WO2018082962A1 - Procédé de préparation de dérivés de tétrahydrothiophène - Google Patents

Procédé de préparation de dérivés de tétrahydrothiophène Download PDF

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WO2018082962A1
WO2018082962A1 PCT/EP2017/077075 EP2017077075W WO2018082962A1 WO 2018082962 A1 WO2018082962 A1 WO 2018082962A1 EP 2017077075 W EP2017077075 W EP 2017077075W WO 2018082962 A1 WO2018082962 A1 WO 2018082962A1
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alkyl
partially
substituted
ring
unsubstituted
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Devendra VYAS
Martin John MCLAUGHLIN
Pascal Bindschaedler
Karsten Koerber
Birgit GOCKEL
Sebastian Soergel
Arun Narine
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Basf Se
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a process for the preparation of tetrahydrothiophene derivatives of formula I
  • R 1 is halomethyl
  • each R 2 is independently H, halogen, CN, N 3 , NO 2 , SCN, SF 5 , C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, which groups are unsubstituted, partially or fully halogenated and/or substituted by one or more same or different R 8 ,
  • phenyl which may be partially or fully substituted by R 11 , and a 3- to 10-membered satura- ted, partially or fully unsaturated heteromonocyclic or heterobicyclic ring containing 1, 2, 3 or 4 heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or substitu- ted by one or more same or different R 11 , preferably the unsubstituted or substituted HET; n is 0, 1, or 2;
  • R 3 halogen, OH, C1-C6-alkoxy, C1-C6-haloalkoxy, C3-C6-alkenyloxy, C3-C6-haloalkenyloxy, C3- C6-alkynyloxy, C3-C6-haloalkynyloxy, C3-C6-cycloalkyloxy, C3-C6-halocycloalkyloxy, OS(O) n -C 1 -C 4 -alkyl, heterocyclyloxy, or hetaryloxy which groups are unsubstituted or par- tially or fully substituted by R 8 ;
  • G 1 , G 2 , G 3 and G 4 are each independently selected from N and CR 4 , with the proviso that at most two of G 1 , G 2 , G 3 , and G 4 are N;
  • each R 4 is independently selected from the meanings mentioned for R 2 ,
  • R 4 bonded to adjacent carbon atoms may form a five- or sixmembered saturated, par- tially or fully unsaturated carbocyclic ring, or
  • R 4 bonded to carbon atoms in position G 2 or G 4 form a bond to the chain *-Q-Z- in group A 4 ;
  • A is a group A 1 , A 2 , A 3 , A 4 , or A 5 ;
  • W is O, or S
  • Y is H, N(R 5 )R 6 , or OR 9 ;
  • R 21 is H, C 1 -C 3 -alkyl, C 2 -C 3 -alkenyl, C 2 -C 3 -alkynyl, C 1 -C 3 -alkoxymethyl, or CH 2 CN;
  • a 4 is
  • R 411 is independently OH, cyano, C 1 -C 2 -alkyl, or C 1 -C 2 -haloalkyl;
  • R 43 is H, or C1-C6-alkyl,
  • R 44 is H, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2- C 6 -alkynyl, C 2 -C 6 -haloalkynyl, or C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C3-C6-cycloalkylmethyl, or C3-C6-halocycloalkylmethyl which rings are unsubstituted or substituted by a cyano;
  • R 45 H C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, CH 2 -CN, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 3 -C 6 -cycloalkylmethyl, C 3 -C 6 - halocycloalkylmethyl, phenyl and hetaryl HET which aromatic rings are unsubstituted or partially or fully substituted by R A ;
  • R 42 C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, or a group as defined for R 41 ;
  • R 46 is independently H, C1-C6-alkyl, or C1-C6-haloalkyl
  • a 5 is halogen, or OSO2R 9 ;
  • R 5 is H, CN, C 1 -C 10 -alkyl, C 3 -C 8 -cycloalkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl, which groups are unsubstituted, partially or fully halogenated and/or substituted by one or more same or dif- ferent R 8 ;
  • each R 6 is independently selected from the meanings mentioned for R 2 ;
  • R 7a , R 7b are each independently H, halogen, CN, C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, C 2 -C 6 -alkenyl, or C 2 -C 6 -alkynyl, which groups are unsubstituted, partially or fully halogenated and/or sub- stituted by same or different R 8 ;
  • each R 8 is independently CN, N 3 , NO 2 , SCN, SF 5 , C 3 -C 8 -cycloalkyl, C 3 -C 8 -halocycloalkyl, wherein the carbon chains may be substituted by one or more R 13 ;
  • phenyl which is unsubstituted or partially or fully substituted by same or different R 16 , or a 3-, 4-, 5-, 6- or 7-membered saturated, partially or fully unsaturated heterocyclic ring comprising 1, 2 or 3 heteroatoms N, O, and/or S as ring members, which ring is unsubsti- tuted or partially or fully substituted by same or different R 16 , or
  • R 8 together with the carbon atoms of the alkyl, alkenyl, alkynyl or cycloalkyl group which they are bonded to, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated or par- tially unsaturated carbocyclic or heterocyclic ring, which heterocyclic ring comprises 1, 2, 3 or 4 heteroatoms N, O, and/or S as ring members, and which ring is unsubstituted, or partially or fully substituted by same or different R 16 ; and R 8 as a substituent on a cycloalkyl ring may additionally be C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, and C2-C6-haloalkynyl, which groups are unsubstituted, or partially or fully substituted by same or different R
  • each R 9 is independently H, CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloal- kyl-C 1 -C 4 -alkyl-, C 3 -C 8 -halocycloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl, or C2-C6-haloalkynyl, which groups are unsubstituted, or partially or fully substituted by same or different R 13 , or
  • a 3- to 7-membered saturated, partially or fully unsaturated heterocyclic ring comprising 1, 2 or 3 heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or par- tially or fully substituted by same or different R 16 ;
