WO2007026221A2 - Procede ameliores d'elaboration de derives d'heteroaryl amide benzocondenses de thienopyridines - Google Patents

Procede ameliores d'elaboration de derives d'heteroaryl amide benzocondenses de thienopyridines Download PDF

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Publication number
WO2007026221A2
WO2007026221A2 PCT/IB2006/002371 IB2006002371W WO2007026221A2 WO 2007026221 A2 WO2007026221 A2 WO 2007026221A2 IB 2006002371 W IB2006002371 W IB 2006002371W WO 2007026221 A2 WO2007026221 A2 WO 2007026221A2
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Prior art keywords
compound
formula
butoxide
base
sodium
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PCT/IB2006/002371
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English (en)
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WO2007026221A3 (fr
Inventor
Katheryn E. Harrison
Sean Timothy Neville
Robert William Scott
John Lloyd Tucker
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Pfizer Inc.
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Publication of WO2007026221A3 publication Critical patent/WO2007026221A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention provides improved methods for preparing benzofused heteroaryl amide derivatives of thienopyridines and intermediates thereof, which are useful in the treatment of hyperproliferative diseases, such as cancers and ophthalmic diseases such as age-related macular degeneration.
  • R 4 is C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylhydroxy, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylamino or C 1 -C 6 alkyl C 3 -C 10 cycloalkyl; comprising, a) formyiating a compound of formula Il to provided a compound of formula III; b) cyclizing the compound of formula III to provide a compound of formulal IV; c) alkylating the compound of formula IV to provide a compound of formula V:
  • the invention provides methods for preparing compounds of the formula I, wherein the compound of formula Il is formylated using an alkyl lithium reagent and N,N-dimethyl formamide.
  • the invention provides methods for preparing compounds of the formula I, wherein the alkyl lithium reagent is n-butyl lithium.
  • the invention provides methods for preparing compounds of the formula I, wherein the compound of formula III is cyclized using glyoxal trimer, ammonium acetate and acetic acid.
  • the invention provides methods for preparing compounds of the formula I, wherein the compound of formula IV is alkylated with methyl tosylate in the presence of a base.
  • the invention provides methods for preparing compounds of the formula I, wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, potassium f-butoxide, sodium f-butoxide, triethylamine, N, N-diisopropyl ethyl amine or mixtures thereof.
  • the invention provides methods for preparing compounds of the formula I, wherein the base is sodium f-butoxide.
  • the invention provides methods for preparing compounds of the formula I, wherein the compound of formula Vl is couple with benzophenone hydrazone using a palladium catalyst.
  • the invention provides methods for preparing compounds of the formula I, wherein the palladium catalyst is palladium acetate.
  • the invention provides methods for preparing compounds of the formula I, wherein the compound of formula VII is alkylated with methyl tosylate in the presence of a base.
  • the invention provides methods for preparing compounds of the formula I, wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, potassium f-butoxide, sodium f-butoxide, triethylamine, N, N-diisopropyl ethyl amine or mixtures thereof.
  • the invention provides methods for preparing compounds of the formula I, wherein the base is sodium f-butoxide.
  • the invention provides methods for preparing compounds of the formula I, wherein the compound of formula VIII is cyclized in acid with a compound of formula R 3 COCH 2 CONHR 4 to form the compound of formula IX, wherein R 3 and R 4 are as described.
  • the invention provides methods for preparing compounds of the formula I, wherein the acid is methane sulfonic acid.
  • the invention provides methods for preparing compounds of the formula I, wherein W is benzyl.
  • the invention provides methods for preparing compounds of the formula I, wherein W is removed by catalytic hydrogenation.
  • the invention provides methods for preparing compounds of the formula I, wherein the catalyst is a palladium catalyst.
  • the invention provides methods for preparing compounds of the formula I, wherein the catalyst is palladium hydroxide.
  • the invention provides methods for preparing compounds of the formula I, wherein the compound of formula V is couple to the compound of formula X in the presence of a base.
  • the invention provides methods for preparing compounds of the formula I, wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, potassium f-butoxide, sodium f-butoxide, triethylamine, N, N-diisopropyi ethyl amine or mixtures thereof.
  • the invention provides methods for preparing compounds of the formula I, wherein the base is cesium carbonate or sodium f-butoxide. In another aspect, the invention provides methods for preparing compounds of the formula I, further comprising a solvent.
  • the invention provides methods for preparing compounds of the formula I, wherein the solvent is dimethylsulfoxide.
  • the invention provides methods for preparing compounds of the formula I, wherein the reaction is carried out at about 100 0 C.
