Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
  • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
  • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
  • C07C211/57—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems of the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
  • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
  • C07C211/57—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems of the carbon skeleton
  • C07C211/60—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems of the carbon skeleton containing a ring other than a six-membered aromatic ring forming part of at least one of the condensed ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2602/00—Systems containing two condensed rings
  • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
  • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
  • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

• the present invention relates to a process for the preparation of substituted amino-indane derivatives by cyclization.
• 4-amino-indanes and corresponding derivatives are important intermediates for the preparation of bioactive compounds, which can be used especially for controlling harmful microorganisms in crop protection.
• pyrazole-indanylcarboxamides are known to have fungicidal activity (e.g., WO 1992/12970, WO 2012/065947, Org. Chem. 1995, 60, 1626 and WO 2012/084812).
• Indanes without amino functionality on aromatics can be prepared by Friedel-Crafts cyclizations according to established methods in classical organic chemistry. For this purpose, aromatics having hydroxyalkyl or alkene side chains by adding BrOnsted acids such as HCl, HBr, HF, H2SO4, H3PO4, KHSO4, AcOH, p-toluenesulfonic acid, polyphosphoric acid or Lewis acids such as AICI 3 , BF 3 , AgOTf converted to the corresponding indanes.
• BrOnsted acids such as HCl, HBr, HF, H2SO4, H3PO4, KHSO4, AcOH, p-toluenesulfonic acid, polyphosphoric acid or Lewis acids such as AICI 3 , BF 3 , AgOTf converted to the corresponding indanes.
• substituted 4-amino-indan derivatives obtainable by this desired process should preferably be obtained in high yield and high purity.
• the intended method should enable the desired target compounds to be obtained without the need for complex purification methods such as column chromatography.
• substituted 4-amino-indane derivatives can be prepared by a sulfonic acid-mediated cyclization reaction.
• Preferred sulfonic acids are methanesulfonic acid or trifluoromethanesulfonic acid and particularly preferably trifluoromethanesulfonic acid. This is all the more surprising because so far no such reaction has been described and the skilled person would have expected that it would come by the action of these very strong acids to a decomposition of the starting material and / or the resulting products. In addition, it was to be assumed that - as with the use of other Br ⁇ nsted or Lewis acids - there would be no successful cyclization.
• the present invention accordingly provides a novel process for the preparation of substituted 4-amino-indan derivatives of the general formula (I):
• R independently of one another are halogen, cyano, (Ci-Ci 2 ) alkyl, (C3-C7) cycloalkyl, (Ci-Ce) alkoxy, (Ci-Ce) alkylphenyl, aryl, cyano (Ci-Ce) alkyl, halogen (Ci -Ce) alkyl having 1 to 9 identical or different halogen atoms, halogen (C3-C7) cycloalkyl having 1-9 identical or different halogen atoms, halogen (Ci-Ce) alkoxy having 1 to 9 identical or different halogen atoms, (Ci-C6) Alkoxycarbonyl (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy (C 1 -C 6) alkyl, (C 1 -C 6) alkylsulfanyl, halo (C 1 -C 6) alkylsulfanyl having 1 to 9 identical
• Halogen atoms (Ci-C6) alkylsulfonyl or halogen (Ci-C6) alkylsulfonyl having 1-9 identical or different halogen atoms, n is an integer between 0 and 3,
• R 1 , R 2 , R 3 and R 4 are each independently hydrogen, (Ci-C8) alkyl, (C3-C8) cycloalkyl, (C 3 -C 8 ) cycloalkyl (Ci-C 8 ) alkyl, (C3-C 8) cycloalkyl (C3-C8) cycloalkyl, (Ci-C8) alkylphenyl,
• R independently of one another are halogen, (Ci-C alkyl, (Ci-C alkoxy, (Ci-C alkylphenyl, aryl, cyano (Ci-C4) alkyl, halogeno (Ci-C4) alkyl with 1-9 identical or different
• Halogen atoms (Ci-C4) alkoxycarbonyl (Ci-C4) alkyl, (Ci-C4) alkoxy (Ci-C4) alkyl or halo (Ci- C4) alkoxy (Ci-C 4) alkyl, n is an integer between 0 and 3, - -
• R 1, R 2, R 3 and R 4 are each independently hydrogen, (Ci-C 4) alkyl, (Ci-C 4) alkylphenyl, (Ci C 4) alkoxy, aryl, cyano (Ci-C 4) alkyl , (Ci-C 4) alkoxycarbonyl (Ci-C4) alkyl or (Ci- C4) alkoxy (Ci-C 4) alkyl and
• Q 1 and Q 2 are each independently hydrogen, substituted (Ci-C 4) alkylsulfonyl, substituted alkoxycarbonyl (Ci-C 4) alkyl or substituted (Ci-C4) haloalkylsulfonyl.