  • R 9 in the groups S(O) n R 9 and OSO 2 R 9 may additionally be C 1 -C 6 -alkoxy, or C 1 -C 6 -haloalk- oxy;
  • R 10a , R 10b are independently from one another H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 8 -cycloal- kyl, C 3 -C 8 -halocycloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl, C 2 -C 6 -haloalky- nyl, which groups are unsubstituted, or partially or fully substituted by same or different R 13 ;
  • phenyl which is unsubstituted, or partially or fully substituted by same or different R 16 ; and a 3-, 4-, 5-, 6- or 7-membered saturated, partially or fully unsaturated heterocyclic ring comprising 1, 2, 3 or 4 heteroatoms N, O, and/or S as ring members, which ring is unsub- stituted, or partially or fully substituted by same or different R 16 , preferably unsubstituted or substituted HET; or
  • R 10a and R 10b together with the nitrogen atom they are bonded to form a 3- to 8-membered saturated, partially or fully unsaturated heterocyclic ring, which ring may additionally con- tain one or two heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or partially or fully substituted by same or different halogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-haloalkylthio, C3-C8-cycloalkyl, C3- C 8 -halocycloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl, C 2 -C 6 -haloalkynyl, p
  • R 11 is halogen, CN, N 3 , NO 2 , SCN, SF 5 , C 1 -C 10 -alkyl, C 3 -C 8 -cycloalkyl, C 2 -C 10 -alkenyl, C 2 -C 10 - alkynyl, which groups are unsubstituted, partially or fully halogenated, and/or may be sub- stituted by same or different R 8 , or
  • phenyl which is unsubstituted, or partially or fully substituted by same or different R 16 ; and a 3- to 7-membered saturated, partially or fully unsaturated aromatic heterocyclic ring comprising 1, 2, 3, or 4 heteroatoms N, O, and/or S as ring members, which ring is unsub- stituted, or partially or fully substituted by same or different R 16 ; or
  • each R 12 is independently C1-C4-alkyl and phenyl, which is unsubstituted, or partially or fully substituted by same or different C1-C4-alkyl;
  • R 13 as a substituent of a cycloalkyl ring may additionally be C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl or C2-C6-alkynyl, which groups are unsubstituted, partially or fully halogenated, or substituted by 1 or 2 CN, C3-C4-cycloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, and oxo; and
  • each R 14 is independently H, CN, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, SO n -C 1 -C 6 -alkyl, SO n -C 1 - C6-haloalkyl, Si(R 12 )3; C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, which groups are unsubstituted, partially or fully halogenated, or substituted by 1 or 2 CN, C1-C4-alkoxy, C1-C4-haloalkoxy, SOn-C1-C4-al- kyl, C 3 -C 6 -cycloalkyl which is unsubstituted or substituted by 1 or 2 substituents halogen and CN;
  • C 3 -C 8 -cycloalkyl which is unsubstituted, or partially or fully halogenated or substituted by 1 or 2 CN, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, SO n -C 1 -C 6 -alkyl, C 3 -C 4 -cycloalkyl, C 3 -C 4 -cycloalkyl-C 1 -C 4 -alkyl-, which groups are unsubstituted, or substituted by 1 or 2 sub- stituents selected from halogen and CN;
  • R 14a and R 14b independently of each other, have one of the meanings given for R 14 ; or R 14a and R 14b , together with the nitrogen atom to which they are bound, form a 3- to 7- membered saturated, partially, or fully unsaturated heterocyclic ring, wherein the ring may additionally contain 1 or 2 heteroatoms N, O, and/or S as ring members, which ring is un- substituted, or partially or fully substituted by same or different halogen, C 1 -C 4 -alkyl, C 1 - C4-haloalkyl, C1-C4-alkoxy, or C1-C4-haloalkoxy; or
  • each R 15 is independently H, CN, Si(R 12 ) 3
  • C1-C6-alkyl C2-C6-alkenyl, C2-C6-alkynyl, which groups are unsubstituted, partially or fully halogenated, or substituted by 1 or 2 radicals C3-C4-cycloalkyl, C1-C4-alkoxy, C1-C4-haloal- koxy, SO n -C 1 -C 6 -alkyl, or oxo;
  • C 3 -C 8 -cycloalkyl which is unsubstituted, partially or fully halogenated or substituted by 1 or 2 radicals C1-C4-alkyl, C3-C4-cycloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, SOn-C1-C6-alkyl, or oxo;
  • phenyl, benzyl, pyridyl, and phenoxy which rings are unsubstituted, partially or fully halo- genated, or substituted by 1, 2 or 3 substituents C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, or (C1-C6-alkoxy)carbonyl;
  • each R 16 is independently halogen, NO 2 , CN, OH, SH, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, SO n - C 1 -C 6 -alkyl, SO n -C 1 -C 6 -haloalkyl, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -haloalkylcarbonyl, C 1 -C 4 - alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, aminocarbonyl, C1-C4-alkylaminocarbonyl, di- (C 1 -C 4 -alkyl)-aminocarbonyl, Si(R 12 ) 3 ;
  • phenyl, benzyl, pyridyl and phenoxy which rings are unsubstituted, partially or fully halo- genated, or substituted by 1, 2 or 3 substituents C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C1-C6-haloalkoxy, or (C1-C6-alkoxy)carbonyl; or
  • two R 16 on two adjacent carbon atoms form together with the carbon atoms they are bonded to a 4- to 8-membered saturated, partially or fully unsaturated ring, wherein the ring may contain 1 or 2 heteroatoms N, O, and/or S as ring members, which ring is unsub- stituted, or partially or fully substituted by same or different halogen, C1-C4-alkyl, C1-C4- haloalkyl, C 1 -C 4 -alkoxy, or C 1 -C 4 -haloalkoxy;
  • each n is independently 0, 1, or 2;
  • each m is independently 0, or 1; by reacting an ⁇ , ⁇ -unsaturated compound of formula II,
  • R 3 has the meaning given for formula I, in the presence of a catalyst.
