WO1999006351A1 - Procede permettant de convertir des amino-n-oxydes propargyliques en enaminones - Google Patents

Procede permettant de convertir des amino-n-oxydes propargyliques en enaminones Download PDF

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WO1999006351A1
WO1999006351A1 PCT/US1998/015391 US9815391W WO9906351A1 WO 1999006351 A1 WO1999006351 A1 WO 1999006351A1 US 9815391 W US9815391 W US 9815391W WO 9906351 A1 WO9906351 A1 WO 9906351A1
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phenyl
chain alkyl
group
cycloalkyl
branched chain
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PCT/US1998/015391
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Russell George Dushin
Eugene John Trybulski
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American Home Products Corporation
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Priority claimed from US09/106,471 external-priority patent/US5932745A/en
Application filed by American Home Products Corporation filed Critical American Home Products Corporation
Priority to EP98935990A priority Critical patent/EP1000012A1/fr
Priority to AU85121/98A priority patent/AU747543B2/en
Priority to JP2000505115A priority patent/JP2001512095A/ja
Priority to CA002298595A priority patent/CA2298595A1/fr
Publication of WO1999006351A1 publication Critical patent/WO1999006351A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
    • C07C291/02—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds
    • C07C291/04—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds containing amino-oxide bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • 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
    • 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

  • This invention relates to a process for the production of ena inones from propargylic amine N-oxides. More particularly, this invention relates to a process for preparing amine N-oxides from corresponding propargylic amines using conventional oxidative methods and forming enaminones from the amine N-oxides by exposure to hydroxylic solvents in the presence or absence of metal catalysts with or without heating.
  • Enaminones are versatile synthetic intermediates that are easily converted into a wide variety of functional groups, including (but not limited to) ⁇ -aminoketones, ⁇ -hydroxyketones, alkyl-substituted enones, and numerous heterocycles including isoxazoles, pyrazoles, pyrimidines, pyridines and thiophenes. Enaminones are oftimes used in the production of compounds of commercial importance (pharmaceuticals, insecticides, dyestuffs, etc.).
  • Enaminones can be synthesized by a variety of methods including the reaction of an amine with a 1 ,3-diketone, a 3-keto ester, a vinylogous ester, a vinylogous acid chloride, a ⁇ -dialkoxy ketone, a ⁇ -cyanovinyl ketone, an acetylenic ketone, by the condensation of a ketone with N,N-dimethylformamide acetal, by the acylation of enamines, by reaction of ketene with enamines, by reaction of oxime sulfonates with silyl enol ethers, by the palladium assisted amination of an olefin, by the palladium catalyzed dehydrogenation of a ⁇ -amino ketone, or by the Mannich reaction of a ketone with a secondary amine and an orthoester.
  • Functionalized propargylic amines can be conveniently prepared by the copper- catalyzed Mannich reaction of terminal acetylenes with formaldehyde and amines (Mannich, Chem. Ber. 1933, 66, 418) or, in the case of 3-aryl or 3-vinyl substituted prop-2-ynyl amines, by palladium-catalyzed couplings of l-amino-prop-2-ynes with aryl or vinyl halides or triflates (Sanogashira, et.al. Tetrahedron Lett. 1975, 4467; Unroe, et.al. Synthesis 1987, 981; Stille, J.K. Angew. Chem.. Intl. Ed.
  • Substituted enaminones can result from the hydrolytic breakdown of certain substituted isoxazolines (Equation 2, below), as described by Liguori, et.al. Tetrahedron 1988, 44, 1255.
  • the isoxazolines of Liguori et al. were prepared by the 1, 3 -dipolar cycloaddition reaction of C-benzoyl-N-phenylnitrone with alkynes (formed as a mixture with its regioisomer). It appears that the substitution pattern about the isoxazoline ring influences the outcome of this hydrolytic reaction. This process is an isolated example of enaminone formation from isoxazolines and is not a generally applicable nor synthetically useful transformation.
  • the present invention provides a novel synthesis of enaminones from propargylic amine N-oxides upon exposure to hydroxylic solvents.