  • the invention provides methods for preparing compounds of the formula I, wherein R 1 , R 2 , and R 3 are methyl; and R 4 is cyclopropyl.
  • the invention provides methods for preparing compounds of the formula Xl:
  • Y is -O-, -S- or -NH-;
  • R 1 is H or C 1 -C 6 alkyl:
  • R 2 is H or C 1 -C 6 alkyl:
  • R 3 is H or C 1 -C 6 alkyl
  • R 4 is C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylhydroxy, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylamino or C 1 -C 6 alkyl C 3 -C 10 cycloalkyl; comprising, a) formylating a compound of formula Il to provided a compound of formula III; b) cyclizing the compound of formula III to provide a compound of formulal IV; c) alkylating the compound of formula IV to provide a compound of formula V:
  • the invention provides methods for preparing compounds of the formula Xl, wherein the compound of formula Il is formylated using the alkyl lithium reagent and N, N-dimethyl formamide.
  • the invention provides methods for preparing compounds of the formula Xl, wherein the alkyl lithium reagent is n-butyl lithium. In another aspect, the invention provides methods for preparing compounds of the formula Xl, wherein the compound of formula III is cyclized using glyoxal trimer, ammonium acetate and acetic acid to form the compound of formula IV.
  • the invention provides methods for preparing compounds of the formula Xl, wherein the compound of formula IV is alkylated with methyl tosylate in the presence of a base,
  • the invention provides methods for preparing compounds of the formula Xl, wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, potassium f-butoxide, sodium f-butoxide, triethylamine, N, N-diisopropyl ethyl amine or mixtures thereof.
  • the invention provides methods for preparing compounds of the formula Xl, wherein the base is sodium f-butoxide.
  • the invention provides methods for preparing compounds of the formula Xl, wherein the compound of formula Xl is alkylated with a compound of formula R 3 CI-IXCOCO 2 H in the presence of a base, wherein X is Cl, Br or I.
  • the invention provides methods for preparing compounds of the formula Xl, wherein R 3 is CH 3 ; and X is Br.
  • the invention provides methods for preparing compounds of the formula Xl, wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, potassium f-butoxide, sodium f-butoxide, triethylamine, N, N-diisopropyl ethyl amine or mixtures thereof.
  • the invention provides methods for preparing compounds of the formula Xl, wherein the base is potassium carbonate.
  • the invention provides methods for preparing compounds of the formula Xl, wherein the compound of formula XII is cyclized in acid.
  • the invention provides methods for preparing compounds of the formula Xl, wherein the acid is sulfuric acid.
  • the invention provides methods for preparing compounds of the formula Xl, wherein the compound of formula XIII is amidified using CDI and R 4 NH 2 . In another aspect, the invention provides methods for preparing compounds of the formula Xl, wherein R 4 is methyl.
  • the invention provides methods for preparing compounds of the formula Xl, wherein W is methyl.
  • the invention provides methods for preparing compounds of the formula Xl, wherein W is removed with methane sulfonic acid.
  • the invention provides methods for preparing compounds of the formula Xl, wherein the compound of formula V is couple to the compound of formula XV in the presence of a base.
  • the invention provides methods for preparing compounds of the formula Xl, wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, potassium f-butoxide, sodium f-butoxide, triethylamine, N, N-diisopropyl ethyl amine or mixtures thereof.
  • the invention provides methods for preparing compounds of the formula Xl, wherein the base is cesium carbonate or sodium f-butoxide.
  • the invention provides methods for preparing compounds of the formula Xl, further comprising a solvent.
  • the invention provides methods for preparing compounds of the formula Xl, wherein the solvent is dimethylsulfoxide.
  • the invention provides methods for preparing compounds of the formula Xl, wherein the reaction is carried out at about 100°C.
  • the invention provides methods for preparing compounds of the formula Xl, wherein R 1 , R 3 , and R 4 is methyl.
  • the invention provides methods for preparing compounds of the formula V:
  • R 1 is H or C 1 -C 6 alkyl
  • X is Cl, Br or I
  • the invention provides methods for preparing compounds of the formula V, wherein the compound of formula Il is formylated using an alkyl lithium reagent and N, N-dimethyl formamide.
  • the invention provides methods for preparing compounds of the formula V, wherein the alkyl lithium reagent is n-butyl lithium.
  • the invention provides methods for preparing compounds of the formula V, wherein the compound of formula III is cyclized using glyoxal trimer, ammoniuim acetate and acetic acid to form the compound of formula IV.
  • the invention provides methods for preparing compounds of the formula V, wherein the compound of formula IV is alkylated with methyl tosylate in the presence of a base.