  • the reaction of compounds of formula II and compounds of formula III is carried out at temper- atures of from -20°C to 100°C, preferably from 0°C to 40°C, in an inert solvent such as ethers, such as tetrahydrofurane (THF), diethyl ether, and dioxane, or toluene, in the presence of or- ganic bases, for example tertiary amines, such as diisopropylethylamine (DIPEA), trimethyla- mine, triethylamine, and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic amines, or inorganic bases such as al- kali metal and alkaline earth metal oxides, such as Li 2 O, Na 2 O, CaO, and MgO, in the presence of a catalyst, which is selected from lewis acids, and urea and
  • Lewis acids are preferably alkali metal halides, such as LiBr, LiI, LiCl, LiF, NaBr, NaI, NaCl, NaF, KBr, KI, KF, KCl, CsBr, CsI, CsCl, CsF; or BF 3 , AlCl 3 , FeCl 3 , ZnCl 4 , TiCl 4 , ZnCl 2 ,
  • Preferred lewis acids are alkali
  • R 51 is phenyl substituted by one or more OCF3, CF3, NO2, F, and OCH3; preferably CF3; R 52 CH2CH2N(CH3)2;
  • W is O, or S, preferably S.
  • the lewis acid is used in 2 to 3, preferably 2 to 2.5, particularly about 2.2 mol equivalents of compound II.
  • the urea derivative is used in 0.01 to 0.5, preferably 0.1 to 0.5, particularly about 0.1 mol equivalents of compound II.
  • the starting materials are generally reacted with one an- other in equimolar amounts. In terms of yield, it may be advantageous to employ an excess of III, based on II.
  • Compounds of formula II can be obtained by condensation of a ketone of formula VI with an acetyl compound of formula VII
  • Suitable solvents are aliphatic hydrocarbons such as pentane, hexane, cyclohexane, and pet- rol ether, aromatic hydrocarbons such as toluene, o-, m-, and p-xylene, halogenated hydrocar- bons such as CH 2 Cl 2 , CHCl 3 , dichloroethane and chlorobenzene, ethers such as diethyl ether, diisopropylether, tert.-butylmethyl ether, 1,4-dioxane, anisole, and THF, nitrils such as acetoni- trile, and propionitrile, alcohols such as methanol, ethanol, n-propanol, iso
  • Suitable bases are, in general, inorganic compounds, such as alkali metal and alkaline earth metal hydroxides, such as LiOH, NaOH, KOH and Ca(OH)2, alkali metal and alkaline earth metal oxides, such as Li 2 O, Na 2 O, CaO, and MgO, alkali metal and alkaline earth metal hydri- des, such as LiH, NaH, KH and CaH 2 , alkali metal and alkaline earth metal carbonates, such as Li2CO3, K2CO3 and CaCO3, and also alkali metal bicarbonates, such as NaHCO3, moreover or- ganic bases, for example tertiary amines, such as N(CH 3 ) 3 , N(C 2 H 5 ) 3 , DIPEA and N-methylpi- peridine, pyridine, substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and also bicycl
  • alkali metal and alkaline earth metal carbonates and organic bases especially sodium or potassium carbonate and triethylamine.
  • the bases are generally employed in catalytic amounts; however, they can also be used in equimolar amounts, in excess or, if appropriate, as solvent. It is also possible to use mixtures of the bases mentioned.
  • a base such as an alkali metal hydroxide such as KOH, NaOH, or preferably LiOH
  • a solvent such as THF, dioxane, or methanol, or an aqueous mixture thereof, preferably a THF-water mixture (c.f. WO 2015/169723).
  • ester group A being COOR 9 in formula I is hydrolysed to COOH in formula VIII.
  • Compounds o ormua can e prepare rom compoun s y e y ra ve ecarboxylation of compounds of formula VIII with reagents such as methyl sulphonyl chroride (CH 3 SO 2 Cl), or dineopentylacetal in a solvent such as dimethylsulfoxide (DMSO), DMF, or N-methylpyrrolidone (NMP), preferably in DMF.
  • DMSO dimethylsulfoxide
  • NMP N-methylpyrrolidone
  • the reaction is carried out at temperature from 25°C to 250°C, pref- erably at 100°C to 150°C (c.f. WO 2014/072480).
  • R 9 usually is C 1 -C 4 -alkyl.
  • Compounds IV, wherein A is a group A 1 correspond to formula IV.1.
  • Such compounds wherein W is O, can be prepared by reacting a compound IV wherein A is A 5 , which is Cl, Br, I, or OSO2- R 9 , and the other variables are as defined for formula IV (such compounds represent formula IV.5), with carbon monoxide in the presence of a Pd catalyst and an alcohol R 9 OH, wherein R 9 is C1-C4-alkyl or R 9 , to a compound of formula IV.1.
  • Suitable Pd catalysts are for example those described in WO 2011/161130.
  • Hydrolyzation can be carried out under standard conditions, e.g. under acidic conditions using for example hydrochloric acid, sulfuric acid or trifluoroacetic acid, or under basic conditions using for example an alkali metal hydrox- ide, such as LiOH, NaOH, or KOH.
  • Amidation is preferably carried out by activation of the car- boxylic acids with oxalylchloride [(COCl)2] or thionylchloride (SOCl2) to the respective acid chlo- rides, followed by reaction with an amine NHR 5 R 6 .
  • amidation is carried out in the presence of a coupling reagent.
  • Suitable coupling reagent are well known and are for instance selected from carbodiimides, such as DCC (dicyclohexylcarbodiimide) and DIC (diisopropylcarbodiimide), benzotriazol derivatives, such as HATU (O-(7-azabenzotriazol-1-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate), HBTU ((O-benzotriazol-1-yl)-N,N,N',N'-tet- ramethyluronium hexafluorophosphate) and HCTU (1H-benzotriazolium-1-[bis(dimethylami- no)methylene]-5-chloro tetrafluoroborate) and phosphonium-derived activators, such as BOP ((benzotriazol-1-yloxy)-tris(dimethylamino)phosphonium hexa
  • Compounds IV.1, wherein W is S can be prepared by reacting the corresponding oxo-com- pound (W is O) with Lawesson's reagent (c.f. Jesberger et al., Synthesis, 2003, 1929-1958). Solvents such as Hexamethylphosphoramide (HMPA) or THF at an elevated temperature such as 60°C to 100°C can be used. Preferred reaction conditions are THF at 65°C.