  • This new method of enaminone synthesis provides a convenient alternative to existing methods and further extends the range of starting materials that can be converted into enaminone products.
  • This invention provides a novel process for the synthesis of enaminones of Formula (I): (I wherein:
  • X is selected from the group of H, C,-C 6 straight chain alkyl, C 3 -C 6 branched chain alkyl, C 3 -C 7 cycloalkyl, -CH 2 -phenyl, or -CH 2 -substituted phenyl;
  • Rj is selected from the group of hydrogen, C r C 6 straight chain alkyl, C 3 -C 6 branched chain alkyl, C 3 -C 7 cycloalkyl, phenyl, substituted phenyl, -CH 2 -phenyl, or - CH 2 -substituted phenyl or a group of the formulae:
  • the C 3 -C 7 cycloalkyl groups being optionally substituted by from 1 to 3 groups independently selected from R,-R ⁇ ,;
  • R 2 and R 3 are independently selected from the group of C,-C 6 straight chain alkyl, C - C 6 branched chain alkyl, C 3 -C 7 cycloalkyl, or -CH 2 -phenyl;
  • R 2 and R 3 may also be joined to form a ring of from three to six atoms.
  • cyclic versions of -NR 2 R 3 include, but are not limited to, the following:
  • R 4 and R 4 are independently selected from the group of hydrogen, CpC 6 straight chain alkyl, C -C 6 branched chain alkyl, C 3 -C 7 cycloalkyl, -OR,,, -NR,,R ]3 , - NR,,C(O)OR, 0 , -NR,,C(O)R 10 , -OC(O)R, 0 , -OC(O)OR, 0 , or -OC(O)NHR, 0 ;
  • Substituted phenyl and -CH 2 -substituted phenyl are, respectively:
  • R 10 is selected from the group of hydrogen, C r C
  • R,, and R are independently selected from the group of hydrogen, C]-C 6 straight chain alkyl, C 3 -C 6 branched chain alkyl, C 3 -C 7 cycloalkyl, phenyl, or -CH 2 - phenyl;
  • R ]2 and R, 2 are independently selected from the group of hydrogen, C r C 6 straight chain alkyl, C 3 -C 6 branched chain alkyl, C 3 -C 7 cycloalkyl, phenyl, substituted phenyl, -CH 2 -phenyl or -CH 2 -substituted phenyl, the C 3 -C 7 cycloalkyl groups being optionally substituted by from 1 to 3 groups independently selected from
  • R, 2 and R, 2 may also optionally be taken together with their associated carbon to form a carbocyclic ring of from three to seven carbon atoms;
  • R 13 is an amino-protecting group used to protect the moiety NR, herein which may be any group known to be useful to protect amino groups under the conditions contemplated as outlined in Greene, Protective Groups in Organic Synthesis Volume 2, Chapter 7, 1991, and references therein. Examples of such useful amino protecting groups include but are not limted to:
  • acyl type protective groups such as formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, o- nitrophenoxyacetyl, sec-butyryl, pivaloyl- (also known as tert-butyryl), cyclopropanoyl, benzoyl, o-nitrobenzoyl, -chlorobutyryl, or the like; or (b) sulfonyl type protecting groups such as benzenesulfonyl, toluenesulfonyl
  • sulfenyl type protecting groups such as benznesulfenyl, o- nitrobenzenesulfenyl, pentachlorobenzenesulfenyl, and the like; or
  • urethane type protecting groups such as benzyloxycarbonyl, p- chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p- bromobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o- nitrobenzyloxycarbonyl, tert-butyloxycarbonyl, tert-amyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, allyloxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, 9- fluorenylmethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, and the like.
  • NR,,R 13 may also be optionally concatentated together or exist as a cyclic imide of the formula:
  • R, 2 and R 12 are selected from non-substituted phenyl or benzyl.
  • Another subgroup among those disclosed herein are those in which the -CH 2 -phenyl groups symbolized by X are unsubstituted.