  • the invention provides methods for preparing compounds of the formula V, wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, potassium f-butoxide, sodium f-butoxide, triethylamine, N, N-diisopropyl ethyl amine or mixtures thereof.
  • the invention provides methods for preparing compounds of the formula V, wherein the base is sodium f-butoxide.
  • the invention provides methods for preparing compounds of the formula V, wherein R 1 is methyl; and X is Cl.
  • the invention provides methods for preparing compounds of the formula X:
  • Y is -0-, -S- or -NH-;
  • R 2 is H or C r C 6 alkyl:
  • R 3 is H or C 1 -C 6 alkyl:
  • R 4 is C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylhydroxy, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylamino or C 1 -C 6 alkyl C 3 -C 10 cycloalkyl; comprising, a) coupling a compound of formula Vl with bgenzophenone hydrazone to provide a compound of formula VII, wherein W is a protecting group, and X is Cl, Br or I; b) alkylating the compound of formula VII to provide a compound of formula VII; c) cyclizing the compound of formula VIII to provide a compound of formula IX; and d) removing W in the compound of formula IX to provide a compound of formula X:
  • the invention provides methods for preparing compounds of the formula X, wherein the compound of formula Vl is coupled with benzophenone hydrazone using a palladium catalyst. In another aspect, the invention provides methods for preparing compounds of the formula X, wherein the palladium catalyst is palladium acetate.
  • the invention provides methods for preparing compounds of the formula X, wherein the compound of formula VII is alkylated with methyl tosylate in the presence of a base.
  • the invention provides methods for preparing compounds of the formula X, wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, potassium f-butoxide, sodium f-butoxide, triethylamine, N, N-diisopropyl ethyl amine or mixtures thereof.
  • the invention provides methods for preparing compounds of the formula X, wherein the base is sodium t-butoxide.
  • the invention provides methods for preparing compounds of the formula X, wherein the compound of formula VIII is cyclized in acid with a compound of formula R 3 COCH 2 CONHR 4 to form the compound of formula IX, where in R 3 , and R 4 are as described.
  • the invention provides methods for preparing compounds of the formula X, wherein the acid is methane sulfonic acid.
  • the invention provides methods for preparing compounds of the formula X, wherein W is benzyl. In another aspect, the invention provides methods for preparing compounds of the formula X, wherein W is removed by catalytic hydrogenation.
  • the invention provides methods for preparing compounds of the formula X, wherein the catalyst is a palladium catalyst.
  • the invention provides methods for preparing compounds of the formula X, wherein the catalyst is palladium hydroxide.
  • the invention provides methods for preparing compounds of the formula X, wherein R 2 , and R 3 are methyl; and R 4 is cyclopropyl.
  • inventive compounds may exist in various stereoisomeric or tautomeric forms.
  • the present invention encompasses all such cell proliferation-inhibiting compounds, including active compounds in the form of single pure enantiomers (i.e., essentially free of other stereoisomers), racemates, mixtures of enantiomers and/or diastereomers, and/or tautomers.
  • inventive compounds that are optically active are used in optically pure form.
  • an optically pure compound having one chiral center is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure.
  • the compounds of the present invention are used in a form that is at least 90% optically pure, that is, a form that contains at least 90% of a single isomer (80% enantiomeric excess ("e.e.") or diastereomeric excess (“d.e.”)), more preferably at least
  • Diasteromeric mixtures of the compounds of the present invention may be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as by chromatography or fractional crystallization.
  • Enantiomers may be separated by converting the enantiomeric mixtures into a diastereomric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomer mixtures and pure enantiomers are considered as part of the invention.
  • an appropriate optically active compound e.g., alcohol
  • Formula I includes compounds of the indicated structure in both hydrated and non-hydrated forms. Additional examples of solvates include the structures in combination with isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
  • pharmaceutically acceptable refers to pharmacologically acceptable agents being substantially non-toxic to the subject being administered the agent.
  • pharmaceutically acceptable salts refers to salts which retain the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable.
  • a compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioates, hexyne-1 ,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenz
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such, as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2- acetoxy
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines, such as benzylamines, pyrrolidines, piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • amino acids such as glycine and arginine
  • ammonia carbonates, bicarbonates, primary, secondary, and tertiary amines
  • cyclic amines such as benzylamines, pyrrolidines, piperidine, morpholine and piperazine
  • inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • the terms “comprising” and “including” are used herein in their open, non-limiting sense.
  • alcohol refers to the radical R-OH where R is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl or cycloalkyl as defined above.
  • examples of alcohols include methanol, ethanol, propanol, phenol and the like.