  • Compounds I wherein A is a group A 2 can be prepared by reacting a compound I wherein A is an aldehyde group CHO with NH2-NH-C(O)-NHR 22 .
  • Suitable reaction conditions for this conden- sation reaction include heating in a solvent such as a lower alcohol under the influence of an acid (e.g. acetic acid or HCl), where the acid may be used in catalytic or equimolar amounts.
  • Such compounds can be prepared by reducing an aldehyde IV.1 wherein Y is H (such al- dehyde represents formula IV.1a) for example with LAH (lithium aluminium hydride) or DIBAL-H (diisobutyl aluminium hydride) to a compound 20.
  • amidation is preferably carried out by activation of the car- boxyl group with oxalylchloride [(COCl) 2 ] or thionylchloride (SOCl 2 ) to the respective acid chlo- rides, followed by reaction with the benzylic amine.
  • oxalylchloride [(COCl) 2 ] or thionylchloride (SOCl 2 )
  • SOCl 2 thionylchloride
  • Suitable coupling reagents are well known and are for instance selected from carbodiimides, such as DCC (dicyclohexylcarbodiimide) and DIC (di- isopropylcarbodiimide), benzotriazol derivatives, such as HATU (O-(7-azabenzotriazol-1-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate), HBTU ((O-benzotriazol-1-yl)-N,N,N',N'-tet- ramethyluronium hexafluorophosphate) and HCTU (1H-benzotriazolium-1-[bis(dimethylami- no)methylene]-5-chloro tetrafluoroborate) and phosphonium-derived activators, such as BOP ((benzotriazol-1-yloxy)-tris(dimethylamino)phosphonium he
  • the activator is used in excess.
  • the benzotri- azol and phosphonium coupling reagents are generally used in a basic medium.
  • Compounds IV wherein A is a group A 2 represent formula IV.2.
  • Such compounds wherein R 7a is optionally substituted alkyl or optionally substituted cycloalkyl and R 7b is H, can be prepared by subjecting a ketone 22, wherein R 7a is optionally substituted C1-C6-alkyl or optionally substi- tuted C3-C8-cycloalkyl, to a reductive amination to yield compounds 21.
  • Typical conditions for the reductive amination are: Reacting ketone 22 with an amine H 2 NR 21 to yield the correspond- ing imine which is reduced to amine 21 with a reducing agent reagent such as NaBH 3 CN.
  • the reaction from ketone 22 to amine 21 may also be carried out as a one pot procedure.
  • the amine 21 is then r reof, such as its acid chloride R 22 -COCl, in an amidation reaction, as described above.
  • the ketone 22 is prepared from the aldehyde IV.1a which is reacted with a Grignard reagent R 7a -MgHal, where Hal is Cl, Br or I, or an organolithium compound R 7a -Li to obtain an alcohol of formul
  • R 7a and R 7b are optionally substituted alkyl, optionally sub- stituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl, carbonyl com- pounds such as 22, where R 7a is optionally substituted C 1 -C 6 -alkyl, optionally substituted C 3 -C 8 - cycloalkyl, optionally substituted C2-C6-alkenyl or optionally substituted C2-C6-alkynyl, is reacted with a Grignard reagent R 7b -MgHal, where Hal is Cl, Br or I, or an organolithium compound R 7b - Li, where R 7b is optionally substituted C 1 -C 6 -alkyl, optionally substituted C 3 -C 8 -cycloalkyl, option- ally substituted C2-C6-alkenyl or optionally substituted C2-C6-alkynyl, to obtain an
  • Alcohol 24 can then be converted into amine 25 via the corresponding azide (c.f. in Organic Let- ters, 2001, 3(20), 3145-3148.
  • this can be converted into compounds IV.2 by standard alkylation or acylation reac- tions.
  • Compounds IV.2, wherein R 7a is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl or CN and R 7b is H, can be prepared by converting an aldehyde IV.1a into an imine 26 by reaction with an amine derivative NH2R, wherein R is tert-butyl sulfinyl, or, for preparing a compound with R 7a being CN.
  • Suitable reagents are for example Si(CH3)3-CN or HCN for introducing CN as R 7a , or Si(CH3)3-CF3 for introducing CF3 as R 7a , or methyl magnesium bromide (CH3-MgBr) for introducing a methyl group as R 7a .
  • Suitable conditions are described, for example, in J. Am. Chem. Soc.2009, 3850-3851 and the references cited therein or in Chemistry - A European Journal 2009, 15, 11642-11659.
  • R tert- butylsulfinyl
  • R can then be removed under acidic conditions, such as hydrochloric acid in metha- nol, to yield an amino group.
  • the group C(O)R 22 can then be introduced as described above by acylating this amino group with an acid R 22 -COOH or a derivative thereof, such as its acid chlo- ride R 22 -COCl.
  • Compounds I wherein A is a group A 2 can be prepared by reacting a compound I wherein A is an aldehyde group CHO with NH 2 -NH-C(O)-NHR 22 .
  • Suitable reaction conditions for this conden- sation reaction include heating in a solvent such as a lower alcohol under the influence of an acid (e.g. acetic acid or HCl), where the acid may be used in catalytic or equimolar amounts.
  • Compounds IV.1a can be prepared by reaction of a compound IV.5, in which A 5 is Cl, Br, I or OSO 2 -R 9 , with carbon monoxide and a hydride source, such as triethylsilane, in the presence of a transition metal complex catalyst, preferably a palladium catalyst, to the aldehyde IV.1a.
  • This reaction converts the starting group A 5 into a carbonyl group CHO.
  • Compounds IV wherein A is A 3 represent formula IV.3.
  • Such compounds can be prepared by standard ring coupling reactions.
  • compounds, wherein A 3 is an N-bound heterocy-rod ring can be prepared by reacting a compound IV.5 wherein A 5 is Cl, Br or I with the respec- tive ring A 3 -H (H being on the nitrogen ring atom to be coupled) under Ullmann coupling condi- tions, such as described, for example, in WO 2007/075459.
  • copper(I) iodide or cop- per(I) oxide and a ligand such as 1,2-cyclohexyldiamine is used, c.f. Kanemasa et al., European Journal of Organic Chemistry, 2004, 695-709.