  • Ri is selected from the group of C,-C 6 straight chain alkyl, C 3 - branched chain alkyl, C 3 -C 7 cycloalkyl, phenyl, -CH 2 -phenyl, or the moieties:
  • R 2 and R are independently selected from the group of C,-C 6 straight chain alkyl, C 3 - C 6 branched chain alkyl, C 3 -C 7 cycloalkyl, or -CH 2 - phenyl.
  • R 2 and R 3 may also be joined to form a ring of from three to six atoms to create cyclic versions of -NR 2 R 3 , which include, but are not limited to, the following:
  • R 5 , R 6 R 8 , Ro are independently selected from the group of hydrogen, halogen, trifluoromethyl, C 2 -C 6 perfluoroalkyl, C r C 6 straight chain alkyl, C 3 -C 6 branched chain alkyl, C 3 -C 7 cycloalkyl, -CN, -NO 2 , -OR,,, -CO 2 R, rule -NR,,R 13 , -NR,,C(O)OR,, . -NR M C(O)R ⁇ ., -OC(O)R,,, -OC(O)OR,,, or -OC(O)NHR n ;
  • R 2 and R 3 are independently is selected from the group of C,-C 6 straight chain alkyl
  • cyclic versions of -NR 2 R 3 include but are not limited to the following:
  • R 5 , R 6 R 8 , R g are independently selected from the group of hydrogen, halogen, trifluoromethyl, C 2 -C 6 perfluoroalkyl, C C 6 straight chain alkyl, C 3 -C 6 branched chain alkyl, C 3 -C 7 cycloalkyl, -CN, -NO,, -OR, , , -CO 2 R, , ,
  • R,, and R, are selected from the group of hydrogen, C r C 6 straight chain alkyl, C 3 -C 6 branched chain alkyl, C 3 -C 7 cycloalkyl, phenyl, or -CH 2 -phenyl;
  • R, 3 is selected from the group of hydrogen, C,-C 6 straight chain alkyl, C 3 -C 6 branched chain alkyl, C 3 -C 7 cycloalkyl, phenyl, or an amino-protecting group used to transiently protect the moiety NR, herein which may be any group known to be useful to protect amino groups under the conditions contemplated as outlined in Greene, Protective Groups in Organic Synthesis Volume 2, Chapter 7, 1991, and references therein. Examples of such useful amino protecting groups include those described above.
  • NR,,R, 3 may also optionally exist as a cyclic imide of the formula:
  • R ! is the moiety:
  • R 2 and R 3 are independently selected from the group of C,-C 6 straight chain alkyl, C 3 - C 6 branched chain alkyl, -CH 2 - phenyl or C 3 -C 7 cycloalkyl. R 2 and R 3 may also be joined to form a ring of from three to six atoms.
  • cyclic versions of -NR 2 R 3 include but are not limited to the following:
  • R 5 , R 6 R 8 , R 9 are independently selected from the group of hydrogen, halogen, trifluoromethyl, C 2 -C 6 perfluoroalkyl, C r C 6 straight chain alkyl, C 3 -C branched chain alkyl, C 3 -C 7 cycloalkyl, -CN, -NO 2 , -OR,,, -CO 2 R,,, -NR,,R, 3 , -NR,,C(O)OR,, rule -NR,,C(O)R meaning,, -OC(O)R,,, -OC(O)OR,, or -OC(O)NHR réelle;
  • R,, and R, r are independently selected from the group of hydrogen, C r C 6 straight chain alkyl, C 3 -C 6 branched chain alkyl, C 3 -C 7 cycloalkyl, phenyl, or -CH 2 - phenyl;
  • R 13 is selected from the group of hydrogen, C straight chain alkyl, C 3 -C 6 branched chain alkyl, C 3 -C 7 cycloalkyl, phenyl, or an amino-protecting group used to transiently protect the moiety NR, herein which may be any group known to be useful to protect amino groups under the conditions contemplated as outlined in Greene, Protective Groups in Organic Synthesis volume 2, Chapter 7, 1991, and references therein. Examples of such useful amino protecting groups include, but are not limted to, those described above.