  • acyl refers to -C(O)R, -C(O)OR, -OC(O)R or -OC(O)OR where R is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl or cycloalkyl as defined herein.
  • alkyl refers to straight or branched chain alkyl groups having from one to twelve carbon atoms, preferably from 1 to 6 carbons, and more preferably from 1 to 3 carbons.
  • exemplary alkyl groups include methyl (Me), ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and the like.
  • alkenyl refers to straight or branched chain alkenyl groups having from two to twelve carbon atoms, preferably from 2 to 6 carbons, and more preferably from 2 to 4 carbons.
  • Illustrative alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2- methylprop-2-enyl, hex-2-enyl, and the like.
  • alkynyl refers to straight- and branched-chain alkynyl groups having from two to twelve carbon atoms, preferably from 2 to 6 carbons, and more preferably from 2 to 4 carbons.
  • Illustrative alkynyl groups include prop-2-ynyl, but-2-ynyl, but- 3-ynyl, 2-methylbut-2-ynyl, hex-2-ynyl, and the like.
  • amide refers to the radical -C(O)N(R')(R") where R' and R" are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl and aryl as defined above; or R' and R" cyclize together with the nitrogen to form a heterocycloalkyl or heteroaryl as defined above.
  • alkoxy refers to the radical -OR where R is an alkyl as defined above. Examples of alkoxy groups include methoxy, ethoxy, propoxy, and the like.
  • aryl refers to monocyclic or polycyclic aromatic ring structures containing only carbon and hydrogen. Preferred aryl groups have from 4 to 20 ring atoms, preferably from 6 to 14 ring atoms, and more preferably from 6 to 10 ring atoms.
  • cycloalkyl refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated, partially unsaturated, or fully unsaturated.
  • Preferred cycloalkyl groups include groups having from 3 to 12 ring atoms, more preferably from 5 to 10 ring atoms, and still more preferably from 5 to 6 ring atoms.
  • halogen or refers to chlorine, fluorine, bromine or iodine.
  • halo refers to chloro, fluoro, bromo or iodo.
  • heteroalkyl refers to straight or branched chain alkyl groups containing one or more heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • the polycyclic heteroaryl group may be fused or non-fused and the like.
  • heterocycloalkyl refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur.
  • the radicals may be fused with an aryl or heteroaryl.
  • heterocyclic comprises both heterocycloalkyl and heteroaryl groups.
  • substituted refers to that the group in question, e.g., alkyl group, etc., may bear one or more substituents.
  • alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups and the substituents containing these groups, as defined hereinabove, may be optionally substituted by at least one other substituent.
  • optionally substituted is intended to expressly indicate that the specified group is unsubstituted or substituted by one or more substituents as defined herein.
  • Various groups may be unsubstituted or substituted (i.e., they are optionally substituted) as indicated.
  • the substituent may be protected with a suitable protecting group that is stable to the reaction conditions used in these methods.
  • the protecting group may be removed at a suitable point in the reaction sequence of the method to provide a desired intermediate or target compound.
  • suitable protecting groups and the methods for protecting and de- protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, New York (1999), which is incorporated herein by reference in its entirety.
  • a substituent may be specifically selected to be reactive under the reaction conditions used in the methods of this invention. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful in an intermediate compound in the methods of this invention or is a desired substituent in a target compound.
  • the reactions set forth below were done generally under a positive pressure of argon or nitrogen or with a drying tube, at ambient temperature (unless otherwise stated), in anhydrous solvents, and the reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried. Analytical thin layer chromatography (TLC) was performed on glass-backed silica gel 60 F 254 plates Analtech (0.25 mm) and eluted with the appropriate solvent ratios (v/v), and are denoted where appropriate. The reactions were assayed by TLC and terminated as judged by the consumption of starting material.
  • TLC thin layer chromatography
  • IR Infrared
  • the compounds of the invention are prepared according to the following reaction schemes. As shown below, the compound of formula I is prepared by coupling the compound of formula V with the compound of formula X in the presence of a base and suitable solvent.
  • the compound of formula V is prepared by formylating the thienopyridine compound of formula Il to provide the C-2 aldehyde compound of formula III. Cylization and alkylation of the compounds of formulae III and IV, respectively, provides the compound of formula V.
  • the compound of formula X is prepared by coupling the 1 ,3 disubstituted phenyl compound of formula Vl with benzophenone hydrazone to provide the compound of formula VII. Alkylation, cyclization and deprotection of the W group of the compounds of formula VII, VIII and IX, respectively, provides the compound of formula X.
  • the compound of formula Xl is prepared by coupling the compound of formula V with the compound of formula XV in the presence of a base and suitable solvent.
