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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
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  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
  • C07C233/11—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
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  • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
  • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
  • C07C235/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and unsaturated
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings 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
  • C07D233/44—Nitrogen atoms not forming part of a nitro radical
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  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings 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
  • C07D233/44—Nitrogen atoms not forming part of a nitro radical
  • C07D233/48—Nitrogen atoms not forming part of a nitro radical with acyclic hydrocarbon or substituted acyclic hydrocarbon radicals, attached to said nitrogen atoms
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  • 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
  • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
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  • 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
  • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
  • C07D241/28—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms
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  • 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
  • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
  • C07D241/28—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms
  • C07D241/30—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms in which said hetero-bound carbon atoms are part of a substructure —C(=X)—X—C(=X)—X— in which X is an oxygen or sulphur atom or an imino radical, e.g. imidoylguanidines
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  • 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
  • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
  • C07D241/28—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms
  • C07D241/30—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms in which said hetero-bound carbon atoms are part of a substructure —C(=X)—X—C(=X)—X— in which X is an oxygen or sulphur atom or an imino radical, e.g. imidoylguanidines
  • C07D241/32—(Amino-pyrazinoyl) guanidines
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
  • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
  • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
  • C07D241/40—Benzopyrazines
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  • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
  • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
  • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
  • C07D241/40—Benzopyrazines
  • C07D241/44—Benzopyrazines 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 carbon atoms of the hetero ring
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
  • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
  • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
  • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

• the present invention relates to a novel process for the preparation of compounds of general formula (I)
• tert-butyl-methylisoxazolium perchlorate also referred to as “Woodward's reagent L” is known from the prior art as an intermediate for the synthesis of compounds of formula (III) (Laeckmann, D. et al. Bioorg. Med. Chem. 10 (2002) 1793-1804). Due to the known oxidizing properties of the perchlorate ion, the use of tert-butyl-methylisoxazolium perchlorate may constitute a substantial hazard, especially when applied in larger scale.
• the problem of the present invention is to provide a process, which avoids the use of highly hazardous intermediates or reagents, for preparing compounds of formula (I).
• Especially the problem of the present invention is to provide a process, which avoids the use of highly hazardous intermediates, for preparing compounds of formula (III) or (IV).
• Especially the problem of the present invention is to provide a process for preparing compounds of formula (I) without the use of 2-tert-butyl-5-methyl-1,2-oxazol-2-ium perchlorate, other perchlorate salts, perchloric acid, HATU, O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) or other reagents based on 1-hydroxy-7-azabenzotriazole (HOAt) or 1-hydroxybenzotriazole (HOBT) or hydrogen sulphide.
• exothermic decomposition energy of reagents and intermediates applied in the process should be less than 2000 J/g and the onset of exothermic decomposition (if applicable) should be above 180° C.
• onset of exothermic decomposition if applicable
• Differential Scanning calorimetry data Closed gold vessel
• the present invention solves the above-mentioned problems by the method of synthesis described hereinafter.
• the invention thus relates to a process for the preparation of compounds of general formula (I)
• R 1 denotes a group of formula (i)
• a further embodiment of the current invention is a process for the preparation of compounds of general formula (III)
• the invention further relates to a process for the preparation of compounds of general formula (II),
• the invention further relates to a compound of formula (II),
• Preferred is a compound wherein X ⁇ denotes PF 6 ⁇ and R t denotes methyl.
• the invention further relates to the use of a compound of formula (II) for the preparation of acylguanidines and acylthioureas, preferably for the preparation of acylguanidines.
• the invention further relates to the use of a compound of formula (II) for the preparation of carboxylic acid 2-(2-methyl-C 1-6 -alk-2-yl)carbamoyl-1-methyl-vinyl esters, preferably for the preparation of a compound of formula (III).
• the invention further relates to a compound of formula (III.1)
• the compounds according to the invention may be present in the form of the tautomers as well as in the form of the free bases or the corresponding acid addition salts with pharmaceutically acceptable acids—such as for example acid addition salts with hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, or maleic acid.
• pharmaceutically acceptable acids such as for example acid addition salts with hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, or maleic acid.
• radicals, or moieties defined below the number of carbon atoms is often specified preceding the group, for example, —C 1-6 -alkyl means an alkyl group or radical having 1 to 6 carbon atoms.
