarbonyl.
  • Arylalkylthio means an arylalkyl-S- group in which the arylalkyl group is as previously described.
  • An exemplary arylalkylthio group is benzylthio.
  • Aryloxy means an aryl-O- group in which the aryl group is as previously described.
  • exemplary aryloxy groups include phenoxy and naphthoxy, each optionally substituted.
  • exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
  • Arylsulfinyl means an aryl-SO- group in which the aryl group is as previously described.
  • Arylsulfonyl means an aryl-S0 2 - group in which the aryl group is as previously described.
  • Arylthio means an aryl-S- group in which the aryl group is as previously described. Exemplary arylthio groups include phenylthio and naphthylthio. “Azaheteroaryl” means an aromatic carbocyclic moiety of about 5 to about 10 ring members in which one of the ring members is nitrogen and the other ring members are selected from carbon, oxygen, sulfur, and nitrogen.
  • azaheteroaryl groups include benzimidazolyl, imidazolyl, indazolinyl, indolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, quinazolinyl and tetrahydroindolizinyl.
  • cyclic amines include pyrrolidine, piperidine, morpholine, piperazine, indoline, pyrindoline, tetrahydroquinoline and the like groups.
  • Cycloalkenyf ' means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms.
  • Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl and cycloheptenyl.
  • Cycloalkyl means a saturated monocyclic or bicyclic ring system of about 3 to about 10 carbon atoms, optionally substituted by oxo.
  • Exemplary monocyclic cycloalkyl rings include C3_gcycloalkyl rings such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Cycloalkylalkyl means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as previously described.
  • Exemplary monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
  • Halo or "halogen” means fluoro, chloro, bromo, or iodo. Preferred are fluoro and chloro.
  • exemplary heteroaryl groups include pyridylcarbonyl.
  • Heteroaroylamino means a heteroaroyl-NH- group in which the heteroaryl moiety is as previously described.
  • Heteroaryl as a group or part of a group denotes: (i) an optionally substituted aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur (examples of such groups include benzimidazolyl, benztbiazolyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups, optionally substituted by one or more aryl group substituents as defined
  • Heteroarylalkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a Cj ⁇ alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.
  • Heteroarylalkyloxy means an heteroarylalkyl-0- group in which the heteroarylalkyl group is as previously described.
  • exemplary heteroaryloxy groups include optionally substituted pyridylmethoxy.
  • Heteroaryloxy means an heteroaryl-O- group in which the heteroaryl group is as previously described.
  • exemplary heteroaryloxy groups include optionally substituted pyridyloxy.
  • Heterocycloalkyl means: (i) a cycloalkyl group of about 3 to 7 ring members which contains one or more heteroatoms or heteroatom-containing groups selected from O, S and NY 7 and mat be optionally substituted by oxo; (ii) a partially saturated multicyclic heterocarbocyclic moiety in which an aryl (or heteroaryl) ring, each optionally substituted by one or more "aryl group substituents,” and a heterocycloalkyl group are fused together to form a cyclic structure.
  • aryl or heteroaryl
  • aryl group substituents each optionally substituted by one or more "aryl group substituents”
  • heterocycloalkyl group include chromanyl, dihydrobenzofuranyl, indolinyl and pyrindolinyl groups).
  • Heterocycloalkylalkyl means a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as previously described.
  • the present invention is directed to the microwave mediated synthesis of substituted bicyclic pyrroles involving nucleophilic aromatic substitution, biaryl/heterobiaryl coupling and decarboxylation.
  • These microwave assisted reactions all provide improved rate enhancement and yield over traditional thermal heating methods in the preparation of protein kinase inhibitors or of the intermediates in the preparation thereof.
  • this invention is directed to processes for the synthesis of 2-aryl and 2-heteroaryl- pyrrolo[2,3-b]-pyridines of formula (la), 2-aryl and 2-heteroaryl-pyrrolo[2,3-b]-pyridazines of formula (lb) and 5-aryl and 5-heteroaryl-pyrrolo[2,3-d]imidazoles of formula (Ic), which processes involve one or more steps that are assisted by the use of microwave energy.
  • R , R 2 , R 3 , R ⁇ ' R 1 and R ⁇ 2 are as hereinbefore defined.
  • Such compounds have utility for the treatment of diseases moderated by the inhibition of protein kinases, particularly FAK, KDR, Syk kinase or Aurora2.