  • reaction is typically run in a polar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrroli- done, and in the presence of an inorganic base such as sodium, potassium or cesium car- bonate.
  • a polar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrroli- done
  • an inorganic base such as sodium, potassium or cesium car- bonate.
  • a 3 is a C-bound heterocyclic ring
  • a 3 is a C-bound heterocyclic ring
  • a 3 is Br or I
  • R is H or C1-C4- alkyl or the two R form together a C 2 -C 6 -alkylene bridge, e.g. -CH 2 -CH 2 - under Suzuki reaction conditions via Pd-catalyzed cross coupling, such as described, for example, in WO
  • a typical catalyst is tetrakis(triphenylphosphine)palladium(0). Solvents such as tetrahydrofuran, acetonitrile, diethyl ether and dioxane are suitable.
  • the boronic acids A 3 - B(OH) 2 are either commercially available or can be prepared by known methods. Other meth- ods for introduction of the heterocyclic groups A 3 are the Heck, Stille, Kumada and Buchwald- Hartwig coupling procedures; c.f. Tetrahedron, 2004, 60, 8991-9016.
  • reaction mixtures are worked up in a customary manner, for example by mixing with wa- ter, separating the phases and, if appropriate, chromatographic purification of the crude prod- ucts.
  • Some of the intermediates and end products are obtained in the form of colorless or slightly brownish viscous oils which are purified or freed from volatile components under re- Jerusalem pressure and at moderately elevated temperature. If the intermediates and end products are obtained as solids, purification can also be carried out by recrystallization or digestion.
  • halogen denotes in each case fluorine, bromine, chlorine or iodine, in particular flu- orine, chlorine or bromine.
  • CN denotes in each case cyano.
  • alkyl as used herein and in the alkyl moieties of alkylamino, alkylcarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl and alkoxyalkyl denotes in each case a straight-chain or branched al- kyl group having usually from 1 to 10 carbon atoms, frequently from 1 to 6 carbon atoms, prefer- ably 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms.
  • alkyl group examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl, tert-butyl, n-pentyl, 1-methyl- butyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpro- pyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-di- methylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dime- thylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-
  • haloalkyl as used herein and in the haloalkyl moieties of haloalkylcarbonyl, haloalk- oxycarbonyl, haloalkylthio, haloalkylsulfonyl, haloalkylsulfinyl, haloalkoxy and haloalkoxyalkyl, denotes in each case a straight-chain or branched alkyl group having usually from 1 to 10 car- bon atoms, frequently from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms.
  • Preferred haloalkyl moieties are selected from C1-C4-haloalkyl, more preferably from C1-C3-haloalkyl or C 1 -C 2 -haloalkyl, in particular from C 1 -C 2 -fluoroalkyl such as fluoromethyl, difluoromethyl, trifluo- romethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like.
  • alkoxy denotes in each case a straight-chain or branched alkyl group which is bonded via an oxygen atom and has usually from 1 to 10 carbon atoms, fre- quently from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
  • alkoxy group examples are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butyloxy, 2-butyloxy, iso-butyloxy, tert.-butyloxy, and the like.
  • alkoxyalkyl refers to alkyl usually comprising 1 to 10, frequently 1 to 4, preferably 1 to 2 carbon atoms, wherein 1 carbon atom carries an alkoxy radical usually com- prising 1 to 4, preferably 1 or 2 carbon atoms as defined above. Examples are CH2OCH3, CH 2 -OC 2 H 5 , 2-(methoxy)ethyl, and 2-(ethoxy)ethyl.
  • haloalkoxy denotes in each case a straight-chain or branched alk- oxy group having from 1 to 10 carbon atoms, frequently from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms, in particular fluorine atoms.
  • haloalkoxy moieties include C 1 -C 4 - haloalkoxy, in particular C1-C2-fluoroalkoxy, such as fluoromethoxy, difluoromethoxy, trifluoro- methoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-flu- oroethoxy, 2-chloro-2,2-difluoro-ethoxy, 2,2dichloro-2-fluorethoxy, 2,2,2-trichloroethoxy, penta- fluoroethoxy and the like.
  • C1-C2-fluoroalkoxy such as fluoromethoxy, difluoromethoxy, trifluoro- methoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-flu-
  • alkylthio refers to a straight-chain or branched saturated alkyl group having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms (C 1 -C 4 -alkylthio), more preferably 1 to 3 carbon atoms, which is attached via a sulfur atom.
  • haloalkylthio refers to an alkylthio group as mentioned above wherein the hydrogen atoms are partially or fully substituted by fluorine, chlorine, bromine and/or iodine.
  • haloalkylsulfinyl refers to an alkylsulfinyl group as mentioned above wherein the hydrogen atoms are partially or fully substituted by fluorine, chlorine, bromine and/or iodine.
  • haloalkylsulfonyl refers to an alkylsulfonyl group as mentioned above wherein the hydrogen atoms are partially or fully substituted by fluorine, chlorine, bro- mine and/or iodine.
  • haloalkylcarbonyl refers to an alkylcarbonyl group as mentioned above, wherein the hydrogen atoms are partially or fully substituted by fluorine, chlorine, bromine and/or iodine.
  • alkoxycarbonyl refers to an alkylcarbonyl group as defined above, which is bonded via an oxygen atom to the remainder of the molecule.
  • haloalkoxycarbonyl refers to an alkoxycarbonyl group as mentioned above, where- in the hydrogen atoms are partially or fully substituted by fluorine, chlorine, bromine and/or io- dine.
  • alkenyl denotes in each case a singly unsaturated hydrocarbon rad- ical having usually 2 to 10, frequently 2 to 6, preferably 2 to 4 carbon atoms, e.g. vinyl, allyl (2- propen-1-yl), 1-propen-1-yl, 2-propen-2-yl, methallyl (2-methylprop-2-en-1-yl), 2-buten-1-yl, 3- buten-1-yl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 1-methylbut-2-en-1-yl, 2-ethylprop-2-en- 1-yl and the like.
