WO2019145174A1 - Preparation of optionally substituted 5-substituted pyridine - Google Patents

Preparation of optionally substituted 5-substituted pyridine Download PDF

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Publication number
WO2019145174A1
WO2019145174A1 PCT/EP2019/050790 EP2019050790W WO2019145174A1 WO 2019145174 A1 WO2019145174 A1 WO 2019145174A1 EP 2019050790 W EP2019050790 W EP 2019050790W WO 2019145174 A1 WO2019145174 A1 WO 2019145174A1
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Prior art keywords
alkyl
formula
halogenalkyl
compound
halogen
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PCT/EP2019/050790
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French (fr)
Inventor
Bernd Mueller
Michael Rack
Michael Seet
Ana Escribano Cuesta
Georg Christoph RUDOLF
Jan Klaas Lohmann
Markus Nett
Rainer Jung
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Basf Se
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Publication of WO2019145174A1 publication Critical patent/WO2019145174A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • R 1 is in each case independently selected from hydrogen, halogen, Ci-C 6 -alkyl and Ci-
  • R 2 is in each case independently selected from hydrogen, halogen, Ci-C 6 -alkyl and Ci-
  • R 3 , R 4 are independently selected from Ci-C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 - halogenalkyl, C 2 -C 6 -halogenalkenyl and C 2 -C 6 -halogenalkynyl;
  • R 5 is halogen
  • R 6 is halogen; o is 0, 1 , 2 or 3; and
  • R 78 are independently selected from halogen, Ci-C 6 -alkyl, Ci-C 6 -alkoxy, C 1 -C 6 - halogenalkyl and Ci-C 6 -halogenalkoxy;
  • R 10 is independently selected from H, halogen, 0(R 95 ), Ci-C 6 -alkyl and C 1 -C 6 - halogenalkyl; wherein R 95 is Ci-C 6 -alkyl, Ci-C 6 -halogenalkyl;
  • R 3 , R 4 , R 5 , R 6 R 78 and o are as defined above and
  • X is a metal ion
  • R 1 , R 2 , R 9 and R 10 are as defined above in the presence of a catalyst.
  • the process of this invention is effective and suitable for a production on a large scale. Since it is a convergent synthesis route it is of a short reaction sequence resulting in low production cost and minimum waste. Moreover it is compatible with the substituents present in the target mole- cules.
  • the catalyst comprises a Cu source, a Pd source and an optional ligand.
  • the catalyst system (Pd+ligand) can be added together or sepa- rately either at room temperature or at an elevated temperature.
  • the system can be prepared separately, immediately before the reaction is carried out, by combining a Pd salt and the lig and, or it can be synthesized before or purchased in pure form or in solution.
  • the direct addition of the ligand and of the palladium source to the batch (in situ process). Alter- natively the reaction can be carried out with a palladium source alone without addition of an additional ligand.
  • the palladium catalysts used are optionally produced in situ from at least one palladium(ll) salt or a palladium(O) compound and the corresponding phosphine ligands. How- ever, they may also be used directly as palladium(O) compound without reducing the initial cata- lytic activity.
  • the Pd source is selected from the group consist- ing of Pd(OAc) 2 , Pd(ll)Cl 2 , Palladium(ll)-1 ,2-bis(diphenylphosphino)ethan dichloride, Palladi- um(ll)- 1 ,3-Bis(diphenylphosphino)propan dichloride, Palladium(ll)- 1 ,4- Bis(diphenylphosphino)butan dichloride, Palladium(ll)-1 ,T-Bis(diphenylphosphino)ferrocene dichloride, Palladium(0)-tetrakis(triphenylphosphin, Palladium(ll)- bis(triphenylphosphin)dichloride, Pd(P(t-Bu)3)2, Pd(acac)2, Pd(iPr)2Ph2, Pd(P(t-Bu)2Ph)2Cl2, Pd(dba)
  • the ligand is mono- or bidentate phosphorus-con- taining ligand.
  • P ' , P " , P '" are independently selected from Ci-C 6 -alkyl, C 3 -C 6 -cycloalkyl, aryl and heteroaryl, which are unsubstituted or substituted.
  • monodentate phosphorus-containing ligand selected from the group consis- ting of: triethylphosphin, tri-n-butylphosphin, tri-t-butylphosphin, tribenzylphosphin,
  • 2,2'-Bis(diphenylphosphino)- 1 ,1 '-binaphthyl BINAP
  • 1 ,1-bis(diphenylphosphino)methane DPPM
  • 1 ,2- bis(diphenylphosphino)ethan DPPE
  • 1 ,3-bis(diphenylphosphino)propan DPPP
  • DPPF 1,1 '-bis(diphenylphosphino)ferrocen
  • Xantphos 1, 4,5- bis(diphenylphosphino)-9,9-dimethylxanthen (Xantphos)
  • DPPE 1,2- bis(diphenylphosphino)ethan
  • DPPP 1,3-bis(diphenylphosphino)propan
  • DPPB 1,4- bis(diphenylphosphino)butan
  • DPPF 1,1 '-bis(diphenylphosphino)ferrocen
  • the molar ratio of palladium to the phosphine ligand should be between 4: 1 and 1:100 and is preferably between I: I and l:5, particularly preferably between I: I and l:2.
  • the Cu salts is selected from the group Cul,
  • CuBr CuCI, CuF, CU2O, Cu(OAc), Cu2(C03)(0H)2,CuS0 4 , CuO, Cu(Otriflate)2, Cu(OAc)2.
  • Most preferred are CuBr, CuCI, CU 2 O, CuS0 4 and CuO.
  • the molar ratio of palladium to Cu salt should be between 0,01 and 50, preferably between 0,05 and 20, preferred between 0,1 and 5.
  • the reaction can be carried out in a single solvent or in solvent mixtures.
  • Suitable organic solvents for the reaction are aprotic solvents, for example aromatic hydrocar- bons such as benzene, toluene, xylenes, cumene, chlorobenzene, dichlorobenzenes, nitroben- zene or tert-butylbenzene, aprotic polar solvents, for example cyclic or acyclic ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether (MTBE), tert-butyl ethyl ether, tetrahydro- furan (THF) or dioxane, cyclic or acyclic amides such as dimethylformamide, dimethylacetam- ide, N-methylpyrrolidone or tetramethylurea, aliphatic esters like ethyl acetate, butyl
  • reaction ususally takes place at temperatures between 50°C and 200°C, preferred between 70 °C and 170°C, especially preferred between 90°C and 160°C.
  • X is selected form the group consisting of Li, NA, K and Cs. Most preferred is Li.
  • R 3 , R 4 , R 5 , R 6 R 78 and o are as defined above and
  • Y is selected from Ci-C 6 -alkyl, Ci-C 6 -halogenalkyl, phenyl and benzyl, wherein phenyl and benzyl are unsubstituted or substituted by CN, NO 2 , halogen, Ci-C 6 -alkyl, C 1 -C 6 - halogenalkyl or Ci-C 6 -alkoxy;
  • R 3 , R 4 are independently selected from Ci-C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 - halogenalkyl, C 2 -C 6 -halogenalkenyl and C 2 -C 6 -halogenalkynyl;
  • R 78 is independently selected from halogen, Ci-C 6 -alkyl, Ci-C 6 -alkoxy, C 1 -C 6 - halogenalkyl and Ci-C 6 -halogenalkoxy;
  • o 0, 1 , 2 or 3;
  • Y is selected from Ci-C 6 -alkyl, Ci-C 6 -halogenalkyl, phenyl and benzyl, wherein phenyl and benzyl are unsubstituted or substituted by CN, NO 2 , halogen, Ci-C 6 -alkyl, C 1 - C 6 -halogenalkyl or Ci-C 6 -alkoxy; in the presence of an acid to provide a compound of the formula VII
  • R 3 , R 4 , R 78 , o and Y are as defined above;
  • reaction (ii) is preferably a bromination.
  • reaction is carried out in the presence of an acid.
  • the acid is selected from inorganic acids such as sulfuric acid, fuming sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, organic acids such as trifluoromethane sulfonic acid, methane sulfonic acid, trifluoro acetic acid, trichloro ace- tic acid and mixtures thereof.
  • inorganic acids such as sulfuric acid, fuming sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid
  • organic acids such as trifluoromethane sulfonic acid, methane sulfonic acid, trifluoro acetic acid, trichloro ace- tic acid and mixtures thereof.
  • acid More preferred as acid are sulfuric acid, fuming sulfuric acid and trifluoro acetic acid. Most preferred is the use of sulfuric acid. Preferred amounts of the acid used are 1-10 equivi- lants related to the alcohol V used, more preferred 2 to 8 equivilants, even more preferred 2,5 to 5 equivilants.
  • reaction between V and VI is carried out in an inert solvent.
  • inert organic solvent is meant an organic solvent which, under the reaction conditions of the process of this invention, does not enter into any appreciable reaction with either the reac- tants or the products.
  • the inert organic solvent is selected from non-halogenated inert organic solvents; preferably from non-halogenated aliphatic hydrocarbons, non-halogenated cycloali- phatic hydrocarbons, non-halogenated aromatic hydrocarbons, halogenated aliphatic hydrocar- bons, halogenated aromatic hydrocarbons, amides, ethers, esters, ketones, nitriles and any combination thereof.
  • non-halogenated aliphatic hydrocarbons examples include pentane, hexane, hep- tane, petrolether and the like. Preference is given to saturated aliphatic hydrocarbons having from 5 to 10 carbon atoms.
  • non-halogenated cycloaliphatic hydrocarbons examples include cyclopentane, cy- clohexane, cycloheptane, and the like. Preference is given to non-halogenated saturated cyclo- aliphatic hydrocarbons having from 5 to 10 carbon atoms. Cyclohexane is particularly preferred.
  • Suitable a non-halogenated aromatic hydrocarbons include toluene, o-xylene, m- xylene, p-xylene, ethylbenzene, 2-propylbenzene (cumene), 2-isopropyltoluene (o-cymol), 3-isopropyltoluene (m-cymol), 4-isopropyltoluene (p-cymol), 1 ,3,5-trimethylbenzene (mesity- lene), and the like.
  • toluene Preference is given to toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 1 ,3,5-trimethylbenzene (mesitylene), and any combination thereof.
  • Especially preferred among the non-halogenated aromatic hydrocarbons are toluene, o-xylene, m-xylene, p-xylene, and any combination thereof, with toluene being the most preferred.