• the last named group is the radical attachment point, for example, “thioalkyl” means a monovalent radical of the formula HS-Alk-.
• conventional definitions of terms control and conventional stable atom valences are presumed and achieved in all formulas and groups.
• substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound.
• lower-molecular groups regarded as chemically meaningful are groups consisting of 1-200 atoms. Preferably such groups have no negative effect on the pharmacological efficacy of the compounds.
• the groups may comprise:
• pharmaceutically acceptable prodrug means a prodrug of a compound of the invention which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible.
• phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
• examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
• the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
• such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
• inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
• organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic,
• the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
• such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
• aryl as used herein, either alone or in combination with another substituent, means either an aromatic monocyclic system or aromatic multicyclic systems containing carbon atoms.
• aryl includes a phenyl or a naphthyl ring system, wherein aryl means generally an aromatic system, for example phenyl.
• heteroaryl denotes five- or six-membered heterocyclic aromatic groups or 5-10 membered, bicyclic heteroaryl rings which may contain one, two or three heteroatoms, selected from among oxygen, sulphur and nitrogen, which contain sufficient conjugated double bonds that an aromatic system is formed.
• the ring may be linked to the molecule through a carbon atom or if present through a nitrogen atom.
• five- or six-membered heterocyclic aromatic groups denotes five- or six-membered heterocyclic aromatic groups or 5-10 membered, bicyclic heteroaryl rings which may contain one, two or three heteroatoms, selected from among oxygen, sulphur and nitrogen, which contain sufficient conjugated double bonds that an aromatic system is formed.
• the ring may be linked to the molecule through a carbon atom or if present through a nitrogen atom.
• Examples of 5-10-membered bicyclic heteroaryl rings include pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyrane, benzothiazole, benzoisothiazole, pyridopyrimidine, pteridine and pyrimidopyrimidine.
• annelated species of aryl or heteroaryl as used herein, either alone or in combination with another substituent wherein the annelated species presents as a aryl-het (a), a het-aryl (b) or a het-het (c) annelation means a monovalent substituent derived by removal of one hydrogen from
• an aromatic monocyclic system or aromatic multicyclic systems containing carbon atoms which is annelated to a five-, six- or seven-membered saturated or unsaturated (including aromatic) heterocycle containing carbon atoms and one, two, three or four ring heteroatoms selected from nitrogen, oxygen and sulfur or
• a five-, six-, or seven-membered saturated or unsaturated (including aromatic) heterocycle containing carbon atoms and one, two, three or four ring heteroatoms selected from nitrogen, oxygen and sulfur which is annelated to a five-, six-, or seven-membered saturated or unsaturated (including aromatic) heterocycle containing carbon atoms and one, two, three or four ring heteroatoms selected from nitrogen, oxygen and sulfur.
• Suitable examples of an annelated species of aryl or het include: quinolinyl, 1-indoyl, 3-indoyl, 5-indoyl, 6-indoyl, indolizinyl, benzimidazyl or purinyl.
• halogen as used herein means a halogen substituent selected from fluoro, chloro, bromo or iodo.
• C 1-6 -alkyl (including those which are part of other groups) are meant branched and unbranched alkyl groups with 1 to 6 carbon atoms, and by the term “C 1-4 -alkyl” are meant branched and unbranched alkyl groups with 1 to 4 carbon atoms.
• Alkyl groups with 1 to 4 carbon atoms are preferred. Examples of these include: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl or hexyl.
• Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. may optionally also be used for the above-mentioned groups.
• the definitions propyl, butyl, pentyl and hexyl include all the possible isomeric forms of the groups in question.
• propyl includes n-propyl and iso-propyl
• butyl includes iso-butyl, sec-butyl and tert-butyl etc.
• C 1-6 -alkylene (including those which are part of other groups) are meant branched and unbranched alkylene groups with 1 to 6 carbon atoms and by the term “C 1-4 -alkylene” are meant branched and unbranched alkylene groups with 1 to 4 carbon atoms.
• Alkylene groups with 1 to 4 carbon atoms are preferred. Examples include: methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene or hexylene.
• propylene, butylene, pentylene and hexylene also include all the possible isomeric forms of the relevant groups with the same number of carbons.
• propyl also includes 1-methylethylene and butylene includes 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene.