  • NR,,R, 3 may also optionally exist as a cyclic imide of the formula:
  • Another preferred process of this invention provides for synthesis of enaminones of the forumula:
  • X is selected from the group of H, C,-C 6 straight chain alkyl, C,-C 6 branched chain alkyl, C 3 -C 7 cycloalkyl, phenyl, or -CH 2 -phenyl;
  • Ri is selected from the group of hydrogen, C,-C 6 straight chain alkyl, C -C 6 branched chain alkyl, C 3 -C 7 cycloalkyl, phenyl, substituted phenyl, -CH 2 -phenyl, or -CH 2 -substituted phenyl, the substituents of which are as described above, or a group of the formulae:
  • R 2 and R are independently is selected from the group of C,-C 6 straight chain alkyl
  • cyclic versions of -NR 2 R 3 include, but are not limited to, the following:
  • R, 2 and R, 2 are independently selected from the group of hydrogen, C r C 6 straight chain alkyl, C -C 6 branched chain alkyl, C 3 -C 7 cycloalkyl, phenyl, or -CH 2 - phenyl, the C 3 -C 7 cycloalkyl, phenyl, and -CH 2 -phenyl being optionally substituted as described in the groups above; with a proviso that R 12 and R, 2 . are not both phenyl or substituted phenyl; the process comprising converting an amine N-oxide of the formula (II):
  • the conversion of the amine N-oxide into an enaminone may be accomplished by a number of embodiments within the scope of this invention.
  • the amine N-oxide may be introduced into a suitable hydroxylic solvent, preferably with stirring, at or between about room or ambient temperature and about the reflux temperature of the solvent.
  • the introduction of the amine N-oxide to a hydroxylic solvent, preferably with stirring may be accomplished in the presence of an acceptable catalyst, such as a palladium(II) catalyst or a copper (I) catalyst, at or between room temperature and the reflux temperature of the solvent.
  • the amine N-oxide may be converted into the enaminone in a biphasic mixture of water and a water immiscible solvent, such as dichloromethane, in the presence or absence of a suitable catalyst, such as a palladium(ll) catalyst or a copper (I) catalyst, and a phase transfer catalyst, such as a quaternary ammonium salt, at or between ambient temperature and the reflux temperature of the organic solvent, preferably with stirring.
  • a suitable catalyst such as a palladium(ll) catalyst or a copper (I) catalyst
  • phase transfer catalyst such as a quaternary ammonium salt
  • the amine N-oxides converted in this process may be formed by oxidizing an amine of the formula (HI):
  • this invention comprises a process for converting an amine of Formula (III) to an enaminone of Formula (I), the process comprising the steps of:
  • step b) converting the amine N-oxide of step a) to an enaminone of Formula (I) by treating the amine N-oxide with a hydroxylic solvent in a manner described above.
  • the hydroxylic solvents useful with this invention may be defined as any solvent or combination of solvents composed of or containing water, any C,-C 8 straight chain or branched chain alkyl alcohol, ethylene glycol, polyethylene glycol, 1 ,2- propylene diol, polypropylene glycol, glycerol, 2-methoxyethanol, 2-ethoxyethanol, 2,2,2-trifluoroethanol, benzyl alcohol, phenol, or any equivalent solvent that contains one or more free hydroxyl (-OH) substituent(s) that is known to those skilled in the art.
  • Solvent systems containing one or more cosolvents, along with one or more solvents may be used for the processes of this invention.
  • the cosolvents referred to herein may be defined as a diluent of the main solvent(s) and can be selected from: hydrocarbons such as pentane, hexane or heptane; aromatic hydrocarbon such as benzene, toluene or xylene; ethers such as diethyl ether, tetrahydrofum, dioxane or dimethoxy ethane; chlorinated hydrocarbons such as dichloromethane, chloroform, dichloroethane, or tetrachloroethane; or other common solvents such as ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dimethylsulfoxide, acetone, or the like.
  • R 2 ⁇ R 3j R 5? R 6, R 8j R 9 ⁇ and Rj i are as defined above, may be readily prepared from the corresponding aryl bromide, iodide, or triflate in a manner similar to that described in the literature (e.g. Sanogashira, et.al. Tetrahedron Lett. 1975, 4467; Unroe, et.al. Synthesis-Stuttgart 1987, 981) and are readily converted by any of a number of standard oxidative methods (Albini, A. Synthesis 1993. 263) or by treatment with dioxirane reagents (Murray, R.W. Chem. Rev.