  • halogenated aliphatic hydrocarbons examples include dichloromethane, chloroform, carbon tetrachloride, 1 ,2-dichloroethane, 1 ,1 ,1 ,2-tetrachloroethane, 1 ,1 ,2,2-tetrachloroethane,
  • halogenated aromatic hydrocarbons examples include chlorobenzene, bromoben- zene, o-dichlorobenzene, m-dichlorobenzene, a,a,a-trifluorotoluene (benzotrifluoride) and the like and any combination thereof.
  • Suitable amides include N,N-dimethylformamide, N,N-dimethylacetamide, N,N- diethylacetamide, N-methyl-pyrrolidone, and the like and any combination thereof.
  • Suitable ethers include cyclic and acyclic ethers such as diethyl ether, diisopropyl ether, n-butyl methyl ether, isobutyl methyl ether, sec-butyl methyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, 1 ,4-dioxane, and the like and any combination there- of.
  • cyclic and acyclic ethers such as diethyl ether, diisopropyl ether, n-butyl methyl ether, isobutyl methyl ether, sec-butyl methyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, 1 ,4-dioxane, and the like and any combination there- of.
  • esters examples include ethyl acetate, n-propylacetate, isopropyl acetate, tert-butyl acetate, and the like and any combination thereof.
  • suitable ketones include acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, cyclopropyl methyl ketone and the like, and any combination thereof.
  • Suitable nitriles include acetonitrile, benzonitrile, and the like and any combination thereof.
  • the inert solvent selected from the group consisting of aliphatic and aromatic hydro- carbons and halohydrocarbons such as cyclohexane, heptane, benzene, toluene, xylenes, cu- mene, mesitylene, chlorobenzene, dichlorobenzenes and tert-butylbenzene, cyclic or acyclic ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether (MTBE), tert-butyl ethyl ether, methyl cyclopentylether, tetrahydrofuran (THF), methyl tetrahydrofuran (methyl THF) or dioxane, nitriles such as acetonitrile and propionitrile, aliphatic halohydrocarbons such as di- chloromethane, dichloroethane, trichlorome,
  • the inert solvent is chlorobenzene, cyclohexane, heptane or petrolether.
  • R 3 , R 4 are independently selected from Ci-C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 - halogenalkyl, C 2 -C 6 -halogenalkenyl and C 2 -C 6 -halogenalkynyl;
  • R 78 is independently selected from halogen, Ci-C 6 -alkyl, Ci-C 6 -alkoxy, C 1 -C 6 - halogenalkyl and Ci-C 6 -halogenalkoxy;
  • o 0, 1 , 2 or 3;
  • Y is selected from Ci-C 6 -alkyl, Ci-C 6 -halogenalkyl, phenyl and benzyl, wherein phenyl and benzyl are unsubstituted or substituted by CN, NO 2 , halogen, Ci-C 6 -alkyl, C 1 - C 6 -halogenalkyl or Ci-C 6 -alkoxy.
  • the present invention relates further to the process comprises the following step:
  • the brominating agent in the process according to the invention is selected from the group consisting of is selected from the group consisting of Br 2 , N-bromosuccinimide (NBS), 1 ,3-dibromo-5,5-dimethylhydantoin (DBDMH) or a system con- sisting of HBr/hhC ⁇ .
  • the brominating agent is N-bromosuccinimide (NBS).
  • the brominating agent is1 ,3-dibromo-5,5-dimethylhydantoin (DBDMH).
  • the brominating agent is used in an amount of 1.5 eq to 5 eq, in particular 2.0 to 3.0 eq, in relation to one equivalent of compound VII.
  • Typical reaction times are in the range of from 10 minutes to 12 hours, preferably from 30 minutes to 8 hours, also preferred from 1 to 4 hours.
  • radical generating condions typically the bromination is carried out under radical generating condions.
  • Preferred radical generating conditions are the use of UV-light or the use of radical initiators like azo compounds or peroxides.
  • Preferred conditions are the use of radical initiators.
  • the nature of the radical initor depends on the reaction temperatures applied, most preferred are benzoyl peroxide or AIBN (azo isobutyro dinitrile).
  • AIBN azo isobutyro dinitrile
  • the amounts of radical initiators used range from 0,001 equiv. to 0,5 equiv., preferably 0,005 eqiv. to 0,3 equiv., also preferred 0,01 to 0,2 equiv. related to corn- pound V used.
  • the reaction is carried out in an inert solvent as defined above.
  • Preferred inert solvents for this bromination step are chlorobenzene, cyclohexane, heptane, trichloromethane, tetrachlo- romethane, ethyl acetate, butyl acetate or acetonitrile.
  • the solvent used is chloroben- zene, cyclohexane, ethyl acetate or buryl acetate.
  • the pyridine derivatives of the formula I can be prepared in high yields.
  • the yields are at least 60%, more preferably 70 %, even more preferred at least 75%, even more preferred at least 80%.
  • R 3 , R 4 are independently selected from Ci-C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 - halogenalkyl, C 2 -C 6 -halogenalkenyl and C 2 -C 6 -halogenalkynyl;
  • R 78 is independently selected from halogen, Ci-C 6 -alkyl, Ci-C 6 -alkoxy, C 1 -C 6 - halogenalkyl and Ci-C 6 -halogenalkoxy;
  • o 0, 1 , 2 or 3;
  • Y is selected from Ci-C 6 -alkyl, Ci-C 6 -halogenalkyl, phenyl and benzyl, wherein phenyl and benzyl are unsubstituted or substituted by CN, NO 2 , halogen, Ci-C 6 -alkyl, C 1 - C 6 -halogenalkyl or Ci-C 6 -alkoxy.
  • the fluorinating agent is selected from the group consisting of NaF, CsF, KF, KHF 2 , Olah reagent, HF, a polyhydrofluoride complex of a trialkylamine or mixtures of HF in trialkylamines (Ci-Ce-alkyl ⁇ N.
  • Mixtures of HF in trialkylamines (Ci-C 6 -alkyl) 3 N are mixture with a content of 5-95 % HF in trial- kylamines (Ci-C 6 -alkyl) 3 N, preferred 10-60 % HF, further preferred 20-40 %.
  • the fluorinating agent is HF in triethylamine solution, preferred (C 2 H 5 ) 3 N x 3 HF, op- tionally diluted with (C 2 H 5 ) 3 N or with mixtures of (C 2 H 5 ) 3 N and polar solvents like acetonnitril, dimethylformamide or N-methyl-pyrrolidone.
  • the fluorinating agent is used in an amount of 1.2 eq to 10 eq, in particular 2.2 to 7.8 eq, more specifically 4.4 to 5.6 eq, in relation to one equivalent of compound VIII.
  • the fluorinating reaction is carried out in the presence of a solvent, preferably a polar solvent.
  • Suitable organic solvents for the reac- tion are protic polar solvents, for example water, aliphatic alcohols having preferably from 1 to 4 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or tert- butanol, or carboxylic acids such as acetic acid, aromatic hydrocarbons such as benzene, tolu- ene, xylenes, cumene, chlorobenzene, nitrobenzene or tert-butylbenzene, aprotic polar sol- vents, for example cyclic or acyclic ethers such as diethyl ether, diisopropyl ether, tert-butyl me- thyl ether (MTBE), tert-butyl ethyl ether, tetrahydrofuran (THF) or dioxane, cyclic or
  • the polar solvent is acetonitril or triethylamine.
  • Further preferred solvent systems are (CaHs ⁇ N x 3 HF alone or (CaHs ⁇ N x 3 HF with addition of triethylamine, acetonitrile or dimethylformamide.
  • the reaction ususally takes place at temperatures between 10°C and 150°C, preferred between 20 °C and 100°C, especially preferred between 50°C and 90°C.
  • Typical reaction times are in the range of from 0,5 to 18 hours, preferred 1 to 5 hours, preferably from 1 to 3 hours.
  • R 1 is in each case independently selected from hydrogen, halogen, Ci-C 6 -alkyl and C 1 -C 6 - halogenalkyl;
  • R 2 is in each case independently selected from hydrogen, halogen, Ci-C 6 -alkyl and C 1 -C 6 - halogenalkyl;
  • R 10 is in each case independently selected from H, halogen, 0(R 95 ), Ci-C 6 -alkyl and C 1 -C 6 - halogenalkyl; wherein
  • R 95 is Ci-C 6 -alkyl, Ci-C 6 -halogenalkyl
  • R 1 , R 2 and R 10 are as defined above;
  • R 1 , R 2 and R 10 are as defined above;
  • R 1 , R 2 and R 10 are as defined above.
  • the brominating agent in the process according to the invention is selected from the group consisting of such as N-bromosuccinimide (NBS), 1 ,3-dibromo-5,5-dimethylhydantoin (DBDMH) or a system consisting of HBr/hhC ⁇ .
  • NBS N-bromosuccinimide
  • DBDMH 1 ,3-dibromo-5,5-dimethylhydantoin
  • HBr/hhC ⁇ HBr/hhC ⁇
  • the preferred brominating agents are NBS und DBDMH.
  • the most preferred brominating agent is 1 ,3-dibromo-5,5-dimethylhydantoin
  • Typical reaction times are in the range of from 1 to 20 hours, preferably from 2 to 15 hours and more preferably from 3 to 10 hours, most preferably 3 to 5 hours.
  • Typical the product will be extracted using an inert organic solvent.
  • inert organic solvent is meant an organic solvent which, under the reaction conditions of the process of this invention, does not enter into any appreciable reaction with either the reac- tants or the products.
  • the inert organic solvent is selected from non-halogenated inert organic solvents; preferably from non-halogenated aliphatic hydrocarbons, non-halogenated cycloali- phatic hydrocarbons, non-halogenated aromatic hydrocarbons, halogenated aliphatic hydrocar- bons, halogenated aromatic hydrocarbons, , ethers, esters, ketones, and any combination thereof.
  • suitable non-halogenated aliphatic hydrocarbons include pentane, hexane, hep- tane, and the like. Preference is given to saturated aliphatic hydrocarbons having from 5 to 10 carbon atoms.
  • non-halogenated cycloaliphatic hydrocarbons examples include cyclopentane, cy- clohexane, cycloheptane, and the like. Preference is given to non-halogenated saturated cyclo- aliphatic hydrocarbons having from 5 to 10 carbon atoms. Cyclohexane is particularly preferred.
  • Suitable a non-halogenated aromatic hydrocarbons include toluene, o-xylene, m- xylene, p-xylene, ethylbenzene, 2-propylbenzene (cumene), 2-isopropyltoluene (o-cymol), 3-isopropyltoluene (m-cymol), 4-isopropyltoluene (p-cymol), 1 ,3,5-trimethylbenzene (mesity- lene), and the like.
  • toluene Preference is given to toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 1 ,3,5-trimethylbenzene (mesitylene), and any combination thereof.