• C 2-6 -alkenyl denotes branched and unbranched alkenyl groups with 2 to 6 carbon atoms and the term “C 2-4 -alkenyl” denotes branched and unbranched alkenyl groups with 2 to 4 carbon atoms, provided that they have at least one double bond.
• alkenyl groups with 2 to 4 carbon atoms examples include: ethenyl or vinyl, propenyl, butenyl, pentenyl, or hexenyl. Unless otherwise stated, the definitions propenyl, butenyl, pentenyl and hexenyl include all possible isomeric forms of the groups in question. Thus, for example, propenyl includes 1-propenyl and 2-propenyl, butenyl includes 1-, 2- and 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl etc.
• C 2-6 -alkenylene (including those which are part of other groups) are meant branched and unbranched alkenylene groups with 2 to 6 carbon atoms and by the term “C 2-4 -alkenylene” are meant branched and unbranched alkylene groups with 2 to 4 carbon atoms. Alkenylene groups with 2 to 4 carbon atoms are preferred.
• Examples include: ethenylene, propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene, pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene, 1,2-dimethylpropenylene, 1,3-dimethylpropenylene or hexenylene.
• the definitions propenylene, butenylene, pentenylene and hexenylene include all the possible isomeric forms of the respective groups with the same number of carbons.
• propenyl also includes 1-methylethenylene and butenylene includes 1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene.
• C 2-6 -alkynyl (including those which are part of other groups) are meant branched and unbranched alkynyl groups with 2 to 6 carbon atoms and by the term “C 2-4 -alkynyl” are meant branched and unbranched alkynyl groups with 2 to 4 carbon atoms, provided that they have at least one triple bond.
• Alkynyl groups with 2 to 4 carbon atoms are preferred. Examples include: ethynyl, propynyl, butynyl, pentynyl, or hexynyl.
• propynyl, butynyl, pentynyl and hexynyl include all the possible isomeric forms of the respective groups.
• propynyl includes 1-propynyl and 2-propynyl
• butynyl includes 1-, 2- and 3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyl etc.
• C 2-6 -alkynylene (including those which are part of other groups) are meant branched and unbranched alkynylene groups with 2 to 6 carbon atoms and by the term “C 2-4 -alkynylene” are meant branched and unbranched alkylene groups with 2 to 4 carbon atoms. Alkynylene groups with 2 to 4 carbon atoms are preferred.
• Examples include: ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene, 1,2-dimethylpropynylene, 1,3-dimethylpropynylene or hexynylene.
• the definitions propynylene, butynylene, pentynylene and hexynylene include all the possible isomeric forms of the respective groups with the same number of carbons.
• propynyl also includes 1-methylethynylene and butynylene includes 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene.
• C 1-6 -alkoxy (including those which are part of other groups) are meant branched and unbranched alkoxy groups with 1 to 6 carbon atoms and by the term “C 1-4 -alkoxy” are meant branched and unbranched alkoxy groups with 1 to 4 carbon atoms. Alkoxy groups with 1 to 4 carbon atoms are preferred. Examples include: methoxy, ethoxy, propoxy, butoxy or pentoxy.
• OMe, OEt, OPr, etc. may optionally be used for the above-mentioned groups.
• the definitions propoxy, butoxy and pentoxy include all the possible isomeric forms of the respective groups.
• propoxy includes n-propoxy and iso-propoxy
• butoxy includes iso-butoxy, sec-butoxy and tert-butoxy etc.
• C 3-8 -cycloalkyl (including those which are part of other groups) as used herein means cyclic alkyl groups with 3 to 8 carbon atoms, preferred are cyclic alkyl groups with 5 to 6 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
• C 3-6 -cycloalkenyl is a cyclic alkyl group meant with 5 or 6 carbon atoms which contain one or two double bonds. Examples include: cyclopentenyl, cyclopentadienyl, cyclohexenyl or cyclohexadienyl.
• C 1-6 -haloalkyl (including those which are part of other groups) are meant branched and unbranched alkyl groups with 1 to 6 carbon atoms wherein one or more hydrogen atoms are replaced by a halogen atom selected from among fluorine, chlorine or bromine, preferably fluorine and chlorine, particularly preferably fluorine.
• C 1-4 -haloalkyl are meant correspondingly branched and unbranched alkyl groups with 1 to 4 carbon atoms, wherein one or more hydrogen atoms are replaced analogously to what was stated above.