  • protein kinases particularly FAK, KDR, Syk kinase or Aurora2.
  • reactive functional groups for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions.
  • Conventional protecting groups may be used in accordance with standard practice, for examples see T.W. Greene and P.G.M.Wuts in "Protective Groups in Organic Chemistry” John Wiley and Sons, 1991.
  • R ⁇ is aryl or heteroaryl substituted by -OS0 2 CH3 with amines of formula HNYl ⁇ , wherein Y* and Y 2 are as hereinbefore defined, in a microwave oven at a temperature at about 200°C.
  • This microwave assisted reaction may conveniently be carried out in a mixture of inert solvents, such as dioxane and dimethylformamide. This reaction is particularly suitable for the preparation of
  • Compounds of formula (1) wherein R 2 and are as hereinbefore defined, and R* is aryl or heteroaryl substituted by -NY ⁇ Y 2 (in which ⁇ l and Y 2 are as hereinbefore defined), may also be prepared by reaction of compounds of formula (IT), wherein R* 4 is aryl or heteroaryl substituted by halo, preferably bromo or iodo, with amines of formula HNY ⁇ Y 2 , wherein Y* and Y 2 are as hereinbefore defined, in the presence ofcopper (I) iodide and sodium carbonate, in a microwave oven at a temperature at about 200°C.
  • This microwave assisted reaction may conveniently be carried out in an inert solvent, such as dimethylforma ide.
  • RIO is halo, preferably bromo or iodo, with amines of formula HN ⁇ l ⁇ 2 , wherein ⁇ l and Y 2 are as hereinbefore defined, in a microwave oven at a temperature at about 210°C.
  • This microwave assisted reaction may conveniently be carried out in an inert solvent, such as ⁇ , , ⁇ -trifluorotoluene.
  • Compounds of formula (1) wherein R z and are as hereinbefore defined, and R! is aryl or heteroaryl substituted by aryl or heteroaryl, may be prepared by reaction of the corresponding compounds of formula (1), wherein R! is aryl or heteroaryl substituted by halo, preferably bromo or iodo, with the appropriate aryl- or heteroaryl-boronic acid, in the presence of tetrakis(triphenylphosphine)palladium(0) and aqueous sodium carbonate, in a microwave oven at a temperature at about 180°C.
  • This microwave assisted reaction may conveniently be carried out in an inert solvent, such as dioxane.
  • R is aryl or heteroaryl substituted by aryl or heteroaryl, may be prepared by reaction of compounds of formula (HI):-
  • X-*- is iodo, with the appropriate aryl- or heteroaryl-boronic acid, in the presence of tetrakis(triphenylphosphine)palladium(0) and aqueous sodium hydrogen carbonate, in a microwave oven at a temperature at about 60°C.
  • This microwave assisted reaction may conveniently be carried out in an inert solvent, such as dimethylformamide.
  • Intermedaites of formula (III) wherein R 2 and are as hereinbefore defined, and X* is iodo may be prepared by treatment of compounds of formula (I T), wherein R 2 and hereinbefore defined, and X 1 is hydrogen, with lithium diisopropylamide in tetrahydrofuran, at about -78°C, followed by reaction of the resulting anion with iodine.
  • Intermediates in the synthesis of compounds of formula (I) may also be prepared using microwave mediated reactions.
  • the intermediate (XI) in the preparation of Example 6 in scheme (1) may be prepared by decarboxylation of 2-methylsulfonyl-l-methylpyrrolo[2,3-d]imidazole-5- carboxylic acid (V) in the presence of copper in quinoline in a microwave oven. This microwave assisted reaction may conveniently be carried out at about 250°C.
  • the present invention is further exemplified but not limited by the following Illustrative Examples and Reference Examples.
  • 400M Hz 1H nuclear magnetic resonance spectra (NMR) were recorded on a Varian Unity LNOVA machine.
  • NMR nuclear magnetic resonance spectra
  • ⁇ the chemical shifts ( ⁇ ) are expressed in ppm relative to tetramethylsilane.