  • Especially preferred among the non-halogenated aromatic hydrocarbons are toluene, o-xylene, m-xylene, p-xylene, and any combination thereof, with toluene being the most preferred.
  • halogenated aliphatic hydrocarbons examples include dichloromethane, chloroform, carbon tetrachloride, 1 ,2-dichloroethane, 1 ,1 ,1 ,2-tetrachloroethane, 1 ,1 ,2,2-tetrachloroethane,
  • halogenated aromatic hydrocarbons examples include chlorobenzene, bromoben- zene, o-dichlorobenzene, m-dichlorobenzene, a,a,a-trifluorotoluene (benzotrifluoride) and the like and any combination thereof.
  • Suitable ethers include cyclic and acyclic ethers such as diethyl ether, diisopropyl ether, n-butyl methyl ether, isobutyl methyl ether, sec-butyl methyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, methyl-tetrahydrofuran, tetrahydrofuran, 1 ,4-dioxane, and the like and any combination thereof.
  • cyclic and acyclic ethers such as diethyl ether, diisopropyl ether, n-butyl methyl ether, isobutyl methyl ether, sec-butyl methyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, methyl-tetrahydrofuran, tetrahydrofuran, 1 ,4-dioxane, and the like and any combination thereof.
  • esters examples include ethyl acetate, n-propylacetate, isopropyl acetate, n-butyl acetate, tert-butyl acetate, and the like and any combination thereof.
  • ketones examples include acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, cyclopropyl methyl ketone and the like, and any combination thereof.
  • the preferred brominating agent is 1 ,3-dibromo-5,5-dimethylhydantoin (DBDMH).
  • DBDMH 1,3-dibromo-5,5-dimethylhydantoin
  • the reaction temperature is preferably in the range from 0 to 150°C and espe- cially 80 to 125°C temperature and the reaction times are in the range of from 2 to 10 hours, more preferred 2 to 5 hours.
  • the purification is a distillation under reduced pressure (50-55°C; 1.6-2.0 mbar).
  • the chlorination step is carried out in an inert sol- vent.
  • inert organic solvent is meant an organic solvent which, under the reaction conditions of the process of this invention, does not enter into any appreciable reaction with either the reac- tants or the products.
  • the inert organic solvent is selected from non-halogenated inert organic solvents; preferably from non-halogenated aliphatic hydrocarbons, non-halogenated cycloali- phatic hydrocarbons, non-halogenated aromatic hydrocarbons, halogenated aliphatic hydrocar- bons, halogenated aromatic hydrocarbons, amides, ethers, esters, nitriles and any combination thereof.
  • non-halogenated aliphatic hydrocarbons examples include pentane, hexane, hep- tane, and the like. Preference is given to saturated aliphatic hydrocarbons having from 5 to 10 carbon atoms.
  • non-halogenated cycloaliphatic hydrocarbons examples include cyclopentane, cy- clohexane, cycloheptane, and the like. Preference is given to non-halogenated saturated cyclo- aliphatic hydrocarbons having from 5 to 10 carbon atoms. Cyclohexane is particularly preferred.
  • non-halogenated aromatic hydrocarbons examples include toluene, o-xylene, m- xylene, p-xylene, ethylbenzene, 2-propylbenzene (cumene), 2-isopropyltoluene (o-cymol), 3-isopropyltoluene (m-cymol), 4-isopropyltoluene (p-cymol), 1 ,3,5-trimethylbenzene (mesity- lene), and the like.
  • toluene Preference is given to toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 1 ,3,5-trimethylbenzene (mesitylene), and any combination thereof.
  • Especially preferred among the non-halogenated aromatic hydrocarbons are toluene, o-xylene, m-xylene, p-xylene, and any combination thereof, with toluene being the most preferred.
  • halogenated aliphatic hydrocarbons examples include dichloromethane, chloroform, carbon tetrachloride, 1 ,2-dichloroethane, 1 ,1 ,1 ,2-tetrachloroethane, 1 ,1 ,2,2-tetrachloroethane,
  • halogenated aromatic hydrocarbons examples include chlorobenzene, bromoben- zene, o-dichlorobenzene, m-dichlorobenzene, a,a,a-trifluorotoluene (benzotrifluoride) and the like and any combination thereof.
  • Suitable amides include N,N-dimethylformamide, N,N-diethylformamide, N,N- dimethylacetamide, N,N-diethylacetamide, N-methyl-pyrrolidone, DMI (dimethylimidazolidinone) or tetramethylurea, and the like and any combination thereof.
  • Suitable ethers include cyclic and acyclic ethers such as diethyl ether, diisopropyl ether, n-butyl methyl ether, isobutyl methyl ether, sec-butyl methyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, methyl-tetrahydrofuran, 1 ,4-dioxane, and the like and any combination thereof.
  • suitable esters include ethyl acetate, n-propylacetate, isopropyl acetate, tert-butyl acetate, and the like and any combination thereof.
  • Suitable nitriles include acetonitrile, propionitrile, benzonitrile, and the like and any combination thereof.
  • the inert solvent selected from the group consisting of aliphatic and aromatic hydro- carbons and halohydrocarbons such as cyclohexane, heptane, benzene, toluene, xylenes, cu- mene, mesitylene, chlorobenzene, dichlorobenzenes and tert-butylbenzene, cyclic or acyclic ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether (MTBE), tert-butyl ethyl ether, methyl cyclopentylether, tetrahydrofuran (THF), methyl tetrahydrofuran (methyl THF) or dioxane, nitriles such as acetonitrile and propionitrile, aliphatic halohydrocarbons such as di- chloromethane, dichloroethane, trichlorome,
  • the inert solvent is chlorobenzene.
  • the chlorinating agent is selected from the group consisting of N-chlorosuccinimide (NCS), sulfuryl chloride, Ch, trichloroisocyanuric acid, 1 ,3-dichloro-5,5-dimethylhydantoin.
  • NCS N-chlorosuccinimide
  • Ch sulfuryl chloride
  • Ch trichloroisocyanuric acid
  • the chlorinating agent is trichloroisocyanuric acid.
  • the chlorinating agent is used in an amount of 0.5 eq to 2 eq, in particular 0.6 to 1.2 eq, more specifically 0.7 to 0.8 eq, in relation to one equivalent of compound II.
  • the chlorination step is carried out in the presence of an organic carboxylic or sulfonic acid and in the absence of an alkali metal salt of said carboxylic acid which leads to decrease of waste.
  • the organic acid is selected from the group consisting of: formic acid, acetic acid, propionic acid, or butyric acid, aliphatic sulfonic acids selected from the group consisting of: methanesulfonic acid, ethanesulfonic acid and trifluoromethanesulfonic acid. More preferably is selected from the group consisting of acetic acid and trifluoroacetic acid. Most preferably is ace- tic acid.
  • Typical reaction times are in the range of from 1 to 20 hours, preferably from 2 to 15 hours and more preferably from 3 to 10 hours, most preferably 3 to 5 hours.
  • the mono-CI-substituted pyridine can be prepared analog.
  • the di-CI substituted pyridine is converted into a di-F substituted pyridine in the presence of a the fluorinating agent.
  • the fluorinating agent is selected from the group consisting of KF, KHF 2 , NaF, CaF 2 , Olah reagent, a polyhydrofluoride complex of a trialkylamine.
  • the fluorinating agent is (C 2 H 5 ) 3 N x 3 HF.
  • the fluorinating agent is used in an amount of 2.0 eq to 10 eq, in particular 2.5 to 8.0 eq, more specifically 3.0 to 6.0 eq, in relation to one equivalent of compound III.
  • the fluorinating reaction is carried out in the presence of an amine.
  • Suitable amines are tertiary amines for example, tri(Ci-C 6 -alkyl)amine such as trimethylamine, triethylamine or diisopropylethylamine, N-methylpiperidine, pyridine, substituted pyridines such as 2,4,6-trimethylpyridine (collidine), 2,6-dimethylpyridine (lutidine), 2-methylpyridine, (a- picoline), 3-methylpyridine (b-picoline), 4-methylpyridine (g-picoline) and 4-dimethylamino- pyridine, and also bicyclic amines such as 1 ,4-diazabicyclo[2.2.2]octane, 1 ,8-diaza- bicyclo[5.4.0]undec-7-ene or 1 ,5-diazabicyclo[4.3.0]non-5-ene.
  • tri(Ci-C 6 -alkyl)amine such as trimethylamine, triethylamine or
  • triethylamine pyridine or 1 ,8-diazabicyclo[5.4.0]undec-7-ene.
  • triethyla- mine is particularly preferred.
  • the amine is used in an amount of 1.0 eq to 10 eq, in particular 1.5 to 8.0 eq, more specifically 2.0 to 6.0 eq, in relation to one equivalent of compound III
  • the fluorinating reaction is carried out in the presence of a phase transfer catalysts.
  • Phase transfer catalysts suitable for use in the process of this invention are those well known in the art.
  • Preferred phase transfer catalysts are selected from quarternary ammonium salts, quar- ternary pyridinium salts, quarternary phosphonium salts and any combination thereof and more preferably selected from quarternary ammonium salts, quarternary phosphonium salts and any combination thereof.
  • phase transfer catalyst is selected from quaternary ammonium salts of the general formula
  • R , R and R are the same or different and are each independently selected from the group consisting of Ci-C 2 o-alkyl, C 3 -Cio-cycloalkyl, C 6 -C 2 o-aryland C 6 -C 2 o-a ry l-C 1 -C 4 -a I ky I , and Zr is a monovalent anion,
  • R R R R P Z 2 - (VII) wherein R , R , R and R are the same or different and are each independently selected from a 5- or 6-membered heterocyclyl group containing 1 , 2 or 3 heteroatoms selected from the group consisting of O, N and S, and Z 2 is a monovalent anion, and any combination thereof.
  • a 5- or 6-membered heterocyclyl group containing 1 , 2 or 3 heteroatoms selected from the group consisting of O, N and S includes but is not limited to 1 -piperidyl, morpholinyl and 4-methyl-1 -piperidyl.
  • the monovalent anion Zr is selected from a halide, hydroxide, hy- drogen sulfate and monomethyl sulfate, more preferably from chloride, bromide, iodide and hy- droxide, even more preferably from chloride or bromide and is most preferably chloride.
  • the monovalent anion Z-r is selected from a halide, more preferably from chloride or bromide is most preferably chloride.
  • the monovalent anion 2. 2 is selected from a halide, hy- droxide, hydrogen sulfate and monomethyl sulfate, more preferably from chloride, bromide, io- dideand hydroxide, even more preferably from chloride or bromide and is most preferably chlo- ride.
  • the monovalent anion Z 2 is selected from a halide, more preferably from chloride or bromide and is most preferably chloride.