• R independently of one another are fluorine, chlorine, bromine, methyl or trifluoromethyl, n is an integer between 0 and 1,
• R 1 , R 2 , R 3 and R 4 are each independently hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl and
• Q 1 and Q 2 are each independently hydrogen, substituted (Ci-C 4) alkylsulfonyl, substituted alkoxycarbonyl (Ci-C 3) alkyl or substituted (Ci-C 3) haloalkylsulfonyl.
• n is 0 or R is fluorine and n is 1, with fluorine preferably in the 5-, 6- or 7-position, more preferably in the 6- or 7-position and most preferably in the 7- Position of the indane residue is located, or
• R is trifluoromethyl and n is 1, with trifluoromethyl being preferably in the 5-, 6- or 7-position, more preferably in the 6- or 7-position and most preferably in the 7-position of the indane radical,
• R 1 , R 2 , R 3 and R 4 independently of one another are hydrogen, methyl, ethyl, n-propyl, n-butyl, isobutyl or sec-butyl and
• n is 0, Q 1 and Q 2 are hydrogen,
• R 1 , R 2 , R 3 and R 4 correspond to the general, preferred, particularly preferred and very particularly preferred meanings given for the formulas (I), (IIa), (IIb) and (IIc) ,
• R is F and n is 1,
• Q 1 and Q 2 are hydrogen, wherein the definitions of the radicals R 1 , R 2 , R 3 and R 4 are the general, preferred, particularly preferred for the formulas (I), (IIa), (IIb) and (IIc) and very particularly preferred meanings. Furthermore, very particularly preferred
• Q 1 and Q 2 are hydrogen, wherein the definitions of the radicals R 1 , R 2 , R 3 and R 4 are the general, preferred, particularly preferred for the formulas (I), (IIa), (IIb) and (IIc) and very particularly preferred meanings.
• R is CF 3 and n is 1,
• Q 1 and Q 2 are hydrogen, wherein the definitions of the radicals R 1 , R 2 , R 3 and R 4 are the general, preferred, particularly preferred for the formulas (I), (IIa), (IIb) and (IIc) and very particularly preferred meanings.
• Q 1 and Q 2 are hydrogen, wherein the definitions of the radicals R 1 , R 2 , R 3 and R 4 are the general, preferred, particularly preferred for the formulas (I), (IIa), (IIb) and (IIc) and very particularly preferred meanings. - -
• Halogen fluorine, chlorine, bromine and iodine and preferably fluorine, chlorine, bromine and more preferably fluorine, chlorine.
• Alkyl saturated, straight-chain or branched hydrocarbon radicals having 1 to 12, preferably 1 to 6 and more preferably 1 to 3 carbon atoms, e.g. (but not limited to) C 1 -C 6 -alkyl such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3 Methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1, 2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,
• alkyl as part of an assembly of substituents such as e.g. Cycloalkylalkyl, hydroxyalkyl, etc. unless otherwise defined, e.g. Alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl or haloalkylthio. If the alkyl is at the end of a compound substituent. such as with alkylcycloalkyl, the initial constituent of the composite substituent, e.g. the cycloalkyl, mono- or polysubstituted by identical or different substituents and independently substituted with alkyl. The same applies to compound substituents where other groups such as e.g. Alkenyl, alkynyl, hydroxy, halogen, formyl, etc. are at the end.
• substituents such as e.g. Cycloalkylalkyl, hydroxyalkyl, etc. unless otherwise defined, e.g. Alkylthio
• Alkoxy saturated, straight or branched alkoxy radicals having 1 to 6, preferably 1 to 3 carbon atoms, e.g. (but not limited to) C 1 -C 6 alkoxy such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3 Methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1, 2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1, 2,
• Cycloalkyl monocyclic saturated hydrocarbon groups having from 3 to 7, preferably from 3 to 6 carbon ring members, eg (but not limited to) cyclopropyl, cyclopentyl and cyclohexyl. This definition also applies to cycloalkyl as part of an assembly of substituents such as cycloalkylalkyl etc. unless otherwise defined elsewhere; - -
• Haloalkyl straight-chain or branched alkyl groups having 1 to 6, preferably 1 to 3 carbon atoms (as mentioned above), in which groups the hydrogen atoms in some or in part may be replaced by halogen atoms as mentioned above, e.g.