  • the compound of formula V is prepared as described above.
  • the compound of formula XV is prepared by coupling the 1,3 disubstituted thiophenol compound of formula X with 2 keto butyric acid to provide the compound of formula XII.
  • the solution is stirred at room temperature for 30 minutes and saturated aqueous sodium bicarbonate (60 mL) is added.
  • the solution is sampled to ensure that the pH is near neutral (note 9).
  • the slurry is stirred for 5 minutes, filtered, and the cake rinsed with a mixture of water and methanol (2 X 530 mL solution containing 430 mL water and 100 mL methanol).
  • the solids are given a final rinse with methyl tert-butyl ether (2 X 250 mL) and dried in a vacuum oven to provide 122.8 g (70%) of the title product as a white powder (notes 10, 11).
  • the flask is equipped with an overhead stirrer, internal temperature probe, and Argon inlet. 2.
  • the bath temperature is maintained at approximately -65 0 C.
  • the internal temperature should be ⁇ -40 0 C.
  • the product is dried in a vacuum oven at 45 to 50 0 C and 25 mm Hg. It is important to dry the product to the lowest water content achievable, probably by an aggressive LOD spec.
  • the flask is equipped with an overhead stirrer, internal temperature probe, and Ar inlet.
  • Glyoxal trimer dihydrate has a molecular weight of 210.14. However, this provides 3 equivalents of glyoxal. The calculation of the moles takes this into account. For this particular procedure, the 117.34 g of the trimer represents 1.675 mol equivalents of glyoxal. 3. The dissolution is slightly endothermic. The internal temperature cools to 19
  • the pad is smoothed periodically as needed to maintain the cake without significant cracks. Upon complete filtration, the cake is smoothed carefully before the final wash.
  • the second portion of base causes the internal temperature to rise to 11 0 C.
  • the cooling bath is removed and the solution is allowed to warm to room temperature.
  • HPLC analysis 20 minutes after cooling bath removal shows 6.4% starting material remaining.
  • HPLC analysis shows no starting material remaining.
  • Water (1 ,275 mL) is added and the solution is distilled at atmospheric pressure to remove tetrahydrofuran. The distillation is deemed to be complete when the internal temperature holds steady at 75 0 C.
  • the solution is allowed to cool to room temperature over 3 hours.
  • the slurry is filtered and the solids are rinsed with water (400 mL).
  • the solids are dried in a vacuum oven to provide 79.06 g (87%) of the title product as a brown powder (notes 4, 5).
  • the flask is equipped with an overhead stirrer, internal temperature probe, and Ar inlet. 2. Due to the insolubility of the reaction components, care must be taken to ensure the HPLC sample is homogeneous. Typically, an aliquot is removed and a few drops of 1M hydrochloric acid is added. The sample volume is made up with 40/60 acetonitrile/water solution and the mixture is sonicated to ensure complete dissolution. Additional acid may be added followed by sonication if the sample is not homogeneous 3.
  • a 1 liter round bottom flask containing degassed toluene (400 mL) is charged with benzophenone hydrazone (32.86 g, 0.167 mol), palladium acetate (Pd(OAc) 2 , 0.34 g, 0.0015 mol) and BINAP ((2,2'-bis(diphenylphosphino)-1,1'-binapthyl, 1.42 g, 0.0023 mol) (notes 1, 2).
  • the mixture is heated to 80 0 C for 15 minutes for activation of the catalyst (note 3). The heating is removed and the mixture is allowed to cool to 60 to 70 °C. 3-benzyloxy bromobenzene (40.07 g, 0.152 mol) and sodium tert-butoxide (20.42 g, 0.212 mol) are added (notes 4, 5) and the mixture is heated to 100 0 C with stirring for 2 hours (note 6). An aliquot is removed and analyzed by HPLC (notes 7, 8). Upon completion of the reaction, the mixture is allowed to cool below 45 0 C and is washed twice with water (1 st wash 400 ml, 2 nd wash 200 ml) (note 9).
  • the organic layer is filtered through Celite ® (note 10) and the cake is washed with toluene (1 x 120 ml).
  • the product-rich filtrate is distilled at atmospheric pressure to a total volume of 321 ml.
  • isopropanol (265 ml_) is added and heating is resumed to displace toluene until a total volume of 321 ml is reached.
  • This sequence is repeated 3 times for effective removal of the toluene (note 11).
  • the solution is cooled below 70 0 C, and a sample is removed and analyzed by 1 H NMR (note 12). Upon acceptable toluene removal, the reaction is cooled below 60 0 C.