  • the phase transfer catalyst is selected from quaternary ammonium salts of the general formula (V) wherein R 4 , R 5 , R 6 and R 7 are the same or different and are each independently selected from the group consisting of Ci-C 2 o-alkyl, C 6 -C 2 o-aryl and C 6 -C 20 - aryl-C-i-C 4 -alkyk
  • the phase transfer catalyst is selected from quaternary ammonium salts of the general formula (V) wherein R 4 , R 5 , R 6 and R 7 are the same or different and are each inde- pendently selected from Ci-C 2 o-alkyl, even more preferably Ci-Ci 2 -alkyl and still more preferably C-i-Cs-alkyl and yet more preferably Ci-C 4 -alkyl.
  • phase transfer catalysts useful for the process of this invention are tetra-n- Ci-Ci 2 -alkyl-ammonium chlorides, bromides, iodides, hydroxides, hydrogen sulfate or monome- thyl sulfate (in particular chlorides), preferably tetra-n-C-i-Cs-alkyl-ammonium chlorides, bro- mides, iodides, hydroxides, hydrogen sulfate or monomethyl sulfate (in particular chlorides), e.g.
  • tetramethylammonium chloride bromide, iodide, hydroxide, hydrogen sulfate or monomethyl sulfate (in particular chloride), tetraethylammonium chloride, bromide, iodide, hydroxide, hydro- gen sulfate or monomethyl sulfate, tetra-n-propylammonium chloride, bromide, iodide, hydrox- ide, hydrogen sulfate or monomethyl sulfate, tetra-n-butylammonium chloride, bromide, iodide, hydroxide, hydrogen sulfate or monomethyl sulfate (in particular chloride), tetra-n- pentylammonium chloride, bromide, iodide, hydroxide, hydrogen sulfate or monomethyl sulfate (in particular chloride), tetra-n-hexylammonium chloride
  • tetra-n-Ci-C 4 -alkyl-ammonium chlorides bromides, iodides, hydroxides, hydrogen sul- fates or monomethyl sulfates (in particular chlorides) is preferred, in particular tetra-n- butylammonium chloride, bromide, iodide, hydroxide, hydrogen sulfate or monomethyl sulfate (more specifically chloride) and methyl-tri-n-butylammonium chloride, bromide, iodide, hydrox- ide, hydrogen sulfate or monomethyl sulfate (more specifically chloride).
  • the phase transfer catalyst is selected from tetra-n-butylammonium chlo- ride, tri-n-octylmethylammonium chloride, n-dodecyltrimethylammonium chloride, benzyl(tri-n- butyl)ammonium chloride, tetrakis(1-piperidyl)phosphonium chloride and any combination thereof.
  • the phase-transfer catalyst which is usually solid in pure form, can be used as such or, prefer- ably, in dissolved form.
  • a solution of the phase transfer catalyst in any of the aforementioned substantially anhydrous (preferably anhydrous) inert organic solvents such as e.g. aromatic or aliphatic hydrocarbons.
  • the fluorinating reaction is carried out in the presence of a polar solvent. It was found that the use of catalytic amounts of a polar sol- vent accelerates the fluorination reaction.
  • Suitable organic solvents for the reaction are , aprotic polar solvents, for example cyclic or acy-root ethers such as diethyl ether, diisopropyl ether, n-butyl methyl ether, isobutyl methyl ether, sec-butyl methyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, methyl-tetrahydrofuran, tetrahydrofuran, 1 ,4-dioxane, cyclic or acyclic amides such as dimethylformamide, diethylfor- mamide, dimethylacetamide, diethylacetamide, N-methylpyrrolidone, DMI (dimethylimidazoli- dinone) or tetramethylurea, or aliphatic nitriles such as acetonitrile or propionitrile, and mixtures of the aforementioned solvents.
  • the polar solvent is DMF.
  • Typical reaction times are in the range of from 1 to 24 hours, preferably from 2 to 16 hours and more preferably from 3 to 15 hours, most preferably 4 to 12 hours.
  • reaction of the halogen exchange is carried our between 70°C and 180°C, preferably be- tween 80°C and 160°C
  • the mono-F-substituted pyridine can be prepared ana- log.
  • C n -C m indicates the number of carbon atoms possible in each case in the substituent or substituent moiety in question.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • Ci-C 6 -alkyl refers to a straight-chained or branched saturated hydrocarbon group having 1 to 6 carbon atoms, e.g. methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2- methylpropyl, 1 ,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,
  • C 2 -C 4 -alkyl refers to a straight-chained or branched alkyl group having 2 to 4 carbon atoms, such as ethyl, propyl (n-propyl), 1-methylethyl (iso-propoyl), butyl, 1-methylpropyl (sec. -butyl), 2-methylpropyl (iso-butyl), 1 ,1-dimethylethyl (tert. -butyl).
  • Ci-C 6 -halogenalkyl refers to an alkyl group having 1 or 6 carbon atoms as defined above, wherein some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as mentioned above.
  • Ci-C 2 -haloalkyl such as chloromethyl, bro- momethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloro- fluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1- fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-
  • C 2 -C 6 -alkenyl refers to a straight-chain or branched unsaturated hydrocarbon radical having 2 to 6 carbon atoms and a double bond in any position.
  • Examples are “C 2 -C 4 -alkenyl” groups, such as ethenyl, 1-propenyl, 2-propenyl (allyl), 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1 -methyl-1 -propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl.
  • C 2 -C 6 -halogenalkenyl refers to an alkyl group having 2 or 6 carbon atoms as defined above, wherein some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as mentioned above.
  • C 2 -C 6 -alkynyl refers to a straight-chain or branched unsaturated hydrocarbon radical having 2 to 6 carbon atoms and containing at least one triple bond.
  • Examples are "C 2 -C 4 - alkynyl” groups, such as ethynyl, prop-1 -ynyl, prop-2-ynyl (propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl , 1 -methyl-prop-2 -ynyl .
  • C 2 -C 6 -halogenalkynyl refers to an alkyl group having 2 or 6 carbon atoms as defined above, wherein some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as mentioned above.
  • Ci-C 6 -alkoxy refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms which is bonded via an oxygen, at any position in the alkyl group.
  • Examples are "C 1 -C 4 - alkoxy” groups, such as methoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy, 1- methyhpropoxy, 2-methylpropoxy or 1 ,1-dimethylethoxy.
  • Ci-C 6 -halogenalkoxy refers to a Ci-C 6 -alkoxy radical as defined above, wherein some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as men- tioned above.
  • Examples are "Ci-C 4 -haloalkoxy” groups, such as OCH 2 F, OCHF 2 , OCF 3 ,
  • 2,3-difluoro ⁇ propoxy, 2 chloropropoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 2-bro- mo-'propoxy, 3 bromopropoxy, 3,3,3-trifluoropropoxy, 3,3,3-trichloropropoxy, OCH 2 -C 2 F 5 , OCF 2 -C 2 F 5 , 1-fluoromethyl-2-fluoroethoxy, 1-chloromethyl-2-chloroethoxy, 1-bromomethyl-2- bromo ⁇ ethoxy, 4-fluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy or nonafluorobutoxy.
  • phenyl-Ci-C 6 -alkyl refers to alkyl having 1 to 6 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl radical is replaced by a phenyl radical.
  • phenyl-C 2 -C 6 -alkenyl and“phenyl-C 2 -C 6 -alkynyl” refer to alkenyl and alkynyl, respective- ly, wherein one hydrogen atom of the aforementioned radicals is replaced by a phenyl radical.
  • R 4 , R 5 , R 6 , R 7 , R 78 , R 95 , R 10 and o apply to compounds and the the compounds of the formula I, II, 111 A, MB, IIC, HID, IV, V, VI, VII and VIII and side products in any of the above detailed inventive processes.
  • R 1 is in each case independently selected from hydrogen and Ci-C 6 -alkyl
  • R 2 is in each case independently selected from hydrogen
  • R 3 , R 4 are independently selected from Ci-C 6 -alkyl and Ci-C 6 -halogenalkyl;
  • R 5 is halogen
  • R 6 is halogen
  • o 0, 1 , 2 or 3;
  • R 78 are independently selected from halogen and Ci-C 6 -alkyl
  • R 9 is in each case independently selected from CH 3 and CHF 2 ;
  • R 10 is independently selected from from Ci-C 6 -alkyl, Ci-C 6 -alkoxy, and C 1 -C 6 - halogenalkyl.
  • R 1 is hydrogen
  • R 2 is hydrogen
  • R 3 , R 4 are independently selected from Ci-C 6 -alkyl and Ci-C 6 -halogenalkyl;
  • R 5 is halogen
  • R 6 is halogen
  • o 0, 1 , 2 or 3;
  • R 78 are independently selected from halogen and Ci-C 6 -alkyl
  • R 9 is in each case independently selected from CH 3 and CHF 2 ;
  • R 10 is independently selected from from Ci-C 6 -alkyl and Ci-C 6 -halogenalkyl.
  • R 1 is hydrogen
  • R 2 is hydrogen
  • R 3 , R 4 are independently Ci-C 6 -alkyl
  • R 5 is halogen
  • R 6 is halogen
  • o 0, 1 , 2 or 3;
  • R 78 are independently selected from halogen and Ci-C 6 -alkyl; R 9 is in each case independently selected from CH 3 and CHF 2 ;
  • R 10 are independently selected from Ci-C 6 -alkyl and Ci-C 6 -halogenalkyl.
  • R 1 is hydrogen
  • R 2 is hydrogen
  • R 3 , R 4 are independently Ci-C 6 -alkyl
  • R 5 is F
  • R 6 is F
  • o 0, 1 , 2 or 3;
  • R 78 are independently selected from halogen and Ci-C 6 -alkyl
  • R 9 is in each case independently selected from CH 3 and CHF 2 ;
  • R 10 is independently selected from Ci-C 6 -alkyl and Ci-C 6 -halogenalkyl.
  • R 1 is hydrogen
  • R 2 is hydrogen
  • R 3 , R 4 are independently Ci-C 6 -alkyl
  • R 5 is F
  • R 6 is F
  • o 0, 1 , 2 or 3;
  • R 78 are independently selected from halogen and Ci-C 6 -alkyl
  • R 9 is in each case independently selected from CH 3 and CHF 2 ;
  • R 10 is independently selected from CH 3 and CHF 2 .
  • Particularly preferred active compounds I are selected from the group consisting of compounds I .A to IZA:
  • I.D 4, 4-difluoro-1-[5-(fluoromethyl)-6-methyl-3-pyridyl]-3, 3-dimethyl-isoquinoline
  • I.E 4, 4-difluoro-1-(5-methoxy-6-methyl-3-pyridyl)-3, 3-dimethyl-isoquinoline
  • I.ZA 1-[6-(difluoromethyl)-5-methoxy-3-pyridyl]-4, 4, 6-trifluoro-3, 3-dimethyl-isoquinoline.