  • METHOD A YMC ODS-A HPLC column (50mm x 4mm) operated under gradient elution conditions with mixtures of water and acetonitrile, (A) 95:5 and (B) 5:95, containing 0.1% formic acid as the mobile phase gradient (0.00 minutes, 95%A:5%B; linear gradient to 100% B at 2 minutes; then hold until 3.4 minutes); flow rate 2ml/minute with approximately 200 ⁇ l/minute split to the Mass Spectrometer; injection volume 10-40 ⁇ l; in line Diode Array (220-450nm), in line Evaporative light scattering (ELS) detection ELS - temperature 50°C, Gain 8 - 1.8m ⁇ /minute; Source temperature 150°C; METHOD B: 3 micron Luna C18 (2) HPLC column (30mm x 4.6mm) operated under gradient elution conditions with mixtures of (A) water containing 0.1% trifluoroactic acid and (B) acetonitrile containing 0.1% trifluoroacetic acid as the mobile
  • Method A CI 8 Phenomenex (150 x 4.6mm) column using gradient elution with a mixture of acetonitrile and water with 0.1% trifluoroacetic acid as the mobile phase (0-1 minute 5% acetonitrile; 1-12 minutes ramp up to 95% acetonitrile; 12-14.95 minutes 95% acetonitrile; 14.95-15 minutes 0% acetonitrile); or Method B, YMC ODS-AQ (2 X 50mm) column using gradient elution with a mixtures of acetonitrile and water with 0.1% formic acid as the mobile phase [95/5/0.1% (A) to 5/95/0.1% (B)] and a flow rate of 0.4 mL/minute); or Method C, 3 micron BDS C18 Hypersil (50 x 4.6 mm) using gradient elution with a mixture of acetonitrile and water with 0.1% formic acid as the mobile phase (95 / 5 / 0.1%, water /
  • a microwave tube (Smith process vial, 2-5ml) was charged with 6-(4-trifluorosulfonyloxyphenyl)-5H- pyrrolo[2,3-b]pyrazine [20mg, Reference Example 1(a)], pyrrolidine (2.39mM), dioxane (3ml) and dimethylformamide (0.5ml).
  • the tube was capped and the resulting mixture was heated at 200°C in a microwave oven for 1 hour after which the 6-(4-trifluorosulfonyloxyphenyl)-5H-pyrrolo[2,3-b]pyrazine had been consumed.
  • the reaction mixture was evaporated and the residue was triturated with a mixture of ethyl acetate and methanol (9:1, v/v). The solid was filtered and then dried under vacuum to give the
  • a microwave tube (Smith process vial, 2-5ml) was charged with 6-(3-bromo-4-methoxyphenyl)-5H- pyrrolo[2,3-b]pyrazine [50mg, Reference Example 2(b)], alanine (148mg), dimethylformamide (3ml), copper(I) iodide (3.2mg) and sodium carbonate (27mg).
  • the tube was capped and the resulting mixture was heated at 200°C in a microwave oven for 2 hours. Water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, then with brine, then dried over magnesium sulfate and then concentrated under vacuum.
  • a microwave tube (Smith process vial, 2-5ml) was charged with 4-bromo-2-iodo-l-(toluene-4- sulfonyl)-lH-pyrrolo[2,3-b]pyridine (lOOmg, Reference Example 17) boronic acid (61mg), saturated aqueous sodium hydrogenocarbonate (1ml), Pd(PPh 3 ) 4 (20mg) and dimethylformamide (4 ml) . The tube was capped and the resulting mixture was heated at 60°C in a microwave oven for 30 minutes. Water (10ml) was added and the reaction mixture was extracted with ethyl acetate (10ml).
  • a mixture of lH-pyrrolo[2,3-b]pyridine-7-oxide (lg, Reference Example 15) and phosphorus oxybromide(10.7g) was stirred at 45°C for 18 hours then 24 hours at 50°C.
  • the reaction mixture was cooled to ambient temperature then treated with phosphorus oxybromide (10.7g).
  • the reaction mixture was then stirred at 50°C for 5 hours.
  • the reaction mixture was carefully treated with water (10ml) then reheated to 80-90°C for 1 hour.

Abstract

L'invention concerne des procédés de préparation de composés de formule (I) faisant appel à l'utilisation d'énergie micro-onde.
PCT/US2002/020206 2001-06-25 2002-06-25 Synthese de composes heterocycliques faisant appel a une technologie micro-onde WO2003000690A1 (fr)

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US30073301P 2001-06-25 2001-06-25
US60/300,733 2001-06-25
GB0119307.7 2001-08-08
GB0119307A GB0119307D0 (en) 2001-06-25 2001-08-08 Synthesis of heterocyclic compounds employing microwave technology

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