Classifications

• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
  • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
  • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D241/20—Nitrogen atoms

Definitions

• the present invention relates to novel pyrazines and to methods of their use in preparing further imidazopyrazine compounds.
• the luminescent chromophores such as Coelenterazine which can be isolated from Aequora Victoria, as described in the Article by Shimomura O, Johnson Fitt. and Morisett in Biochemistry 1974, 13,3278-3286, contain the imidazopyrazine ring system.
• Coelenterazine has been extensively studied because of the bioluminescent process which is triggered by calcium ions and has proved to be a sensitive method for the detection and quantification of calcium ions.
• Coelenterazine and analogues have been prepared by the "Kishi route", as described in the Article by Shimomura O, Musieki B. Kishi Y, Biochem J., 1989, 261,913-920.
• the aromatic groups Ar which can be used include groups such as phenyl, naphthyl and thiophenyl.
• the substituted aromatic groups include alkyl, aryl and substituted aryl, alkaryl, halides, halide substituted aryl groups and groups such as trifiuoromethyl, fluoro and alkoxy groups.
• the Ph group can be substituted by any of the substituents listed above.
• the invention also provides pyrazines of the formula
• Ph is an aromatic or substituted aromatic group e.g.as Ar in (I).
• the invention further provides pyrazines of formula
• the compounds (I) of the present invention can be prepared by the reaction of the 5-halo substituted pyrazine:-
• the catalysts which can be used in the process of the present invention include, but are not limited to, platinum groups catalysts, particularly palladium compounds.
• the preferred palladium catalysts are Pd(II) complexes, particularly organic palladium compounds such as diphenyl phosphino complexes of Pd(II) e.g. [l ,4-bis(diphenylphosphino)butane]palladium(II) chloride and [1,1 bis(diphenylphosphino)ferrocene]palladium(II) acetate.
• reaction of compound B with the arylboronic acid preferably takes place in a solvent which will depend on the nature of the catalyst used.
• solvents which can be used are toluene, tetrahydrofuran, dimethyl formamide, optionally in the presence of co-solvents such as water or an amine such as triethylamine.
• the reaction can be illustrated as follows:
• Preferred Ar groups are 4-MeOC 6 H 4 , C 6 H 5 , naphthyl, 4-FC 6 H 4 , 4-CF 3 C 6 H 4 and 2-thienyl.
• Compound B can be prepared by bromination of the corresponding pyrazine:-
• the pyrazine C can be prepared by known methods, for example, as described in the Article by Turek A, Mojovie L, Queguiner G, Synthesis 1988, 881-884.
• 2-chloropyrazine was metallated using lithium tetramethylpiperidide and reacted with benzaldehyde to afford the alcohol (3) in 88% yield.
• Oxidation of (3) using freshly-prepared MnO 2 gave the ketone (4) in 93% yield.
• Introduction of the amino group was achieved by heating ketone (4) with a solution of ammonia in ethanol at 120°C overnight leading to aminopyrazine (5) in 63% yield.
• the preferred method for cleaving the methyl aryl ether is by reaction with ethanethiolate.
• the phenol (II) obtained can be converted to the phenol (III) by reduction.
• Any reduction which reduces the ketone group can be used such as using a metallic catalyst such as platinum or palladium or carbon, treatment with zinc and hydrochloric acid under usual Clemenson conditions (M Lucas and F Solano, Anal. Biochem, 1992 206,273).
• Reduction of the ketone to alcohol e.g. using NaBH 4 in methanol followed by treatment of the alcohol with Et 3 SiH and trifluoracetic acid.
• a preferred method is a Wolff-Kishner reduction by reaction with hydrazine hydrate and potassium hydroxide in ethylene glycol.
• the above compounds of the present invention can be used as intermediates to prepare compounds containing the imidazopyrazine ring system such as coelenterazine by reduction of the benzoyl substituent to benzyl, condensation with 4-methoxybenzylglyoxal and cleavage of the methyl ethers using pyridinium bromide or by reaction with a ketoaldehyde.
• compounds containing the imidazopyrazine ring system such as coelenterazine by reduction of the benzoyl substituent to benzyl, condensation with 4-methoxybenzylglyoxal and cleavage of the methyl ethers using pyridinium bromide or by reaction with a ketoaldehyde.
• the ⁇ -ketoaldehyde can be prepared by known methods, for example by the route described by S Inove, S Sugiura, H Kakoi and K Hasizume. Chem. Letters 1975, 141. In this route the phenol group in 4-hydroxy phenyl acetic acid is acylated, converted to the acid chloride (with SOCU) and reacted with diazomethane to give the ⁇ -diazoketone.
• the ⁇ -diazoketone was reacted with dry HBr to give the bromomethyl ketone which is reacted with silver nitrate in acetonitrile to give the nitrate ester which is reacted with sodium acetate to give the ⁇ -ketoaldehyde.
• the compound (V) is found to exist mainly in the enol form in solution in many solutions.
• Example 1 The invention is further described in the following Examples in which Examples 1 to 7 describe the preparation of the novel pyrazines of the invention and Example 8 illustrates the production of coelenterazine with the preparation of the 2-amino-3-benzoyl-5-(4'-methoxyphenyl)pyrazine used in Example 8 prepared as in Example 1.
• Example 1
• Phenyl and naphthylboronic acids reacted cleanly with (6) and gave the heterobiaryl products 7b and 7c in very high yields (entries 3 and 4).
• the introduction of electron-withdrawing substituents on the boronic acid moiety presented no problems and both the 4-fluoro and the 4-trifluoromethyl-substituted boronic acids reacted within a reasonable timescale to give the respective coupled products 7d and 7e in high yields.
• Diazald (7.4 g, 0.02 mol) in dry diethyl ether (82 ml) was added dropwise to a warm solution of aqueous potassium hydroxide (7.4 g, in 12 ml of H 2 O) and di(ethyleneglycol)ethyl ether (17 ml). Diazomethane was collected as a co-distillate with diethyl ether.
• Ethanethiol (0.6 ml. 8 mmol), dissolved in dry DMF (3 ml) was added to a suspension of sodium hydride (5.5 equiv) in dry DMF (2 ml) under an atmosphere or argon. The mixture was stirred for 5 mins before a solution of 2-amino-3 -benzoyl -5-(p-methoxyhenyl)pyrazine (520 mg, 1.7 mmol) in DMF (4 ml) was added. The solution was heated at 100°C for 8 hours. On cooling, the mixture was acidified with 10% aqueous HC1 and washed with EtOAc. The aqueous phase was made alkaline (10% aqueous NaOH) and extracted with EtOAc.

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• 1997
  • 1997-05-06 CA CA002253910A patent/CA2253910A1/en not_active Abandoned
  • 1997-05-06 EP EP97920835A patent/EP0914318A1/de not_active Withdrawn
  • 1997-05-06 WO PCT/GB1997/001227 patent/WO1997043267A1/en not_active Application Discontinuation

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