  • the bromocarboxylic acid 1 is converted into the corresponding ester 2 by treating the carboxylic acid with thionyl chloride at temperatures ranging from ambient to the reflux temperature of the solvent, or with oxalyl chloride in an aprotic solvent such as dichloromethane or tetrahydrofuran in the presence of a catalytic amount of dimethylformamide at temperatures ranging from 0°C to 40°C followed by the addition of methanol.
  • thionyl chloride at temperatures ranging from ambient to the reflux temperature of the solvent, or with oxalyl chloride in an aprotic solvent such as dichloromethane or tetrahydrofuran in the presence of a catalytic amount of dimethylformamide at temperatures ranging from 0°C to 40°C followed by the addition of methanol.
  • an aprotic solvent such as dichloromethane or tetrahydrofuran
  • the methylester of formula 2 is coupled with a dialkylamino propyne, preferably 1-dimethylamino propyne, in the presence of a catalyst such as bis(triphenylphosphine) palladium(II) chloride and copper(I) iodide in an organic base such as triethylamine as the solvent and at temperatures ranging from ambient to 80°C essentially according to the procedures of Alami et al. Tetrahedron Lett 1993, 34, 6403, and of Sanogashira et al. Tetrahedron Lett. 1975, 4467 to provide the substituted acetylene 3.
  • a catalyst such as bis(triphenylphosphine) palladium(II) chloride and copper(I) iodide
  • organic base such as triethylamine
  • the intermediate 3 is subsequently converted into its N-oxide by treatment with an oxidizing agent using any of a number of standard oxidative procedures (Albini, A. Synthesis 1993, 263) or with dioxirane reagents (Murray, R.W. Chem. Rev. 1989, 1 187), in an aprotic organic solvent such as dichloromethane at temperatures below ambient.
  • the intermediate N-oxide is not isolated but is rearranged in situ to an enone of formula 4 by heating in a hydroxylic solvent such as methanol or by using any of the procedures described herein.
  • the major isomer, compound 6, is separated by means of chromatography and/or crystallization and subsequently hydrolyzed with an aqueous base such as sodium hydroxide in methanol (or lithium hydroxide in tetrahydrofuran) to the desired carboxylic acid of formula 8.
  • an aqueous base such as sodium hydroxide in methanol (or lithium hydroxide in tetrahydrofuran)
  • the intermediate carboxylic acid 8 is then converted into an acylating species, preferably an acid chloride (bromide or iodide) of formula 9 by procedures analogous to those described hereinbefore.
  • the acylating agent 9 is then used to acylate a tricyclic benzodiazepine such as either 10,1 l-dihydro-5H-pyrrolo[2,l-c][l,4]benzodiazepine (Albright etal. US patent 5,536,718 July 16, 1996) or 6, 1 l-dihydro-5H-pyrido ⁇ 2,3- b][l,5]benzodiazepine to afford compounds 10 and 11, respectively.
  • R 2 ⁇ R 3, R 5 , R ⁇ R 8, R > Ri i and R] r are as defined above, may be readily prepared from the corresponding aryl bromide, iodide, or triflate in a manner similar to that described in the literature (e.g. Sanogashira, et.al. Tetrahedron Lett. 1975, 4467; Unroe, et.al. Synthesis-Stuttgart 1987, 981) and are readily converted by any of a number of standard oxidative methods (Albini, A. Synthesis 1993. 263) or by treatment with dioxirane reagents (Murray, R.W. Chem. Rev.
  • the enaminone 15 (and thence compounds 10 and 11) may also be prepared utilizing this novel chemistry starting from 3-chloro-4-iodo aniline (12) through the sequence of steps shown in Scheme II.
  • the aniline derivative 12 is treated with di-tert- butyl dicarbonate and diisopropylethylamine in refluxing tetrahydrofuran to afford compound 13.