• C1-C3 haloalkyl such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2, 2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and 1, l, l-trifluoroprop-2-yl.
• This definition also applies to haloalkyl as part of an assembly of substituents such as e.g. Hal
• Aryl groups in the context of the present invention are, unless otherwise defined, aromatic hydrocarbon groups which may have no, one, two or more heteroatoms (selected from O, N, P and S).
• this definition includes, for example, the meanings cyclopentadienyl, phenyl, cycloheptatrienyl, cyclooctatetraenyl, naphthyl and anthracenyl; 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3 Pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-imidazolyl, 4-imidazolyl, 1, 2,4-oxadiazole 3-yl, l, 2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl
• Alkylaryl groups are in the context of the present invention, unless otherwise defined, substituted by alkyl groups aryl groups having an alkyl chain and in the aryl skeleton having no, one or more heteroatoms (selected from O, N, P and S) can.
• 4-amino-indane derivatives of the general formula (I) can be prepared by the reaction according to the invention of the corresponding alcohols of the general formulas (IIa), (IIb) or (IIc) with sulfonic acids (see process (a)): - -
• the radicals R, n "R 1 , R 2 , R 3 , R 4 , Q 1 and Q 2 are generally, more preferably, more preferably and most preferably the Radicals which have been defined above for the 4-amino-indanes of general formula (I).
• compounds of the formula (IIa) can also be prepared by reacting appropriately substituted aminobenzonitriles of the general formula (III) with Grignard reagents of the formulas (IVa) and (IVb) via the intermediately formed ketones of the formulas (Va) or (Vb) produce:
• radicals R, n, R 1 , R 2 , R 3 , R 4 , Q 1 and Q 2 are generally preferred particularly preferably and very particularly preferably for the radicals which have been defined above for the 4-amino-indanes of the general formula (I).
• X is preferably chlorine, bromine or iodine and particularly preferably chlorine or bromine.
• the Grignard reagents of the formulas (IVa) and (IVb) are either commercially available or can be prepared from the corresponding chlorides, bromides or iodides by reaction with magnesium turnings by literature methods.
• a further process according to the invention for the preparation of the 4-amino-indan derivatives of the general formula (I) is the reaction of the corresponding alkenes of the formulas (VIA) or (VIB) with sulfonic acids (see process (b)):
• radicals R, n "R 1 , R 2 , R 3 , R 4 , Q 1 and Q 2 are generally, more preferably, and with very particular preference for the radicals which have been defined above for the amino-indanes of the general formula (I).
• 4-amino-indane derivatives of the general formula (I) can be prepared in a further process of the present invention by the reaction of the alkenes of the formulas (Via '), (VIb') or (VIc ') with sulfonic acids (see process (c)):
• the radicals R, n, R 1 , R 2 , R 3 , R 4 , Q 1 and Q 2 are generally, more preferably, more preferably and most particularly preferably for the radicals which have been defined above for the amino-indanes of the general formula (I). - -
• R 1 , R 3 ' and R 4' are each independently (Ci-C7) alkyl, (C3-C7) cycloalkyl, (C 3 -C 8 ) cycloalkyl (Ci-C 7 ) alkyl, (C 3 -C 8 ) Cycloalkyl (C 3 -C 7 ) cycloalkyl, (C 1 -C 7 ) alkylphenyl,
• the radicals R, n, R 1 , R 2 , R 3 , R 4 and Q 1 are generally, more preferably, more preferably and most preferably the radicals, the above for the 4-amino-indanes the general
• the processes (a), (b), (c) and (d) are preferably carried out with methanesulfonic acid or trifluoromethanesulfonic acid, and more preferably with trifluoromethanesulfonic acid.