  • HPLC-MS HPLC-column Kinetex XB C18 1 ,7m (50 x 2,1 mm); eluent: acetonitrile / water + 0.1 % TFA (5 gradient from 5:95 to 100 : 0 in 1.5 min at 60°C, flow gradient from 0.8 to 1.0 ml/min in 1.5 min).
  • MS Quadrupol Electrospray Ionisation, 80 V (positive mode).
  • HPLC-MS HPLC-column Kinetex XB C18 1 ,7m (50 x 2,1 mm); eluent: acetonitrile / water + 0.1 % TFA (5 gradient from 5:95 to 100 : 0 in 1.5 min at 60°C, flow gradient from 0.8 to 1.0 ml/min in 1.5 min).
  • MS Quadrupol Electrospray Ionisation, 80 V (positive mode).
  • HPLC-MS HPLC-column Kinetex XB C18 1 ,7m (50 x 2,1 mm); eluent: acetonitrile / water +
  • Triethylamine x 3 hydrogen fluoride (NEt 3 x 3 HF) were added to 40 g (purity 80 %, 82 mmol) ethyl 4,4-dibromo-3,3-dimethyl-isoquinoline-1-carboxylate in 100 ml acetonitrile.
  • the mixture was heated to reflux for 2 hours, when HPLC showed completion of the reaction. Subsequently the reaction mixture was cooled to room temperature and cautiously poured onto ice cold 20 % NaOH-solution. The aqueous layer was extracted twice with ethylacetate and the combined organic layers were extracted with brine.
  • HPLC-MS HPLC-column Kinetex XB C18 1 ,7m (50 x 2,1 mm); eluent: acetonitrile / water + 0.1 % TFA (5 gradient from 5:95 to 100 : 0 in 1.5 min at 60°C, flow gradient from 0.8 to 1.0 ml/min in 1.5 min).
  • MS Quadrupol Electrospray Ionisation, 80 V (positive mode).
  • HPLC-MS HPLC-column Kinetex XB C18 1 ,7m (50 x 2,1 mm); eluent: acetonitrile / water + 0.1 % TFA (5 gradient from 5:95 to 100 : 0 in 1.5 min at 60°C, flow gradient from 0.8 to 1.0 ml/min in 1.5 min).
  • MS Quadrupol Electrospray Ionisation, 80 V (positive mode).
  • Triethylamine x 3 hydrogen fluoride (NEt 3 x 3 HF) were added to 40 g (purity 80 %, 82 mmol) ethyl 4, 4-dibromo-3,3-dimethyl-isoquinoline-1 -carboxylate in 100 ml acetonitrile.
  • the mixture was heated to reflux for 2 hours, when HPLC showed completion of the reaction. Subsequently the reaction mixture was cooled to room temperature and cautiously poured onto ice cold 20 % NaOH-solution. The aqueous layer was extracted twice with ethylacetate and the combined organic layers were extracted with brine.
  • HPLC-MS HPLC-column Kinetex XB C18 1 ,7m (50 x 2,1 mm); eluent: acetonitrile / water +
  • the reaction mixture was heated at 150°C and stirred for 8h. After the reaction was complete (HPLC) the mixture was cooled to 10°C and subsequently added to a mixture of 300 ml water and 500 ml n-heptane. Afterwards the mixture was basified with 50 ml of 25% ammonia-solution at 25°C (pH 1 1-12) and filtered over Celite. The Celite was washed with n-heptane and the aqueous ammonia layer was separated from the n-hexane layer.
  • This product was dissolved in 400 ml of n-heptane.
  • the heptane-phase was extracted twice with 250 ml of 15 % HCI and the heptane phase was discarded afterwards.
  • the title compound could be further purified via column chromatography with cyclohexane/ethyl acetate mixtures.

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Abstract

The present invention relates to a process for the preparation of optionally substituted 5-substituted pyridine of the formula I.

Description

Preparation of optionally substituted 5-substituted pyridine
The present invention relates to a process for the preparation of optionally substituted 5- substituted pyridine of the formula I
Figure imgf000002_0001
It was an object of the present invention to find a process for the preparation optionally substi- tuted 5-substituted pyridine of the formula I which would be effective and at the same time suit- able for the production on a large scale.
It was now found that pyridine derivatives of the formula I
Figure imgf000002_0002
wherein
R1 is in each case independently selected from hydrogen, halogen, Ci-C6-alkyl and Ci-
C6-halogenalkyl;
R2 is in each case independently selected from hydrogen, halogen, Ci-C6-alkyl and Ci-
C6-halogenalkyl;
R3, R4 are independently selected from Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6- halogenalkyl, C2-C6-halogenalkenyl and C2-C6-halogenalkynyl;
R5 is halogen;
R6 is halogen; o is 0, 1 , 2 or 3; and
R78 are independently selected from halogen, Ci-C6-alkyl, Ci-C6-alkoxy, C1-C6- halogenalkyl and Ci-C6-halogenalkoxy;
R9 CHs, CHF2 and CH2F;
R10 is independently selected from H, halogen, 0(R95), Ci-C6-alkyl and C1-C6- halogenalkyl; wherein R95 is Ci-C6-alkyl, Ci-C6-halogenalkyl;
can be obtained by a reaction of the compound of the formula II
Figure imgf000003_0001
R3, R4, R5, R6 R78 and o are as defined above and
X is a metal ion;
with the compound of the formula III
Figure imgf000003_0002
in which R1, R2, R9 and R10 are as defined above in the presence of a catalyst.
The process of this invention is effective and suitable for a production on a large scale. Since it is a convergent synthesis route it is of a short reaction sequence resulting in low production cost and minimum waste. Moreover it is compatible with the substituents present in the target mole- cules.
According to one embodiment of the invention the catalyst comprises a Cu source, a Pd source and an optional ligand.
When carrying out the reaction, the catalyst system (Pd+ligand) can be added together or sepa- rately either at room temperature or at an elevated temperature. The system can be prepared separately, immediately before the reaction is carried out, by combining a Pd salt and the lig and, or it can be synthesized before or purchased in pure form or in solution. Also possible is the direct addition of the ligand and of the palladium source to the batch (in situ process). Alter- natively the reaction can be carried out with a palladium source alone without addition of an additional ligand. The palladium catalysts used are optionally produced in situ from at least one palladium(ll) salt or a palladium(O) compound and the corresponding phosphine ligands. How- ever, they may also be used directly as palladium(O) compound without reducing the initial cata- lytic activity.
According to one embodiment of the invention the Pd source is selected from the group consist- ing of Pd(OAc)2, Pd(ll)Cl2, Palladium(ll)-1 ,2-bis(diphenylphosphino)ethan dichloride, Palladi- um(ll)- 1 ,3-Bis(diphenylphosphino)propan dichloride, Palladium(ll)- 1 ,4- Bis(diphenylphosphino)butan dichloride, Palladium(ll)-1 ,T-Bis(diphenylphosphino)ferrocene dichloride, Palladium(0)-tetrakis(triphenylphosphin, Palladium(ll)- bis(triphenylphosphin)dichloride, Pd(P(t-Bu)3)2, Pd(acac)2, Pd(iPr)2Ph2, Pd(P(t-Bu)2Ph)2Cl2, Pd(dba)2, Pdl2, PdBr2, or Pd(TFA)2.
According to one embodiment of the invention the ligand is mono- or bidentate phosphorus-con- taining ligand.
As monodentate phosphorus-containing ligand following are preferred:
monodentate phosphorus-containing ligand oft he formula P
Figure imgf000004_0001
wherein
P', P", P'" are independently selected from Ci-C6-alkyl, C3-C6-cycloalkyl, aryl and heteroaryl, which are unsubstituted or substituted.
More preferred are monodentate phosphorus-containing ligand selected from the group consis- ting of: triethylphosphin, tri-n-butylphosphin, tri-t-butylphosphin, tribenzylphosphin,
tri(cyclopentyl)phosphin, tri(cyclohexyl)phosphin, triphenylphosphin, tri(p-tolyl)phosphin, tri(m- tolyl)phosphin, tri (o-tolyl)phosphin, tri(p-methoxyphenyl)phosphin, tri(p-dimethylaminophenyl)- phosphin, tri-(natrium-meta-sulfonatophenyl)-phosphan, diphenyl(2-sulfonatophenyl)phosphin, tri(1-naphthyl)phosphin, di-t-butyl-phenyl-phosphin, XPhos, SPhos, RuPhos und diphenyl-2 - pyridylphosphin. Most preferred are triphenylphosphin, tri(p-tolyl)phosphin und
tri(cyclohexyl)phosphin.
As bidentate phosphorus-containing ligand following are preferred: 2,2'-Bis(diphenylphosphino)- 1 ,1 '-binaphthyl (BINAP), 1 ,1-bis(diphenylphosphino)methane (DPPM), 1 ,2- bis(diphenylphosphino)ethan (DPPE), 1 ,3-bis(diphenylphosphino)propan (DPPP), 1 ,4- bis(diphenylphosphino)butan (DPPB), 1 ,1 '-bis(diphenylphosphino)ferrocen (DPPF), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthen (Xantphos), 1 ,2-bis(di-tert- butylphosphinomethyl)benzol, 1 ,2-bis(di-tert-pentylphosphinomethyl)benzol), 1 ,3- bis(diphenylphosphino)-2,2-dimethylpropane, 1 ,3-bis(diphenylphosphino)-2-methyl-2-butyl- propane und 1 ,2-bis(di-tert-butylphosphinomethyl)naphthalin. Most preferred are1 ,2- bis(diphenylphosphino)ethan (DPPE), 1 ,3-bis(diphenylphosphino)propan (DPPP), 1 ,4- bis(diphenylphosphino)butan (DPPB and 1 ,1 '-bis(diphenylphosphino)ferrocen (DPPF).
The molar ratio of palladium to the phosphine ligand should be between 4: 1 and 1:100 and is preferably between I: I and l:5, particularly preferably between I: I and l:2.
According to one embodiment of the invention the Cu salts is selected from the group Cul,
CuBr, CuCI, CuF, CU2O, Cu(OAc), Cu2(C03)(0H)2,CuS04, CuO, Cu(Otriflate)2, Cu(OAc)2. Most preferred are CuBr, CuCI, CU2O, CuS04 and CuO.
The molar ratio of palladium to Cu salt should be between 0,01 and 50, preferably between 0,05 and 20, preferred between 0,1 and 5.