• C 1-4 -haloalkyl is preferred. Examples include: CH 2 F, CHF 2 , CF 3 ,
• the substituent R 1 denotes a group of formula (i),
• the substituent R 2 denotes hydrogen or a group selected from among C 1-6 -alkyl, C 6-10 -aryl-C 1-6 -alkyl-, heterocyclyl, heterocyclyl-CH 2 —, —, preferably benzyl,
• R 2 denotes a group of formula (ii)
• the substituent R 4 may denote a group selected from among alkylthio, 1-pyrazolyl, 1-imidazolyl and 1,2,4-triazol-1-yl, each optionally substituted by one or two methyl groups, preferably 1-pyrazolyl.
• the substituent R t denotes a group selected from among C 1-4 -alkyl, preferably methyl or ethyl.
• X ⁇ denotes a group selected from among PF 6 ⁇ , BF 4 ⁇ , SbF 6 ⁇ , phenylsulphonate, p-toluenesulphonate, HSO 4 ⁇ , (SO 4 2 ⁇ )/2, FSO 3 ⁇ and F 3 CSO 3 ⁇ ; preferably PF 6 ⁇ and F 3 CSO 3 ⁇ .
• Process step (A) is preferably carried out neat or in a solvent selected from among water, methanol, ethanol, tetrahydrofuran (THF), diethylether, tert-butyl-methylether, dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), N-ethyl-2-pyrrolidone (NEP) and dimethylsulphoxide (DMSO), or mixtures thereof, preferably in a mixture containing water and tetrahydrofuran (THF) and/or diethylether.
• a solvent selected from among water, methanol, ethanol, tetrahydrofuran (THF), diethylether, tert-butyl-methylether, dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), N-ethyl-2-pyrrolidone (NEP) and dimethylsulphoxide (DMSO), or mixtures thereof, preferably in a mixture containing water and
• Process step (A) is carried out in a temperature range of from ⁇ 20° C. to 40° C., preferably from 0° C. to 25° C.
• Process step (B) is preferably carried out in the presence of a base selected from among triethylamine, di-isopropyl-ethylamine and N-methylmorpholine, preferably triethylamine.
• Process step (B) is preferably carried out in a solvent selected from among DMF, NMP, NEP and DMSO, preferably in DMF.
• Process step (B) is preferably carried out at an initial temperature ranging from 20° C. to 60° C., particularly preferably from 20° C. to 50° C.
• the temperature is allowed to lower during the process, most preferably to ambient temperature.
• the skilled person will appreciate that depending on R 1 , the addition of water at a later timepoint during the process may promote precipitation of the compound of formula (III) formed during the process.
• the final temperature when separating the product is preferably ⁇ 20° C. to 25° C., most preferably 0° C. to 20° C.
• Process step (C) is preferably carried out with the addition of a base selected from among triethylamine, di-isopropyl-ethylamine and N-methylmorpholine, preferably triethylamine.
• Process step (C) is preferably carried out neat or applying a solvent selected from among DMF, NMP, NEP and DMSO, preferably DMF.
• Stage 1 of process step (C) is preferably carried out in a temperature range of from 0° C. to 30° C., preferably from 0° C. to 20° C., particularly preferable at a temperature from 0° C. to 5° C.
• the skilled person will appreciate that depending on R 1 , the addition of water at a later timepoint during the process may promote precipitation of the compound of formula (III) formed during the process.
• the final temperature when separating the product is preferably 0° C. to 25° C., most preferably 0° C. to 20° C.
• Process step (D) is preferably carried out applying a base selected from among sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium tert-butylate, sodium methanolate and sodium ethanolate, preferably sodium hydroxide and potassium tert-butylate.
• a base selected from among sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium tert-butylate, sodium methanolate and sodium ethanolate, preferably sodium hydroxide and potassium tert-butylate.
• Process step (D) is preferably carried out applying a solvent selected from among tert-butylmethyl ether (TBME), tetrahydrofuran (THF), dichlormethane (DCM), acetonitrile, diethylether, dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), N-ethyl-2-pyrrolidone (NEP) and dimethylsulphoxide (DMSO), or mixtures thereof, preferably TBME, THF and DCM, or a mixture thereof, particularly preferable TBME and THF or a mixture thereof.