• ethers such as tetrahydrofuran (THF), dioxane, diethyl ether, diglyme, methyl tert-butyl ether (MTBE) tert-amyl methyl ether (TAME), dimethyl ether, 2-methyl-THF; Nitriles such as acetonitrile (ACN) or butyronitrile; Ketones such as acetone, methyl isobutyl ketone (MIBK); aromatic hydrocarbons such as toluene, anisole, xylenes, mesitylene; Esters such as ethyl acetate, isopropyl acetate, butyl acetate, pentyl acetate; Alcohols such as methanol, ethanol, propanol, butanol, ethylene glycol; Carbonates such as ethylene
• processes (a), (b), (c) and (d) using methanesulfonic acid are preferably carried out without solvents or in the following solvents: acetonitrile (ACN), butyronitrile, toluene, anisole, xylenes, mesitylene, ⁇ , ⁇ Dimethylacetamide (DMAc), ⁇ , ⁇ -dimethylformamide (DMF), N-methylpyrrolidone, halohydrocarbons and aromatic hydrocarbons, especially chlorohydrocarbons such as tetrachlorethylene, tetrachloroethane, dichloropropane, methylene chloride (dichloromethane, DCM), dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichlorethylene , Pentachloroethane, difluorobenzene, 1, 2-dichloroethane, chlorobenzene, bromobenzene,
• processes (a), (b), (c) and (d) using methanesulfonic acid are more preferably carried out without solvents or in the following solvents: butyronitrile, toluene, xylenes, mesitylene, ⁇ , ⁇ -dimethylacetamide (DMAc), N, N-dimethylformamide (DMF), N-methylpyrrolidone, halohydrocarbons and aromatic hydrocarbons, in particular chlorohydrocarbons, such as tetrachlorethylene, tetrachloroethane, methylene chloride (dichloromethane, DCM), chloroform, carbon tetrachloride, 1, 2-dichloroethane, chlorobenzene, bromobenzene, dichlorobenzene , in particular 1, 2-dichlorobenzene, chlorotoluene, trichlorobenzene and benzotrifluoride. It is also possible to use solvent mixtures. -
• processes (a), (b), (c) and (d) using methanesulfonic acid are most preferably carried out without solvent in pure methanesulfonic acid.
• the amount of sulfonic acid used in processes (a), (b), (c) and (d) may vary within a wide range, but is preferably in the range of 0.1 to 100 equivalents, more preferably between 0.1 and 50 equivalents and most preferably between 0.1 and 20 equivalents.
• the processes (a), (b), (c) and (d) are generally carried out under normal pressure, but can be carried out both under reduced and under elevated pressure - generally between 0.1 and 100 bar.
• the processes (a), (b), (c) and (d) using trifluoromethanesulfonic acid are generally carried out at a temperature between -80 ° C and 200 ° C, preferably between -20 ° C and 140 ° C, completely more preferably carried out between -5 ° C and 50 ° C.
• the processes (a), (b), (c) and (d) using methanesulfonic acid are generally more particularly at a temperature between -80 ° C and 250 ° C, preferably between 0 ° C and 200 ° C preferably carried out between 0 ° C and 150 ° C.
• the compounds of the general formula (I) may occur as geometric and / or optical isomers or as their corresponding isomer mixtures in various compositions. These isomers are, for example, enantiomers, diastereomers, or geometric isomers. Thus, the invention described herein encompasses both the pure stereoisomers and any mixture of these isomers.
• the isolation and purification of the desired compounds of the general formula (I) can be carried out, for example, by dilution of the reaction mixture with subsequent crystallization and liberation to give the free 4-amino-indan derivative.
• Such processes are known to those skilled in the art and, in particular, include the preferred crystallization from an organic solvent or a mixture of organic solvent with water.
• the phases are separated and the aqueous phase extracted twice with 200 ml of ethyl acetate.
• the combined organic phases are washed once with 400 ml of saturated NaCl solution, dried over Na 2 S0 4 and the solvent evaporated in vacuo.
• the ketone thus obtained is dissolved in 130 ml of dry THF and added dropwise under argon to 100 ml (200 mmol, 2M in THF) of isobutylmagnesium chloride at 0 ° C. within 1 hhhhh. After complete addition, the mixture is stirred for 30 min at room temperature. In a further reaction vessel 200 mL aqueous HCl (IM) are introduced and cooled to 0 ° C. The reaction mixture is slowly added dropwise and then adjusted to pH 4 with concentrated HCl. The phases are separated and the aqueous phase extracted twice with 200 ml of ethyl acetate.
• IM aqueous HCl

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• 2017
  • 2017-01-26 TW TW106103120A patent/TW201738200A/zh unknown
  • 2017-01-27 US US16/074,639 patent/US20190039995A1/en not_active Abandoned
  • 2017-01-27 CN CN201780008850.8A patent/CN108602754A/zh active Pending
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