  • Diisopropyl ether (265 ml) is added and heating is resumed to displace the isopropanol until a total volume of 321 ml is reached (note 13). This sequence is repeated 2 times for effective removal of the isopropanol. A sample is removed and analyzed by 1 H NMR (note 14). Upon acceptable removal of the isopropanol, the solution is allowed to cool to room temperature, at which point the solution becomes a slurry (note 15). After granulating for 40 minutes at ambient temperature, the slurry is cooled and granulated an additional 30 minutes at -10 °C.
  • the flask is equipped with an overhead stirrer, internal temperature probe, and a condenser with nitrogen inlet. 2. Degassing is accomplished via nitrogen flow through a gas dispersion tube immersed in the toluene for 30 minutes.
  • the catalyst is activated when the color changes from a red-orange slurry to a deep purple-red or brown-red slurry; either color change indicates the activation of the catalyst. 4.
  • Sodium tert-butoxide should be added quickly to minimize exposure to moisture.
  • This filtration is to remove residual insoluble material.
  • Solids typically precipitate during these additions, but return to solution upon heating.
  • the reactor may be rinsed out with the mother liquor and this washed over cake to recover additional solids if deemed necessary. Rinsing with clean solvent is not recommended due to the high solubility of the product.
  • the product rich solution is distilled under atmospheric pressure to a total volume of 80 mL. After cooling to below 50 0 C, diisopropyl ether (174 mL) is added and heating is resumed to displace the methyl tert-butyl ether until a total volume of 159 ml is reached. This sequence is repeated and a sample is removed and analyzed by 1 H NMR (note 12). The solution is allowed to cool to 30 to 35 0 C, and is then seeded (note 13). The slurry is allowed to granulate for 12 hours at room temperature (note 14), followed by a two-hour granulation at -10 °C (note 15). The solids are filtered and dried to provide 41.59 g (80% yield) of the title product as a yellow solid (notes 16, 17 and 18).
  • the flask is equipped with mechanical stirrer, internal temperature probe, and nitrogen inlet.
  • the slurry should be cooled between -10 to 0 0 C.
  • Seeding should be done between 25 to 35 0 C to avoid early product precipitation.
  • the slurry should be stirred at room temperature for at least 12 hours.
  • the slurry should be granulated for at least 2 hours at -5 to -10 0 C.
  • the reactor may be rinsed out with the mother liquor and this washed over the cake to recover additional solids if deemed necessary. Rinsing with clean solvent is not recommended due to the high solubility of the product.
  • the solids are dried for 21 hours under vacuum at 50 0 C.
  • the flask is equipped with an overhead stirrer, internal temperature probe, and a condenser with nitrogen inlet.
  • the slurry should be cooled between 0 to 5 °C.
  • reaction is deemed complete by HPLC when less than or equal to 4% acetoacetic cyclopropyl amide and 76-80% of total area is 6-benzyloxy-1 ,2-dimethyl-1 H-indol- 3-carboxylic acid cyclopropyl amide, benzophenone, and regioisomer combined.
  • Cooling down to 40 S C should take at least 1 hour. Slow crystallization is desired to grow larger crystals.
  • Temperature should be held at 40 0 C for at least 12 hours.
  • Cooling down to room temperature should take at least 1 hour.
  • the slurry should be granulated for at least 3 hours at room temperature.
  • the chamber is equipped with a motorized stirrer, a nitrogen inlet, and a hydrogen inlet.
  • the chamber is purged with nitrogen three times and three times with hydrogen.
  • Example 8 Preparation of 1,2-dimethyl-6-[2-(1-methyl-1H-imidazol-2-yl)thieno[3,2- b]pyridine-7-yloxy]-1 H-indole-3-carboxylic acid cyclopropyl amide
  • a 100 ml. round bottom flask is charged with 6-hydroxy-1 ,2-dimethyl-1 H-indol-3- carboxylic acid cyclopropyl amide (1.00 g, 0.0041 mol), 7-chloro-2-(1-methyl-1H-imidazol-2- yl)thieno[3,2-b]pyridine (1.16 g, 0.0046 mol) and dimethyl acetamide (10 mL).
  • the mixture is cooled to below 5 °C and sodium tert-butoxide (0.63 g, 0.0066 mol) is added in one portion (notes 1 , 2, 3, 4).
  • the flask is equipped with an overhead stirrer, internal temperature probe, and a nitrogen inlet.
  • the slurry should be cooled between 0 to 5 °C.
  • reaction is deemed complete when less than 0.5% 6-hydroxy-1 ,2- dimethyl-1H-indol-3-carboxylic acid cyclopropyl amide remains as determined by HPLC.