• a solvent selected from among tert-butylmethyl ether (TBME), tetrahydrofuran (THF), dichlormethane (DCM), acetonitrile, diethylether, dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), N-ethyl-2-pyrrolidone (NEP) and dimethylsulphoxid
• Process step (D) is preferably carried out in a temperature range of from 15° C. to the boiling point of the solvent applied. With the proviso that R 4 denotes alkylthio, process step (D) is most preferably carried out at a temperature from 15 to 25° C.
• Process step (E) is preferably carried out in the presence of a base selected from among sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, sodium methanolate, sodium ethanolate and potassium tert-butanolate. Also preferred is the process step (E) carried out in the presence of an alcoholate generated by addition of sodium or sodium hydride to a solvent selected from methanol, ethanol, 2-propanol and tert-butanol.
• a base selected from among sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, sodium methanolate, sodium ethanolate and potassium tert-butanolate.
• an alcoholate generated by addition of sodium or sodium hydride to a solvent selected from methanol, ethanol, 2-propanol and tert-butanol.
• the process step is carried out in the presence of a base selected from among sodium hydroxide, potassium hydroxide, sodium ethanolate, sodium 2-propanolate, sodium tert-butanolate and potassium tert-butanolate which in the case of sodium alcoholates may be generated by addition of metallic sodium or sodium hydride to the respective alcohol.
• a base selected from among sodium hydroxide, potassium hydroxide, sodium ethanolate, sodium 2-propanolate, sodium tert-butanolate and potassium tert-butanolate which in the case of sodium alcoholates may be generated by addition of metallic sodium or sodium hydride to the respective alcohol.
• formula (VIII) is preferably used as a free base or as an acid addition salt, preferably as an acid addition salt selected from among hydrochloric acid, hydrobromic acid, sulphuric acid, methylsulphonic acid and p-tolylsulphonic acid.
• Process step (E) is preferably carried out in a solvent selected from among tetrahydrofuran (THF), dioxane, methanol, ethanol, 2-propanol and tert-butanol or a mixture thereof, most preferably in ethanol and 2-propanol.
• a solvent selected from among tetrahydrofuran (THF), dioxane, methanol, ethanol, 2-propanol and tert-butanol or a mixture thereof, most preferably in ethanol and 2-propanol.
• Process step (E) is preferably carried out in a temperature range of from 40° C. to 90° C., preferably from 50° C. to 85° C.
• Process step (F) is preferably carried out in the presence of a base selected from among triethylamine di-isopropyl-ethylamine and N-methylmorpholine, preferably triethylamine.
• Process step (F) is preferably carried out in a solvent selected from among methanol, ethanol, 2-propanol, acetonitrile, DCM, tetrahydrofuran (THF), diethylether, dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), N-ethyl-2-pyrrolidone (NEP) and dimethylsulphoxide (DMSO), or mixtures thereof, preferably selected from among methanol, ethanol, DMF and THF or mixtures thereof, most preferably in ethanol and DMF.
• a solvent selected from among methanol, ethanol, 2-propanol, acetonitrile, DCM, tetrahydrofuran (THF), diethylether, dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), N-ethyl-2-pyrrolidone (NEP) and dimethylsulphoxide (DMSO), or mixtures thereof, preferably selected from among
• Process step (F) is preferably carried out in a temperature range of from 50° C. to 90° C., preferably from 65° C. to 80° C.
• the precipitate is filtered off with suction, taken up in THF/water (1:4; 75 ml), filtered again with suction and washed with water.
• the product is dried in vacuo at 60° C. (C 14 H 20 ClN 5 O 3 ).
• HPLC Analytics HPLC method 1 Column: Sunfire C18, 4.6 ⁇ 30 mm, 2.5 ⁇ m Supplier: Waters Gradient: % Sol % Sol Flow Temp time [min] [H2O, 0.1% TFA] [Methanol] [ml/min] [° C.] 0.0 95 5 4 60 0.05 95 5 3 60 2.05 0 100 3 60 2.10 0 100 4.5 60 2.40 0 100 4.5 60 HPLC method 2
• TLC silica glass plates from Merck are used (TLC Silica Gel 60F 254 ; 1.05729.0001).
• r.t. ambient temperature e.g. 18 to 25° C., preferably 20° C.

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