  • haloalkenyl refers to an alkenyl group as defined above, wherein the hydrogen atoms are partially or totally replaced with halogen atoms.
  • alkynyl denotes in each case a singly unsaturated hydrocarbon rad- ical having usually 2 to 10, frequently 2 to 6, preferably 2 to 4 carbon atoms, e.g. ethynyl, pro- pargyl (2-propyn-1-yl), 1-propyn-1-yl, 1-methylprop-2-yn-1-yl), 2-butyn-1-yl, 3-butyn-1-yl, 1-pen- tyn-1-yl, 3-pentyn-1-yl, 4-pentyn-1-yl, 1-methylbut-2-yn-1-yl, 1-ethylprop-2-yn-1-yl and the like.
  • haloalkynyl refers to an alkynyl group as defined above, wherein the hydrogen atoms are partially or totally replaced with halogen atoms.
  • cycloalkyl as used herein and in the cycloalkyl moieties of cycloalkoxy and cycloal- kylthio denotes in each case a monocyclic cycloaliphatic radical having usually from 3 to 10 or from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl or cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • halocycloalkyl as used herein and in the halocycloalkyl moieties of halocycloalkoxy and halocycloalkylthio denotes in each case a monocyclic cycloaliphatic radical having usually from 3 to 10 C atoms or 3 to 6 C atoms, wherein at least one, e.g.1, 2, 3, 4 or 5 of the hydrogen atoms, are replaced by halogen, in particular by fluorine or chlorine.
  • Examples are 1- and 2-fluo- rocyclopropyl, 1,2-, 2,2- and 2,3-difluorocyclopropyl, 1,2,2-trifluorocyclopropyl, 2,2,3,3-tetrafluo- rocyclpropyl, 1- and 2-chlorocyclopropyl, 1,2-, 2,2- and 2,3-dichlorocyclopropyl, 1,2,2-trichloro- cyclopropyl, 2,2,3,3-tetrachlorocyclpropyl, 1-,2- and 3-fluorocyclopentyl, 1,2-, 2,2-, 2,3-, 3,3-, 3,4-, 2,5-difluorocyclopentyl, 1-,2- and 3-chlorocyclopentyl, 1,2-, 2,2-, 2,3-, 3,3-, 3,4-, 2,5-dichlo- rocyclopentyl and the like.
  • cycloalkenyl as used herein and in the cycloalkenyl moieties of cycloalkenyloxy and cycloalkenylthio denotes in each case a monocyclic singly unsaturated non-aromatic radical ha- ving usually from 3 to 10, e.g.3 or 4 or from 5 to 10 carbon atoms, preferably from 3- to 8 car- bon atoms.
  • exemplary cycloalkenyl groups include cyclopropenyl, cycloheptenyl or cycloocte- nyl.
  • halocycloalkenyl as used herein and in the halocycloalkenyl moieties of halocyclo- alkenyloxy and halocycloalkenylthio denotes in each case a monocyclic singly unsaturated non- aromatic radical having usually from 3 to 10, e.g.3 or 4 or from 5 to 10 carbon atoms, preferably from 3- to 8 carbon atoms, wherein at least one, e.g.1, 2, 3, 4 or 5 of the hydrogen atoms, are replaced by halogen, in particular by fluorine or chlorine. Examples are 3,3-difluorocyclopropen- 1-yl and 3,3-dichlorocyclopropen-1-yl.
  • “carbocycle” or“carbocyclyl” includes in general a 3- to 12-membered, preferably a 3- to 8-membered or a 5- to 8-membered, more preferably a 5- or 6-membered mono-cyclic, non-aromatic ring comprising 3 to 12, preferably 3 to 8 or 5 to 8, more preferably 5 or 6 carbon atoms.
  • the term“carbocycle” covers cycloalkyl and cycloalkenyl groups as defined above.
  • the term "3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered saturated, partially or fully unsaturated het- erocyclic ring containing 1, 2 or 3 (or 4) heteroatoms N, O, and/or S, as ring members” denotes a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or fully unsaturated hetero- monocyclic ring or a 8-, 9- or 10-membered saturated, partially or fully unsaturated heterobicy-hack ring containing 1, 2 or 3 (or 4) heteroatoms which are selected from N, O, and S as ring members.
  • Unsaturated rings contain at least one C-C and/or C-N and/or N-N double bond(s). Fully unsaturated rings contain as many conjugated C-C and/or C-N and/or N-N double bonds as allowed by the ring size. Fully unsaturated include aromatic heterocyclic rings.
  • the heterocy-root ring may be attached to the remainder of the molecule via a carbon ring member or via a ni- trogen ring member. Of course, the heterocyclic ring contains at least one carbon ring atom. If the ring contains more than one O ring atom, these are not adjacent.
  • N and S ring atoms may be oxidized, if not mentioned otherwise. The oxidized ring atoms constitue an N-oxide, Sulfox- ide (SO), and a sulfone (SO 2 ), resp., wherein the only the N- or S atom is a ring member.
  • Examples of a 3-, 4-, 5-, 6- or 7-membered saturated, partially or fully unsaturated heteromon- ocyclic ring include: Oxiranyl, thiiranyl, aziridinyl, oxetanyl, thietanyl, azetidinyl, tetrahydrofuran- 2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, pyrrolidin-1-yl, pyrrolidin-2- yl, pyrrolidin-3-yl, pyrazolidin-1-yl, pyrazolidin-3-yl, pyrazolidin-4-yl, pyrazolidin-5-yl, imidazolidin- 1-yl, imidazolidin-2-yl, imidazolidin-4-yl, oxazolidin-2-yl, oxazolidin-3-yl,
  • Examples of a 3-, 4-, 5-, 6- or 7-membered partially unsaturated heterocyclic ring (HET) in- clude: 2,3-dihydrofur-2-yl, 2,3-dihydrofur-3-yl, 2,4-dihydrofur-2-yl, 2,4-dihydrofur-3-yl, 2,3-dihy- drothien-2-yl, 2,3-dihydrothien-3-yl, 2,4-dihydrothien-2-yl, 2,4-dihydrothien-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin-3- yl, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-
  • Examples for a 3-, 4-, 5-, 6- or 7-membered fully unsaturated (including aromatic) heterocyclic ring are 5- or 6-membered heteroaromatic rings (HET), such as 2-furyl, 3-furyl, 2-thienyl, 3-thi- enyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxa- zolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 1-imidazolyl, 2-imidazolyl, 4-im- idazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,2,4-triazol-1-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyr
  • Examples of an 8-membered fully unsaturated saturated heterocyclic ring include: azocinyl, 1,2-, 1,3-, 1,4- and 1,5-diazocinyl and the like.