  • the aryliodide derivative of formula 13 is coupled with a dialkylamino propyne, preferably 1-dimethylamino propyne, in the presence of a catalyst such as bis(triphenylphosphine) palladium(II) chloride and copper(I) iodide in an organic base such as triethylamine as the solvent and at temperatures ranging from ambient to 80°C essentially according to the procedures of Alami et al.. Tetrahedron Lett.. 34, 6403 (1993), and of Sanogashira et al., Tetrahedron Lett.. 4467 (1975) to provide the substituted acetylene 14.
  • a catalyst such as bis(triphenylphosphine) palladium(II) chloride and copper(I) iodide
  • organic base such as triethylamine
  • the intermediate 14 is subsequently converted into its N- oxide by treatment with an oxidizing agent using any of a number of standard oxidative procedures (Albini, A. Synthesis 263 (1993) or with dioxirane reagents (Murray, R.W., Chem. Rev. 1187 (1989), in an aprotic organic solvent such as dichloromethane at temperatures below ambient.
  • the intermediate N-oxide is not isolated but is rearranged in situ to an enaminone of formula 15 by heating in a hydroxylic solvent such as methanol or by using any of the procedures described herein.
  • Treatment of 15 with hydrazine in acetic acid at temperatures ranging from ambient to reflux temperature of the solvent leads to a compound of formula 16.
  • the heterocyclic nitrogen in compound 16 is alkylated by treatment with a strong base such as sodium or potassium hydride and methyl iodide in an aprotic organic solvent such as dimethylformamide or tetrahydrofuran at temperatures ranging from 0°C to 80°C leading to a mixture of regioisomers 17 and 18.
  • a strong base such as sodium or potassium hydride and methyl iodide
  • an aprotic organic solvent such as dimethylformamide or tetrahydrofuran
  • the substituted pyrazole derivative 17 may be dehalogenated by hydrogenation over palladium catalysts in alcohol solvents (Weizmann, A. J. Am. Chem. Soc. 1949, 71, 4154), to afford 19 and then Boc-deprotected by treatment with trifluoroacetic acid to give the pyrazoloaniline 20.
  • This aniline derivative 20 may be chlorinated by treatment with N-chlorosuccinimide (Neale, R.S. et.al. J. Org. Chem. 1964, 29, 3390) to yield compound 21 which is then subjected to the Sandmeyer reaction (Clarke, H.T. et.al. Organic Synthesis. Vol. I. 1941, 514) to provide nitrile 22.
  • Compound 22 may be converted to the carboxylic acid 8 by sequential treatment with basic hydroperoxide (Katritzky, A.R. et.al. Synthesis 1989, 949) followed by hydrolysis of the resulting amide 23 by treatment with dilute sulfuric acid and sodium nitrite (Hales, N.J. et al., Tetrahedron 1995, 57, 7403).
  • the conversion of carboxylic acid 8 to the vasopressin agonists 10 and 11 is shown in Scheme I above.