The reaction can be carried out in a single solvent or in solvent mixtures. Suitable organic solvents for the reaction are aprotic solvents, for example aromatic hydrocar- bons such as benzene, toluene, xylenes, cumene, chlorobenzene, dichlorobenzenes, nitroben- zene or tert-butylbenzene, aprotic polar solvents, for example cyclic or acyclic ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether (MTBE), tert-butyl ethyl ether, tetrahydro- furan (THF) or dioxane, cyclic or acyclic amides such as dimethylformamide, dimethylacetam- ide, N-methylpyrrolidone or tetramethylurea, aliphatic esters like ethyl acetate, butyl acetate or methyl propionate, cyclic or acyclic ketones like cyclohexanone, acetone, 3-methyl-butanone or 4-methyl-pentanone-2, aliphatic chlorinated solvents like dichloromethane, chloroform, tetra- chloromethane, 1 ,2-dichloroethane, 1 ,1 ,2-trichloroethylene or aliphatic nitriles such as acetoni- trile or propionitrile, and mixtures of the aforementioned solvents. The preference is given to acetonitrile, 3-methylbutanone, 4-methyl-pentanone-2, ethyl acetate, butyl acetate, N- methylpyrrolidone, dimethylformamide, toluene, xylenes, even more preferred toluene, N- methylpyrrolidone or butyl acetate.
The reaction ususally takes place at temperatures between 50°C and 200°C, preferred between 70 °C and 170°C, especially preferred between 90°C and 160°C.
According to one embodiment of the invention X is selected form the group consisting of Li, NA, K and Cs. Most preferred is Li.
According to one further embodiment of the invention the compound of the formula II is provided by a reaction of the compound of the formula IV
IV
Figure imgf000005_0001
R3, R4, R5, R6 R78 and o are as defined above and
Y is selected from Ci-C6-alkyl, Ci-C6-halogenalkyl, phenyl and benzyl, wherein phenyl and benzyl are unsubstituted or substituted by CN, NO2, halogen, Ci-C6-alkyl, C1-C6- halogenalkyl or Ci-C6-alkoxy;
with a metal hydroxide to provide the compound of the formula II.
According to one further embodiment of the invention the compound of the formula IV is provid- ed by
(i) a reaction of the compound of the formula V
V
Figure imgf000005_0002
wherein
R3, R4 are independently selected from Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6- halogenalkyl, C2-C6-halogenalkenyl and C2-C6-halogenalkynyl;
R78 is independently selected from halogen, Ci-C6-alkyl, Ci-C6-alkoxy, C1-C6- halogenalkyl and Ci-C6-halogenalkoxy;
o is 0, 1 , 2 or 3;
with a compound of the formula VI
Figure imgf000006_0001
Y is selected from Ci-C6-alkyl, Ci-C6-halogenalkyl, phenyl and benzyl, wherein phenyl and benzyl are unsubstituted or substituted by CN, NO2, halogen, Ci-C6-alkyl, C1- C6-halogenalkyl or Ci-C6-alkoxy; in the presence of an acid to provide a compound of the formula VII
VII
Figure imgf000006_0002
wherein R3, R4, R78, o and Y are as defined above; and
(ii) a chlorination reaction in the presence of a chlorination agent or bromination reaction in the presence of a bromination agent; and
(iii) a subsequent fluorination reaction in the presence of a fluorination agent.
According to one embodiment of the invention the reaction (ii) is preferably a bromination.
According to one embodiment of the invention the reaction is carried out in the presence of an acid.
Preferably the acid is selected from inorganic acids such as sulfuric acid, fuming sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, organic acids such as trifluoromethane sulfonic acid, methane sulfonic acid, trifluoro acetic acid, trichloro ace- tic acid and mixtures thereof.
More preferred as acid are sulfuric acid, fuming sulfuric acid and trifluoro acetic acid. Most preferred is the use of sulfuric acid. Preferred amounts of the acid used are 1-10 equivi- lants related to the alcohol V used, more preferred 2 to 8 equivilants, even more preferred 2,5 to 5 equivilants.
According to embodiment of the invention the reaction between V and VI is carried out in an inert solvent.
By“inert organic solvent” is meant an organic solvent which, under the reaction conditions of the process of this invention, does not enter into any appreciable reaction with either the reac- tants or the products.
In one embodiment, the inert organic solvent is selected from non-halogenated inert organic solvents; preferably from non-halogenated aliphatic hydrocarbons, non-halogenated cycloali- phatic hydrocarbons, non-halogenated aromatic hydrocarbons, halogenated aliphatic hydrocar- bons, halogenated aromatic hydrocarbons, amides, ethers, esters, ketones, nitriles and any combination thereof.
Examples of suitable non-halogenated aliphatic hydrocarbons include pentane, hexane, hep- tane, petrolether and the like. Preference is given to saturated aliphatic hydrocarbons having from 5 to 10 carbon atoms.
Examples of suitable non-halogenated cycloaliphatic hydrocarbons include cyclopentane, cy- clohexane, cycloheptane, and the like. Preference is given to non-halogenated saturated cyclo- aliphatic hydrocarbons having from 5 to 10 carbon atoms. Cyclohexane is particularly preferred.
Examples of suitable a non-halogenated aromatic hydrocarbons include toluene, o-xylene, m- xylene, p-xylene, ethylbenzene, 2-propylbenzene (cumene), 2-isopropyltoluene (o-cymol), 3-isopropyltoluene (m-cymol), 4-isopropyltoluene (p-cymol), 1 ,3,5-trimethylbenzene (mesity- lene), and the like. Preference is given to toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 1 ,3,5-trimethylbenzene (mesitylene), and any combination thereof. Especially preferred among the non-halogenated aromatic hydrocarbons are toluene, o-xylene, m-xylene, p-xylene, and any combination thereof, with toluene being the most preferred.
Examples of suitable halogenated aliphatic hydrocarbons include dichloromethane, chloroform, carbon tetrachloride, 1 ,2-dichloroethane, 1 ,1 ,1 ,2-tetrachloroethane, 1 ,1 ,2,2-tetrachloroethane,
1 ,1-dichloroethylene, 1 ,2-dichloroethylene, and the like. Preference is given to dichloromethane and 1 ,2-dichloroethane and any combination thereof.
Examples of suitable halogenated aromatic hydrocarbons include chlorobenzene, bromoben- zene, o-dichlorobenzene, m-dichlorobenzene, a,a,a-trifluorotoluene (benzotrifluoride) and the like and any combination thereof.
Examples of suitable amides include N,N-dimethylformamide, N,N-dimethylacetamide, N,N- diethylacetamide, N-methyl-pyrrolidone, and the like and any combination thereof.
Examples of suitable ethers include cyclic and acyclic ethers such as diethyl ether, diisopropyl ether, n-butyl methyl ether, isobutyl methyl ether, sec-butyl methyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, 1 ,4-dioxane, and the like and any combination there- of.
Examples of suitable esters include ethyl acetate, n-propylacetate, isopropyl acetate, tert-butyl acetate, and the like and any combination thereof. Examples of suitable ketones include acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, cyclopropyl methyl ketone and the like, and any combination thereof..
Examples of suitable nitriles include acetonitrile, benzonitrile, and the like and any combination thereof.
Preferably the inert solvent selected from the group consisting of aliphatic and aromatic hydro- carbons and halohydrocarbons such as cyclohexane, heptane, benzene, toluene, xylenes, cu- mene, mesitylene, chlorobenzene, dichlorobenzenes and tert-butylbenzene, cyclic or acyclic ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether (MTBE), tert-butyl ethyl ether, methyl cyclopentylether, tetrahydrofuran (THF), methyl tetrahydrofuran (methyl THF) or dioxane, nitriles such as acetonitrile and propionitrile, aliphatic halohydrocarbons such as di- chloromethane, dichloroethane, trichloromethane and mixtures thereof.
More preferably the inert solvent is chlorobenzene, cyclohexane, heptane or petrolether.
Compounds VI are commercially available or can be synthesized according to known proce- dures. For details see: Heteroatom Chemistry, 26(4), 249-256; 2015; CH 675875; Anorganische und Allgemeine Chemie, 510, 136-42; 1984; Tetrahedron Letters, (27), 2517-20; 1979; Journal of Organic Chemistry, 41 (21 ), 3486-7; 1976; Bioorganic & Medicinal Chemistry, 23(24), 7661- 7670; 2015; DE 102014008070; WO 2017059191 ; Tetrahedron, 63(39), 9724-9740; 2007; Chemical Communications, (16), 1775-1777; 2006; Organic & Biomolecuiar Chemistry, 2(13), 1921-1933; 2004; Tetrahedron Letters, (27), 2517-20; 1979.
Compounds V are commercially available or can be synthesized according to known proce- dures. For details see:Tetrahedron, 42(11 ), 2931-5; 1986; Journal of the Indian Chemical Socie ty, 87(5), 595-600; 2010; Chemistry Letters, 37(7), 800-801 ; 2008; Journal of Labelled Com pounds & Radiopharmaceuticals, 43(14), 1321-1326; 2000; Organic Chemistry, 47(7), 1193-6; 1982; Chemische Berichte, 1 14(12), 3813-30; 1981 ; Russian Chemical Bulletin, 55(1), 123-136; 2006; Comptes Rendus des Seances de I'Academie des Sciences, Serie C: Sciences
Chimiques, 283(3), 75-8; 1976; Journal of Organometallic Chemistry, 328(1-2), 81-6; 1987; WO 2016038628; WO 2008090193; Chemistry Letters, 37(7), 800-801 ; 2008; European Journal of Medicinal Chemistry, 14(2), 165-70; 1979; Journal of Organic Chemistry, 45(19), 3925-7; 1980; Chemical Communications, 51 (30), 6637-6639; 2015; Journal of the American Chemical Socie ty, 1 10(23), 7737-45; 1988; Tetrahedron Letters, 50(20), 2320-2321 ; 2009; Journal of Medicinal Chemistry, 14(2), 165-70; 1979; Angewandte Chemie, International Edition, 53(25), 6439-6442; 2014; Bulletin de la Societe Chimique de France, (5), 787-93; 1985; Chemical Communications, 52(82), 12147-12150; 2016; European Journal of Medicinal Chemistry, 14(2), 165-70; 1979.
Preferably, the compound VI is used in an amount of 0.8 eq to 3 eq, in particular 1.05 to 2.5 eq, more specifically 1.05 to 1.8 eq, in relation to one equivalent of compound V.