  • Example 9 Re-crystallization of 1 ,2-dimethyl-6-[2-(1-methyl-1 H-imidazol-2-yl)thieno- [3,2-b]pyridine-7-yloxy]-1 H-indole-3-carboxylic acid cyclopropyl amide
  • the flask is equipped with an internal temperature probe and a condenser with nitrogen inlet.
  • Reaction should be cooled between 35 to 40 0 C.
  • This filtration is to remove DARCO ® and residual insoluble material.
  • Filtrate should be a clear, light orange/brown color.
  • Solids typically precipitate before reaching the total volume of 15.6 mL after the addition of methanol.
  • the distillation temperature should be 64 °C prior to final cooling for product isolation.
  • the flask is immersed in an ice/water bath and stirred until the internal temperature is 15 0 C.
  • Concentrated HCI (97 mL) is added by addition funnel while monitoring the internal pH of the aqueous phase at such a rate that the moderate bubbling and exotherm are controllable (note 12).
  • the target pH is ⁇ 2.
  • the pH of the aqueous layer is 1.9.
  • the solution is added to a separatory funnel and the layers separated.
  • the lower aqueous phase is discarded and the upper organic phase containing the desired product is washed with saturated aqueous sodium chloride (200 mL).
  • the phases are separated and the organic phase is added to a clean flask (notes 13 and 14).
  • the flask is equipped with an overhead stirrer, an internal temperature probe, Argon inlet and condenser.
  • the condenser has a gas-outlet at the top connected to a trap, where the outlet gas is bubbled through an aqueous solution of 75 g of Na 2 S 2 O 3 in 500 mL H 2 O to trap any liberated bromine.
  • the reaction is sampled and the majority of the solvent is removed from the sample by a slow stream of air.
  • the crude oil is dissolved in dichloromethane for 1 H NMR analysis.
  • the ratio of product to starting material is judged by the integration of the methyl doublet in the product (1.85 ppm) to the methyl triplet in the starting material (1.20 ppm).
  • the internal temperature is 20 0 C at the beginning of the 3- methoxybenzenethiol addition.
  • the thiol is added at such a rate that bubbling and exothermicity are controlled.
  • the total addition took 10 minutes at this scale.
  • the maximum internal temperature during addition is 25 0 C.
  • the organic phase is analyzed by HPLC (note 9) and contained negligible product.
  • the main impurity removed at this step is the 4.9 minute impurity believed to be the disulfide of 3-methoxybenzenethiol.
  • the internal temperature during the pH adjustment is 12 +/- 3 0 C.
  • the flask is equipped with an overhead stirrer and an Argon inlet.
  • reaction can be worked up at any time. This particular reaction is ran longer than average.
  • the addition rate of water should be adjusted to control the exotherm at room temperature or below.
  • the addition of precooled water is not necessary, but allows for quicker addition.
  • HPLC analysis of the aqueous layer of the filtrate shows negligible product.
  • HPLC analysis of the organic layer of the filtrate shows the undesired cyclization isomer as the main component , along with a small amount of desired product.
  • the product is 99.4% pure by HPLC analysis, contains no detectable isomeric product and only a trace of methylene chloride by 1 H NMR analysis.
  • the flask is equipped with an overhead stirrer, internal temperature probe, and Ar inlet.
  • the composition of the rinse solution is an estimated ratio of the solution composition after the distillation (measured by 1 H NMR analysis).
  • the solids are dried overnight in a vacuum oven at approximately 25 mm Hg and 45 to 50 0 C. KF shows 0.15% H 2 O.
  • the flask is equipped with an overhead stirrer, internal temperature probe, and Argon inlet.
  • the flask is immersed in a room temperature water bath.
  • the methionine is added in 3 portions to help control this exotherm.
  • the jacket temperature can be lowered for more efficient cooling and smaller time intervals between methionine additions.
  • HPLC analysis shows 18% remaining 7-chloro-2-(1-methyl-1H-imidazol-2- yl)thieno[3,2-b]pyridine (notes 2 and 3). Heating is continued for a total of 24 hours wherein HPLC analysis shows 4% 7-chloro-2-(1-methy!-1H-imidazol-2-yl)thieno[3,2-b]pyridine (note 4). The reaction is heated an additional 4 hours wherein HPLC analysis shows 3.2% 7-chloro- 2-(1 -methyl- 1H-imidazol-2-yl)thieno[3,2-b]pyridine. While still hot, water (800 mL) is added to the reaction mixture causing precipitation of the product (note 5).