  • Structures 10 and 11 are non-peptide mimics of vasopressin (antidiuretic hormone, ADH), a nine amino acid peptide hormone and neurotransnutter
  • Vasopressin plays a vital role in the body's conservation of water by concentrating the u ⁇ ne at the site of the collecting ducts of the kidney
  • the collecting ducts of the kidney are relatively impermeable to water in the absence of vasopressin at its receptors and therefore, the hypotonic fluid formed after filtering through the glomeruh, passing the proximal convoluted tubules, the loops of Henle, and the distal convoluted tubules, will be excreted as dilute urine
  • vasopressin is released from the pituitary and activates the vasopressin V 2 receptors in the collecting ducts of the kidney rendering the ducts very permeable to water, and hence water is reabsorbed and a concentrated u ⁇ ne is excreted
  • ADH antidiuretic
  • vasopressin receptors in the kidneys are normal While they remain very sensitive to the action of vasopressin and vasopressin V2 agonists, little or no vasopressin is produced Because they cannot concentrate the urine, they may produce as high as 10 times the urine volume of their healthy counterparts Vasopressin and desmopressin, which is a peptide analog of the natural vasopressin, are being used in patients with central diabetes insipidus Vasopressin V2 agonists are also useful for the treatment of nocturnal enuresis, noctu ⁇ a, urinary incontinence and temporary delay of urination whenever desirable
  • vasopressin-hke compounds prepared using the intermediates disclosed m this invention, posses therapeutic effects similar to vasopressin without the limitations associated with peptide derived drugs
  • R 4 is hydrogen and R 2 and R 3 are defined as above, may be readily prepared from procedures outlined by Dickinson et al. U.S. Patent No. 3,354,178; wherein R 4 is hydrogen and R, and R 3 are also joined to form a pyrrolidine ring is readily obtained commercially as oxotremorine and, wherein R 4 is defined as above but not hydrogen and R 2 and R 3 are defined as above, may be readily prepared from procedures outlined by Trybulski et al. U.S. Patents Nos. 5,550,257 and 4,937,235;
  • a transition metal catalyst such as palladium on carbon, platinum oxide or raney nickel in an alcohol solvent such as ethanol
  • metal hydride reagents such as by the exposure to boron trifloride etherate and lithium triethylborohydride in tetrahydrofuran at reduced temperatures (as per the methods of Wasserman and Chi, Tetrahedron Letters 1994, 35 (52), 9779), or by exposure to boron trifloride etherate and a copper hydride species generated from cuprous bromide dimethyl sulfide complex and lithium dimethoxyaluminium hydride (as per the methods of Commins and LaMunyon, Tetrahedron Letters 1989, 30 (38), 5053) produce compound 25.
  • Compounds of structure 25 are hydrolytic and possibly metabolic products of oxotremorine-like compounds (Lindeke, B. J. Pharm. Pharmac, 1972, 24, 25-31).
  • R, 2 and R, 2 . are defined above, may be readily prepared by addition of the lithium anion of a propargylic amine by methods known to those skilled in the art, or alternatively and when X as defined above is not H, by addition of the bis-lithium anion of a propargylic alcohol to a l-(dialkylaminomethyl)benzotriazole (Katritzky. A.R.: Gallos, J.K.; Yannakopoulou, K. Synthesis 1989, 31), and are readily converted by any of a number of standard oxidative methods (Albini, A. Synthesis 1993, 263) or by treatment with dioxirane reagents (Murray, R.W. Chem. Rev.
  • the propagylic amine 27 may be prepared by the copper-catalyzed displacement of the propargylic acetate 26 (which is readily prepared according to the methods of Clarke and Pinder, /. Chem. Soc. 1958, 1967) by pyrrolidine.
  • the propargylic amine 27 may be mono-lithiated at the terminal position by treatment at temperatures below ambient, preferably about -78°C, in tetrahydrofuran with a slight molar excess of n-butyl lithium and then added to acetophenone to provide the propargylic amino alcohol 28.
  • Intermediate 28 is subsequently converted into its N- oxide by treatment with an oxidizing agent using any of a number of standard oxidative procedures (Albini, A.
  • Diborane dimethylsulfide complex 35 mL was added via syringe to a suspension of 6,l l-dihydro-5H-pyrido[2,3-b][l,5]benzodiazepin-5-one 1:1 salt with hydrochloric acid of Step A (25 g, 0.1 mole) in dioxane (230 mL) under nitrogen. The mixture was sonicated overnight at room temperature and then evaporated to dryness in vacuo. The green residue was treated with cold 2N hydrochloric acid and diethyl ether. The cold aqueous layer was basified with 50% aqueous sodium hydroxide (to pH 9) and the basic layer extracted with ethyl acetate.
  • the mixture prepared above (Example 38) of 2-(l-(3-dimethylamino-prop-2-en- l-one))-phenol and chromone may be dissolved in methanol (20 ml) and stirred in the presence of Amberlyst® (1 g) for 4 hours. After removing the solvent in vacuo. the residue can be purified by chromatography over silica gel (25% ethyl acetate in hexanes can be used as the eluant) to give the desired chromone product.