  • a group of preferred heterocycles is the following: 2-pyridyl (E-1), 3-pyridyl (E-2), 4-py- ridyl (E-3), 3-pyridazinyl (E-4), 4-pyrimidinyl (E-5), 2-pyrazinyl (E-6), 2-pyrimidinyl (E-7), thio- phen-2-yl (E-8), thiophen-3-yl (E-9), furan-2-yl (E-10), furan-3-yl (E-11), pyrazol-1-yl (E-12), and 1,2,4-triazol-1-yl (E-13); heterocycles E-1, E-2, E-7, E-12, and E-13 are particularly preferred, which rings E-1 to E-13 are unsubstituted or substituted by up to
  • Another particulary preferred heterocycle are E-12, and E-13.
  • Preferred 3-, 4-, 5-, 6- or 7-membered saturated, partially or fully unsaturated heterocyclic rings comprising 1, 2 or 3 heteroatoms N, O, and/or S as ring members (HET) are in any posi- tions of formulae I and IV, the following: azetidin-3-yl (H-1), dioxin-6-yl (H-2), 1,3-dioxolan-2-yl (H-3), 1,1-dioxotetrahydrothiophen-3-yl (H-4), 1,1-dioxothietan-2-yl (H-5), 1,1-dioxothietan-3-yl (H-6), imidazol-2-yl (H-7), imidazol-4-yl (H-8), imidazol-5-yl (H-9), isothiazol-3-yl (H-10), isothia- zol-4-yl (H-11), isothiazol-5-yl (H-12), is
  • More preferred rings HET are the following: E-1, E-7, E-12, E-13, H-6, H-21, H-33, and H-35. Rings E-12, and E-13 are particularly preferred. With respect to the variables, the particularly preferred embodiments of intermediates and final products correspond to those of compounds of formula I.
  • R 1 is preferably fluoromethyl, particularly CF3.
  • R 2 is preferably halogen, halomethyl, halomethoxy, particularly F, Cl, Br, CF 3 , or OCF 3 .
  • Particularly preferred is each one of the following combinations of R 2a , R 2b and R 2c wherein R 2a , R 2b and R 2c are selected from R 2 , H, and F, and at least on of R 2a , R 2b and R 2c is F.
  • Each line of Table P denotes a substitution pattern of the phenyl ring (“P”) bearing the R 2a , R 2b and R 2c moieties.
  • P phenyl ring bearing the R 2a , R 2b and R 2c moieties.
  • a particularly preferred embodiment of compounds of formula I are those wherein the phenyl ring which is substituted by one F and R 2 n groups shows one of the following substi- tution pattern.
  • Groups P-1, P-3, P-8, P-9, P-10, P-11, P-13, P-14, and P-17 are more preferred patterns in formula I and IV compounds.
  • P-8 and P-9 is particularly preferred.
  • R 3 is preferably C1-C6-alkoxy, particularly methoxy or ethoxy.
  • # denotes the bond to the di- or tetrahydrothiophene ring
  • R 4a and R 4b together form with the C-atoms to which they are bonded, a five- or six- membered saturated carbo- or heterocyclic ring which may contain one or two heteroatoms which are preferably selected from oxygen and sulfur.
  • Particularly preferred are the following chains, wherein“a”, and“b” denote the bonds to positions of R 4a and R 4b , resp.:
  • a-CH 2 CH 2 O-b -CH 2 OCH 2 -, -OCH 2 O-, a-CH 2 CH 2 S-b, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and a-CH 2 CH 2 CH 2 O-b; particularly preferred are -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -.
  • R 4a and R 4b in group G are selected from R 4 as follows:
  • R4 a and R4 b have the following meanings:
  • R4 a is H, and CH3, and
  • R4 b is CH 3 , halogen, halomethyl, C 1 -C 4 -alkoxy, and C 1 -C 4 -haloalkoxy. Most preferred is CH 3 and halogen.
  • R 4b is a bond to bridge -Q-Z- in group A 4 .
  • R 6 is preferably H, C1-C6-alkyl, C3-C8-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, which groups are unsubstituted, partially or fully halogenated and/or substituted by one or more same or dif- ferent R 8 , wherein R 8 is preferably S(O) n R 9 and R 9 preferably is C 1 -C 6 -alkyl;
  • phenyl which may be partially or fully substituted by R 11 ; and 3- to 10-membered saturated, partially or fully unsaturated heteromonocyclic or heterobicyclic ring containing 1, 2, 3 or 4 het- eroatoms N, O, and/or S as ring members, which ring is unsubstituted, or substituted by one or more same or different R 11 , preferably a HET, which particularly is selected from E-1, E-7 and H-6, H-21, H-33 and H-35. Rings E-2 and E-7 are particularly preferred. HET is unsubstituted or substituted. Substitution of HET is preferably C 1 -C 4 -alkyl.
  • R 8 is preferably C 3 -C 8 -cycloalkyl, C 3 -C 8 -halocycloalkyl, wherein the carbon chains may be sub- stituted by one or more radicals R 13 ;
  • R 8 together with the carbon atoms of the alkyl, alkenyl, alkynyl or cycloalkyl group which they are bonded to, form a 3- to 8-membered saturated or partially unsaturated carbocy- saw or heterocyclic ring, which heterocyclic ring comprises 1, 2, 3 or 4 heteroatoms N, O, and/or S as ring members, and which ring is unsubstituted, or partially or fully substituted by same or different R 16 ; the heterocyclic ring preferably is selected from E-1, E-7, H-6, H-21, H-33, and H- 35, which is unsubstituted or substituted by R 16 , wherein R 16 is particularly C 1 -C 4 -alkyl.