The substituted dihydroisoquinolines of the formula VII obtained according to the inventive process can be further converted into compounds of the following formula
Figure imgf000009_0001
wherein
R3, R4 are independently selected from Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6- halogenalkyl, C2-C6-halogenalkenyl and C2-C6-halogenalkynyl;
R78 is independently selected from halogen, Ci-C6-alkyl, Ci-C6-alkoxy, C1-C6- halogenalkyl and Ci-C6-halogenalkoxy;
o is 0, 1 , 2 or 3;
Y is selected from Ci-C6-alkyl, Ci-C6-halogenalkyl, phenyl and benzyl, wherein phenyl and benzyl are unsubstituted or substituted by CN, NO2, halogen, Ci-C6-alkyl, C1- C6-halogenalkyl or Ci-C6-alkoxy.
Consequently, the present invention relates further to the process comprises the following step:
(i) providing a compound of the formula VII as described above
(ii) reacting the compound of the formula VII with a brominating agent.
According to one embodiment of the invention the brominating agent in the process according to the invention is selected from the group consisting of is selected from the group consisting of Br2, N-bromosuccinimide (NBS), 1 ,3-dibromo-5,5-dimethylhydantoin (DBDMH) or a system con- sisting of HBr/hhC^.
Preferably the brominating agent is N-bromosuccinimide (NBS).
Preferably the brominating agent is1 ,3-dibromo-5,5-dimethylhydantoin (DBDMH).
Preferably, the brominating agent is used in an amount of 1.5 eq to 5 eq, in particular 2.0 to 3.0 eq, in relation to one equivalent of compound VII.
Typical reaction times are in the range of from 10 minutes to 12 hours, preferably from 30 minutes to 8 hours, also preferred from 1 to 4 hours.
Typically the bromination is carried out under radical generating condions. Preferred radical generating conditions are the use of UV-light or the use of radical initiators like azo compounds or peroxides. Preferred conditions are the use of radical initiators. The nature of the radical initor depends on the reaction temperatures applied, most preferred are benzoyl peroxide or AIBN (azo isobutyro dinitrile). The amounts of radical initiators used range from 0,001 equiv. to 0,5 equiv., preferably 0,005 eqiv. to 0,3 equiv., also preferred 0,01 to 0,2 equiv. related to corn- pound V used.
Typically the reaction is carried out in an inert solvent as defined above. Preferred inert solvents for this bromination step are chlorobenzene, cyclohexane, heptane, trichloromethane, tetrachlo- romethane, ethyl acetate, butyl acetate or acetonitrile. Preferably the solvent used is chloroben- zene, cyclohexane, ethyl acetate or buryl acetate. By means of the inventive process, the pyridine derivatives of the formula I can be prepared in high yields. Preferably, the yields are at least 60%, more preferably 70 %, even more preferred at least 75%, even more preferred at least 80%.
The brominated dihydroisoquinolines of the following formula
Figure imgf000010_0001
obtained according to the inventive process can be further converted into compounds of the following formula
Figure imgf000010_0002
wherein
R3, R4 are independently selected from Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6- halogenalkyl, C2-C6-halogenalkenyl and C2-C6-halogenalkynyl;
R78 is independently selected from halogen, Ci-C6-alkyl, Ci-C6-alkoxy, C1-C6- halogenalkyl and Ci-C6-halogenalkoxy;
o is 0, 1 , 2 or 3;
Y is selected from Ci-C6-alkyl, Ci-C6-halogenalkyl, phenyl and benzyl, wherein phenyl and benzyl are unsubstituted or substituted by CN, NO2, halogen, Ci-C6-alkyl, C1- C6-halogenalkyl or Ci-C6-alkoxy.
According to the one further embodiment of the invention the fluorinating agent is selected from the group consisting of NaF, CsF, KF, KHF2, Olah reagent, HF, a polyhydrofluoride complex of a trialkylamine or mixtures of HF in trialkylamines (Ci-Ce-alkyl^N.
Polyhydrofluoride complex of a trialkylamine can be described by a formula (Ci-C6-alkyl)3N x n HF, wherein (n=1-5) such as: (C2H5)3N x 3 HF, (C4H9)3N x 3 HF.
Mixtures of HF in trialkylamines (Ci-C6-alkyl)3N are mixture with a content of 5-95 % HF in trial- kylamines (Ci-C6-alkyl)3N, preferred 10-60 % HF, further preferred 20-40 %.
Preferably the fluorinating agent is HF in triethylamine solution, preferred (C2H5)3N x 3 HF, op- tionally diluted with (C2H5)3N or with mixtures of (C2H5)3N and polar solvents like acetonnitril, dimethylformamide or N-methyl-pyrrolidone.
Preferably, the fluorinating agent is used in an amount of 1.2 eq to 10 eq, in particular 2.2 to 7.8 eq, more specifically 4.4 to 5.6 eq, in relation to one equivalent of compound VIII. According to the one further embodiment of the invention the fluorinating reaction is carried out in the presence of a solvent, preferably a polar solvent. Suitable organic solvents for the reac- tion are protic polar solvents, for example water, aliphatic alcohols having preferably from 1 to 4 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or tert- butanol, or carboxylic acids such as acetic acid, aromatic hydrocarbons such as benzene, tolu- ene, xylenes, cumene, chlorobenzene, nitrobenzene or tert-butylbenzene, aprotic polar sol- vents, for example cyclic or acyclic ethers such as diethyl ether, diisopropyl ether, tert-butyl me- thyl ether (MTBE), tert-butyl ethyl ether, tetrahydrofuran (THF) or dioxane, cyclic or acyclic am- ides such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone or tetramethylurea, aliphatic esters like ethyl acetate, butyl acetate or methyl propionate, cyclic or acyclic ketones like cyclohexanone, acetone, 3-methyl-butanone or 4-methyl-pentanone-2, aliphatic tertiary amines like triethylamine, tributylamine or diisopropyl ethylamine, or aliphatic nitriles such as acetonitrile or propionitrile, and mixtures of the aforementioned solvents. The preference is giv- en to water, acetonitrile, 3-methylbutanone, butyl acetate, dimethylformamide, ethanol, toluene.
Preferably the polar solvent is acetonitril or triethylamine.
Further preferred solvent systems are (CaHs^N x 3 HF alone or (CaHs^N x 3 HF with addition of triethylamine, acetonitrile or dimethylformamide.
The reaction ususally takes place at temperatures between 10°C and 150°C, preferred between 20 °C and 100°C, especially preferred between 50°C and 90°C.
Typical reaction times are in the range of from 0,5 to 18 hours, preferred 1 to 5 hours, preferably from 1 to 3 hours.
According to one further embodiment of the invention the compound of the formula VIII
VIII
Figure imgf000011_0001
wherein
R1 is in each case independently selected from hydrogen, halogen, Ci-C6-alkyl and C1-C6- halogenalkyl;
R2 is in each case independently selected from hydrogen, halogen, Ci-C6-alkyl and C1-C6- halogenalkyl;
R10 is in each case independently selected from H, halogen, 0(R95), Ci-C6-alkyl and C1-C6- halogenalkyl; wherein
R95 is Ci-C6-alkyl, Ci-C6-halogenalkyl;
in a reaction with a brominating agent in the presence of oleum 65% to provide a compound of the formula IMA MIA
Figure imgf000012_0001
wherein R1, R2 and R10 are as defined above; and
(ii) an optionally selective chlorination of a compound of the formula IMA with a chlorinating agent to provide a compound of the formula NIB or MIC
Figure imgf000012_0003
wherein R1, R2 and R10 are as defined above; and
(iii) followed by an optionally selective fluorination of the compound of the formula NIB or MIC using a fluorination agent to provide a compound of the formula HID or HIE
Figure imgf000012_0002
wherein R1, R2 and R10 are as defined above.
Preferably the brominating agent in the process according to the invention is selected from the group consisting of such as N-bromosuccinimide (NBS), 1 ,3-dibromo-5,5-dimethylhydantoin (DBDMH) or a system consisting of HBr/hhC^. The preferred brominating agents are NBS und DBDMH. The most preferred brominating agent is 1 ,3-dibromo-5,5-dimethylhydantoin
(DBDMH).
Typical reaction times are in the range of from 1 to 20 hours, preferably from 2 to 15 hours and more preferably from 3 to 10 hours, most preferably 3 to 5 hours.
Typical the product will be extracted using an inert organic solvent.
By“inert organic solvent” is meant an organic solvent which, under the reaction conditions of the process of this invention, does not enter into any appreciable reaction with either the reac- tants or the products.
In one embodiment, the inert organic solvent is selected from non-halogenated inert organic solvents; preferably from non-halogenated aliphatic hydrocarbons, non-halogenated cycloali- phatic hydrocarbons, non-halogenated aromatic hydrocarbons, halogenated aliphatic hydrocar- bons, halogenated aromatic hydrocarbons, , ethers, esters, ketones, and any combination thereof. Examples of suitable non-halogenated aliphatic hydrocarbons include pentane, hexane, hep- tane, and the like. Preference is given to saturated aliphatic hydrocarbons having from 5 to 10 carbon atoms.
Examples of suitable non-halogenated cycloaliphatic hydrocarbons include cyclopentane, cy- clohexane, cycloheptane, and the like. Preference is given to non-halogenated saturated cyclo- aliphatic hydrocarbons having from 5 to 10 carbon atoms. Cyclohexane is particularly preferred.
Examples of suitable a non-halogenated aromatic hydrocarbons include toluene, o-xylene, m- xylene, p-xylene, ethylbenzene, 2-propylbenzene (cumene), 2-isopropyltoluene (o-cymol), 3-isopropyltoluene (m-cymol), 4-isopropyltoluene (p-cymol), 1 ,3,5-trimethylbenzene (mesity- lene), and the like. Preference is given to toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 1 ,3,5-trimethylbenzene (mesitylene), and any combination thereof. Especially preferred among the non-halogenated aromatic hydrocarbons are toluene, o-xylene, m-xylene, p-xylene, and any combination thereof, with toluene being the most preferred.
Examples of suitable halogenated aliphatic hydrocarbons include dichloromethane, chloroform, carbon tetrachloride, 1 ,2-dichloroethane, 1 ,1 ,1 ,2-tetrachloroethane, 1 ,1 ,2,2-tetrachloroethane,
1 ,1-dichloroethylene, 1 ,2-dichloroethylene, and the like. Preference is given to dichloromethane and 1 ,2-dichloroethane and any combination thereof.
Examples of suitable halogenated aromatic hydrocarbons include chlorobenzene, bromoben- zene, o-dichlorobenzene, m-dichlorobenzene, a,a,a-trifluorotoluene (benzotrifluoride) and the like and any combination thereof.