  • the solution is cooled to room temperature with a water bath. After the internal temperature is cooled to 25 0 C, the mixture is filtered, the solids are rinsed with water (1 x 300 mL, 1 x 100 mL) and are dried overnight (note 6). The dried cake is added to a 3 liter flask and methylene chloride (1 ,050 mL) and ethanol (700 mL) are added followed by DARCO ® (G-60, -100 mesh, 35 g). The slurry is heated to 40 0 C for approximately 30 minutes with stirring to dissolve the crude product. The solution is cooled slightly (30-35 0 C) over 40 minutes and filtered through Celite ® (note 7).
  • the Celite ® cake is rinsed with solvent mixture (100 mL of 3:2 methylene chloride/ethanol).
  • the filtrate is added to a clean, dry 2 liter flask (note 8).
  • the solution is distilled under atmospheric pressure to remove methylene chloride.
  • the desired product begins to crystallize at an internal temperature of approximately 60 0 C (note 9).
  • the distillation is continued until the internal temperature reaches 75 0 C and the pot is held at this temperature for 15 to 20 min (note 10).
  • the slurry is cooled to room temperature, filtered, and the solids are rinsed with ethanol (2 x 100 mL).
  • the solids are dried to provide 45.09 g (65%) of the title product as a fluffy, off-white solid (notes 11 and 12).
  • the flask is equipped with an overhead stirrer, an internal temperature probe, and Argon inlet.
  • the internal temperature remains between 50 to 60 0 C.
  • the solution can be seeded prior to or at this point if desired.
  • the product is dried under house vacuum with an air bleed at 50 0 C overnight.
  • Tetrahydrofuran 500 mL is slowly added to the mixture by addition funnel and stirring is continued at 55 0 C for 15 minutes. The mixture is cooled to room temperature over 2 hours (note 3). The solution is filtered and the solids rinsed with solvent (220 mL of solution containing 120 mL of ethanol and 100 mL tetrahydrofuran). The solids are dried to provide 65.11 g (95%) of the title product as a yellow powder (notes 4 and 5).
  • 1 H NMR 300 MHz, d 6 -DMSO
  • 2.63 (s, 3), 2.85 (d, 3, J 4.5), 4.04 (s, 3), 6.90 (d, 1 ,
  • the flask is equipped with an overhead stirrer, an internal temperature probe, and addition funnel.

Abstract

L'invention concerne des procédés d'élaboration de composés représentés par les formules (I) et (XI), ou de sels ou solvates pharmaceutiquement acceptables de ces composés. Les composés représentés par la formule (I) ou (XI) sont utiles comme agents anti-angiogéniques et comme agents destinés à moduler et/ou à inhiber l'activité de protéines kinases, et permettent ainsi de traiter le cancer ou d'autres maladies associées à la prolifération cellulaire impliquant les protéines kinases.
PCT/IB2006/002371 2005-09-02 2006-08-31 Procede ameliores d'elaboration de derives d'heteroaryl amide benzocondenses de thienopyridines WO2007026221A2 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4719309A (en) * 1984-12-05 1988-01-12 Basf Aktiengesellschaft Preparation of imidazoles
WO1999024440A1 (fr) * 1997-11-11 1999-05-20 Pfizer Products Inc. Derives de thienopyrimidine et thienopyridine utiles comme agents anticancereux
US20040009965A1 (en) * 2002-06-14 2004-01-15 Agouron Pharmaceuticals, Inc. Benzofused heterozryl amide derivatives of thienopyridines useful as therapeutic agents, pharmaceutical compositions including the same, and methods for their use

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4719309A (en) * 1984-12-05 1988-01-12 Basf Aktiengesellschaft Preparation of imidazoles
WO1999024440A1 (fr) * 1997-11-11 1999-05-20 Pfizer Products Inc. Derives de thienopyrimidine et thienopyridine utiles comme agents anticancereux
US20040009965A1 (en) * 2002-06-14 2004-01-15 Agouron Pharmaceuticals, Inc. Benzofused heterozryl amide derivatives of thienopyridines useful as therapeutic agents, pharmaceutical compositions including the same, and methods for their use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J. A. RAGAN, J.W. RAGGON, P.D. HILL, B. P. JONES, R.E. MCDERMOTT, M.J. MUNCHHOF, M.A. MARX, J.M. CASAVANT, B.A. COOPER, J.L. DOTY: "Cross-coupling Methods for the Large-Scale Preparation of an Imidazole-Thienopyridine: Synthesis of [2-(3-Methyl-3H-imidazol-4-yl)-thieno[3,2- b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-a mine." ORGANIC PROCESS RESEARCH AND DEVELOPMENT, vol. 7, 2003, pages 676-683, XP002414438 *

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