  • R 9 is preferably H, CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-C 1 -C 4 - alkyl-, C 3 -C 8 -halocycloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl, or C 2 -C 6 -haloalky- nyl, which groups are unsubstituted, or partially or fully substituted by same or different R 13 , R 9 in the groups S(O) n R 9 and OSO 2 R 9 may additionally and preferably be C 1 -C 6 -alkoxy, or C 1 - C 6 -haloalkoxy; the group OSO 2 R 9
  • R A4 preferably is selected from H, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C3-C6-cy- cloalkyl, the groups being unsubstituted or substituted by S(O)n-C1-C4-alkyl, or S(O)n-C1-C4- haloalkyl.
  • HPLC-MS high performance liquid chromatography-coupled mass spectrometry
  • HPLC method Phenomenex Kinetex 1.7 ⁇ m XB-C18100A; 50 x 2.1 mm; mobile phase:

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Abstract

L'invention concerne un procédé de préparation de dérivés de tétrahydrothiophène de formule I, (I) les variables ayant les significations telles que définies dans la spécification, par la réaction d'un composé α, β- insaturé de formule II, (II) avec un thioglycolate de formule III, (III) en présence d'un catalyseur.
PCT/EP2017/077075 2016-11-02 2017-10-24 Procédé de préparation de dérivés de tétrahydrothiophène WO2018082962A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111686798A (zh) * 2020-03-10 2020-09-22 秦婷 一种用于制备螺四氢噻吩的binol轴手性硫脲有机催化剂
US10961213B2 (en) 2017-01-25 2021-03-30 Basf Se Process for preparation of benzylic amides
US10961226B2 (en) 2016-11-04 2021-03-30 Basf Se Process for purification of pyrazolpyridazines

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007075459A2 (fr) 2005-12-16 2007-07-05 E. I. Du Pont De Nemours And Company 5-arylisoxazolines pour lutter contre des parasites invertebres
WO2010072781A2 (fr) 2008-12-23 2010-07-01 Basf Se Composés imines pour lutter contre des animaux nuisibles invertébrés
WO2011161130A1 (fr) 2010-06-23 2011-12-29 Basf Se Procédé de production de composés imine destiné à lutter contre les ravageurs invertébrés
WO2014036056A1 (fr) * 2012-08-31 2014-03-06 Zoetis Llc Formes cristallines de la 1-(5'-(5-(3,5-dichloro-4-fluorophényl)-5-(trifluorométhyl)-4,5-dihydroisoxazol-3-yl)-3'h-spiro[azétidine-3,1'-isobenzofuran]-1-yl)-2-(méthylsulfonyl)éthanone
WO2014072480A1 (fr) 2012-11-09 2014-05-15 Syngenta Participations Ag Dérivés de dihydrothiophène utilisés comme composés insecticides
WO2014079937A1 (fr) * 2012-11-21 2014-05-30 Syngenta Participations Ag Composés pesticides à base de dérivés d'arylthiosulfonamide
WO2015128358A1 (fr) 2014-02-26 2015-09-03 Basf Se Composés azoline
WO2015169723A1 (fr) 2014-05-09 2015-11-12 Syngenta Participations Ag Composés insecticides à base de dérivés de thiophène
WO2016102490A1 (fr) 2014-12-22 2016-06-30 Basf Se Composés cycliques substitués par un système cyclique condensé
WO2017153217A1 (fr) * 2016-03-09 2017-09-14 Basf Se Dérivés spirocycliques

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007075459A2 (fr) 2005-12-16 2007-07-05 E. I. Du Pont De Nemours And Company 5-arylisoxazolines pour lutter contre des parasites invertebres
WO2010072781A2 (fr) 2008-12-23 2010-07-01 Basf Se Composés imines pour lutter contre des animaux nuisibles invertébrés
WO2011161130A1 (fr) 2010-06-23 2011-12-29 Basf Se Procédé de production de composés imine destiné à lutter contre les ravageurs invertébrés
WO2014036056A1 (fr) * 2012-08-31 2014-03-06 Zoetis Llc Formes cristallines de la 1-(5'-(5-(3,5-dichloro-4-fluorophényl)-5-(trifluorométhyl)-4,5-dihydroisoxazol-3-yl)-3'h-spiro[azétidine-3,1'-isobenzofuran]-1-yl)-2-(méthylsulfonyl)éthanone
WO2014072480A1 (fr) 2012-11-09 2014-05-15 Syngenta Participations Ag Dérivés de dihydrothiophène utilisés comme composés insecticides
WO2014079937A1 (fr) * 2012-11-21 2014-05-30 Syngenta Participations Ag Composés pesticides à base de dérivés d'arylthiosulfonamide
WO2015128358A1 (fr) 2014-02-26 2015-09-03 Basf Se Composés azoline
WO2015169723A1 (fr) 2014-05-09 2015-11-12 Syngenta Participations Ag Composés insecticides à base de dérivés de thiophène
WO2016102490A1 (fr) 2014-12-22 2016-06-30 Basf Se Composés cycliques substitués par un système cyclique condensé
WO2017153217A1 (fr) * 2016-03-09 2017-09-14 Basf Se Dérivés spirocycliques

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CHEMISTRY - A EUROPEAN JOURNAL, vol. 15, 2009, pages 11642 - 11659
J. AM. CHEM. SOC., 2009, pages 3850 - 3851
JESBERGER ET AL., SYNTHESIS, 2003, pages 1929 - 1958
ORGANIC LETTERS, vol. 3, no. 20, 2001, pages 3145 - 3148
TETRAHEDRON, vol. 60, 2004, pages 8991 - 9016

Cited By (3)

* Cited by examiner, † Cited by third party
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US10961226B2 (en) 2016-11-04 2021-03-30 Basf Se Process for purification of pyrazolpyridazines
US10961213B2 (en) 2017-01-25 2021-03-30 Basf Se Process for preparation of benzylic amides
CN111686798A (zh) * 2020-03-10 2020-09-22 秦婷 一种用于制备螺四氢噻吩的binol轴手性硫脲有机催化剂

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