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Abstract

L'invention concerne l'utilisation d'un solvant hydroxylique pour préparer des énaminones à partir des amino-N-oxydes ou des amines propargyliques correspondantes par le procédé général (A) schématisé ci-dessus.
PCT/US1998/015391 1997-07-30 1998-07-24 Procede permettant de convertir des amino-n-oxydes propargyliques en enaminones WO1999006351A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP98935990A EP1000012A1 (fr) 1997-07-30 1998-07-24 Procede permettant de convertir des amino-n-oxydes propargyliques en enaminones
AU85121/98A AU747543B2 (en) 1997-07-30 1998-07-24 Process for converting propargylic amine-N-oxides to enaminones
JP2000505115A JP2001512095A (ja) 1997-07-30 1998-07-24 プロパルギルアミンｎ−オキシドをエナミノンに変換する方法
CA002298595A CA2298595A1 (fr) 1997-07-30 1998-07-24 Procede permettant de convertir des amino-n-oxydes propargyliques en enaminones

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US90329997A 1997-07-30 1997-07-30
US08/903,299 1997-07-30
US09/106,471 1998-06-30
US09/106,471 US5932745A (en) 1997-07-30 1998-06-30 Process for converting propargylic amine-N-oxides to enaminones

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Cited By (1)

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US6235900B1 (en) * 1999-02-04 2001-05-22 American Home Products Corporation Tricyclic pyridine N-oxides vasopressin agonists

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JP4706320B2 (ja) * 2005-04-25 2011-06-22 宇部興産株式会社 Ｎ，ｎ−ジメチルアミノアルケノン化合物の製法
JP4706325B2 (ja) * 2005-05-10 2011-06-22 宇部興産株式会社 ４−置換−１−ｎ，ｎ−ジアルキルアミノ−１−ブテン−３−オンの取得方法
WO2013006143A1 (fr) * 2011-07-06 2013-01-10 Agency For Science, Technology And Research Procédé de production d'un aminopropyne ou d'une énaminone

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5059709A (en) * 1990-11-13 1991-10-22 American Cyanamid Company Process for the synthesis of α-[(dialkylamino)substituted-methylene]-β-oxo-(substituted)propanentriles

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5059709A (en) * 1990-11-13 1991-10-22 American Cyanamid Company Process for the synthesis of α-[(dialkylamino)substituted-methylene]-β-oxo-(substituted)propanentriles

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ABDUL-HUSSAIN KHUTHIER ET AL.: "Rearrangement of Prop-2-ynylic N-Oxides to O-Allenyl Hydroxylamines", JOURNAL OF THE CHEMICAL SOCIETY, CHEMICAL COMMUNICATIONS., 1979, LETCHWORTH GB, pages 9 - 10, XP002082347 *
G. HALLSTRÖM ET AL.: "Decomposition of Prop-2-ynlic N-Oxides to Acrolein and Schiff Bases via O-Allenyl Hydroxylamines", TETRAHEDRON LETTERS, no. 7, 1980, OXFORD GB, pages 667 - 670, XP002082349 *
J. CYMERMAN CAIG ET AL.: "An Improved Preparation of Tertiary Amine N-Oxides", JOURNAL OF ORGANIC CHEMISTRY, vol. 35, no. 5, May 1970 (1970-05-01), EASTON US, pages 1721 - 1722, XP002082350 *
J. CYMERMAN CRAIG ET AL.: "Novel Rearrangement of Prop-2-ynyl N-Oxides to Hydroxylamine O-Allenyl Ethers: Mechanistic Studies", TETRAHEDRON LETTERS, no. 42, 1979, OXFORD GB, pages 4025 - 4028, XP002082348 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6235900B1 (en) * 1999-02-04 2001-05-22 American Home Products Corporation Tricyclic pyridine N-oxides vasopressin agonists

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AU8512198A (en) 1999-02-22
AU747543B2 (en) 2002-05-16
JP2001512095A (ja) 2001-08-21
CA2298595A1 (fr) 1999-02-11
EP1000012A1 (fr) 2000-05-17
TW513394B (en) 2002-12-11
AR013375A1 (es) 2000-12-27

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