Examples of suitable ethers include cyclic and acyclic ethers such as diethyl ether, diisopropyl ether, n-butyl methyl ether, isobutyl methyl ether, sec-butyl methyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, methyl-tetrahydrofuran, tetrahydrofuran, 1 ,4-dioxane, and the like and any combination thereof.
Examples of suitable esters include ethyl acetate, n-propylacetate, isopropyl acetate, n-butyl acetate, tert-butyl acetate, and the like and any combination thereof.
Examples of suitable ketones include acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, cyclopropyl methyl ketone and the like, and any combination thereof..
After the extraction the inert solvent will be evaporated and the crude product will be purified by distillation.
The molar ratio of the brominating agent DBDMH to the pyridine derivative of the formula I where R1 = H and R2 = H can vary widely and depends on the reaction conditions used, but is generally from 0.40 : 1.1 to 1.5 : 1 , preferably from 0.40 : 1 to 1.2 : 1 , more preferably from 0.40 : 1 to 1.1 : 1 and even more preferably from 0.50 : 1 to 1.0 : 1. It is preferably to use the bromin- ating agent less then 1 eq compared to the pyridine in order to avoid sideproducts. Therefore, the molar ratio of the brominating agent DBDMH to the pyridine derivative of the formula I where R1 = H and R2 = H is preferably 0.4 to 1.1 , more preferably 0.4 to 0.9.
Preferably, a bromination of the compounds of the formula I where R1 = H and R2 = H will be performed. The preferred brominating agent is 1 ,3-dibromo-5,5-dimethylhydantoin (DBDMH). In that case, preference is given to performing the bromination withouth an additional solvent. In this case, the the reaction temperature is preferably in the range from 0 to 150°C and espe- cially 80 to 125°C temperature and the reaction times are in the range of from 2 to 10 hours, more preferred 2 to 5 hours.
Preferably the purification is a distillation under reduced pressure (50-55°C; 1.6-2.0 mbar).
According one embodiment of the invention the chlorination step is carried out in an inert sol- vent.
By“inert organic solvent” is meant an organic solvent which, under the reaction conditions of the process of this invention, does not enter into any appreciable reaction with either the reac- tants or the products.
In one embodiment, the inert organic solvent is selected from non-halogenated inert organic solvents; preferably from non-halogenated aliphatic hydrocarbons, non-halogenated cycloali- phatic hydrocarbons, non-halogenated aromatic hydrocarbons, halogenated aliphatic hydrocar- bons, halogenated aromatic hydrocarbons, amides, ethers, esters, nitriles and any combination thereof.
Examples of suitable non-halogenated aliphatic hydrocarbons include pentane, hexane, hep- tane, and the like. Preference is given to saturated aliphatic hydrocarbons having from 5 to 10 carbon atoms.
Examples of suitable non-halogenated cycloaliphatic hydrocarbons include cyclopentane, cy- clohexane, cycloheptane, and the like. Preference is given to non-halogenated saturated cyclo- aliphatic hydrocarbons having from 5 to 10 carbon atoms. Cyclohexane is particularly preferred.
Examples of suitable non-halogenated aromatic hydrocarbons include toluene, o-xylene, m- xylene, p-xylene, ethylbenzene, 2-propylbenzene (cumene), 2-isopropyltoluene (o-cymol), 3-isopropyltoluene (m-cymol), 4-isopropyltoluene (p-cymol), 1 ,3,5-trimethylbenzene (mesity- lene), and the like. Preference is given to toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 1 ,3,5-trimethylbenzene (mesitylene), and any combination thereof. Especially preferred among the non-halogenated aromatic hydrocarbons are toluene, o-xylene, m-xylene, p-xylene, and any combination thereof, with toluene being the most preferred.
Examples of suitable halogenated aliphatic hydrocarbons include dichloromethane, chloroform, carbon tetrachloride, 1 ,2-dichloroethane, 1 ,1 ,1 ,2-tetrachloroethane, 1 ,1 ,2,2-tetrachloroethane,
1 ,1-dichloroethylene, 1 ,2-dichloroethylene, and the like. Preference is given to dichloromethane and 1 ,2-dichloroethane and any combination thereof.
Examples of suitable halogenated aromatic hydrocarbons include chlorobenzene, bromoben- zene, o-dichlorobenzene, m-dichlorobenzene, a,a,a-trifluorotoluene (benzotrifluoride) and the like and any combination thereof.
Examples of suitable amides include N,N-dimethylformamide, N,N-diethylformamide, N,N- dimethylacetamide, N,N-diethylacetamide, N-methyl-pyrrolidone, DMI (dimethylimidazolidinone) or tetramethylurea, and the like and any combination thereof.
Examples of suitable ethers include cyclic and acyclic ethers such as diethyl ether, diisopropyl ether, n-butyl methyl ether, isobutyl methyl ether, sec-butyl methyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, methyl-tetrahydrofuran, 1 ,4-dioxane, and the like and any combination thereof. Examples of suitable esters include ethyl acetate, n-propylacetate, isopropyl acetate, tert-butyl acetate, and the like and any combination thereof.
Examples of suitable nitriles include acetonitrile, propionitrile, benzonitrile, and the like and any combination thereof.
Preferably the inert solvent selected from the group consisting of aliphatic and aromatic hydro- carbons and halohydrocarbons such as cyclohexane, heptane, benzene, toluene, xylenes, cu- mene, mesitylene, chlorobenzene, dichlorobenzenes and tert-butylbenzene, cyclic or acyclic ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether (MTBE), tert-butyl ethyl ether, methyl cyclopentylether, tetrahydrofuran (THF), methyl tetrahydrofuran (methyl THF) or dioxane, nitriles such as acetonitrile and propionitrile, aliphatic halohydrocarbons such as di- chloromethane, dichloroethane, trichloromethane and mixtures thereof.
More preferably the inert solvent is chlorobenzene.
According to the one further embodiment of the invention the chlorinating agent is selected from the group consisting of N-chlorosuccinimide (NCS), sulfuryl chloride, Ch, trichloroisocyanuric acid, 1 ,3-dichloro-5,5-dimethylhydantoin.
Preferably the chlorinating agent is trichloroisocyanuric acid.
Preferably, the chlorinating agent is used in an amount of 0.5 eq to 2 eq, in particular 0.6 to 1.2 eq, more specifically 0.7 to 0.8 eq, in relation to one equivalent of compound II.
According to the one further embodiment of the invention the chlorination step is carried out in the presence of an organic carboxylic or sulfonic acid and in the absence of an alkali metal salt of said carboxylic acid which leads to decrease of waste.
Preferably the organic acid is selected from the group consisting of: formic acid, acetic acid, propionic acid, or butyric acid, aliphatic sulfonic acids selected from the group consisting of: methanesulfonic acid, ethanesulfonic acid and trifluoromethanesulfonic acid. More preferably is selected from the group consisting of acetic acid and trifluoroacetic acid. Most preferably is ace- tic acid.
Typical reaction times are in the range of from 1 to 20 hours, preferably from 2 to 15 hours and more preferably from 3 to 10 hours, most preferably 3 to 5 hours.
According to the one further embodiment the mono-CI-substituted pyridine can be prepared analog.
In the next step according to the invention the di-CI substituted pyridine is converted into a di-F substituted pyridine in the presence of a the fluorinating agent.
According to the one further embodiment of the invention the fluorinating agent is selected from the group consisting of KF, KHF2, NaF, CaF2, Olah reagent, a polyhydrofluoride complex of a trialkylamine.
Polyhydrofluoride complex of a trialkylamine can be described by a formula (Ci-C6-alkyl)3N x n HF, wherein (n=1-3) such as: (C2H5)3N x 3 HF,
Preferably the fluorinating agent is (C2H5)3N x 3 HF.
Preferably, the fluorinating agent is used in an amount of 2.0 eq to 10 eq, in particular 2.5 to 8.0 eq, more specifically 3.0 to 6.0 eq, in relation to one equivalent of compound III.
According to the one further embodiment of the invention the fluorinating reaction is carried out in the presence of an amine.
Suitable amines are tertiary amines for example, tri(Ci-C6-alkyl)amine such as trimethylamine, triethylamine or diisopropylethylamine, N-methylpiperidine, pyridine, substituted pyridines such as 2,4,6-trimethylpyridine (collidine), 2,6-dimethylpyridine (lutidine), 2-methylpyridine, (a- picoline), 3-methylpyridine (b-picoline), 4-methylpyridine (g-picoline) and 4-dimethylamino- pyridine, and also bicyclic amines such as 1 ,4-diazabicyclo[2.2.2]octane, 1 ,8-diaza- bicyclo[5.4.0]undec-7-ene or 1 ,5-diazabicyclo[4.3.0]non-5-ene. Particular preference is given to using triethylamine, pyridine or 1 ,8-diazabicyclo[5.4.0]undec-7-ene. Most preferred is triethyla- mine. Preferably, the amine is used in an amount of 1.0 eq to 10 eq, in particular 1.5 to 8.0 eq, more specifically 2.0 to 6.0 eq, in relation to one equivalent of compound III
According to one further embodiment the fluorinating agent is NaF or KF, most preferably KF.
According to the one further embodiment of the invention the fluorinating reaction is carried out in the presence of a phase transfer catalysts.
Phase transfer catalysts suitable for use in the process of this invention are those well known in the art. Preferred phase transfer catalysts are selected from quarternary ammonium salts, quar- ternary pyridinium salts, quarternary phosphonium salts and any combination thereof and more preferably selected from quarternary ammonium salts, quarternary phosphonium salts and any combination thereof.
More preferably, the phase transfer catalyst is selected from quaternary ammonium salts of the general formula
(R R R R N)· Zf wherein R , R , R and R are the same or different and are each independently selected from the group consisting of Ci-C2o-alkyl, C3-Cio-cycloalkyl, C6-C2o-aryland C6-C2o-a ry l-C 1 -C4-a I ky I , and Zr is a monovalent anion,
and quarternary phosphonium salts of the general formula
(R R R R P)· Z2- (VII) wherein R , R , R and R are the same or different and are each independently selected from a 5- or 6-membered heterocyclyl group containing 1 , 2 or 3 heteroatoms selected from the group consisting of O, N and S, and Z2 is a monovalent anion, and any combination thereof.
The term“a 5- or 6-membered heterocyclyl group containing 1 , 2 or 3 heteroatoms selected from the group consisting of O, N and S” as used herein includes but is not limited to 1 -piperidyl, morpholinyl and 4-methyl-1 -piperidyl.
In a preferred embodiment, the monovalent anion Zr is selected from a halide, hydroxide, hy- drogen sulfate and monomethyl sulfate, more preferably from chloride, bromide, iodide and hy- droxide, even more preferably from chloride or bromide and is most preferably chloride.
In another preferred embodiment, the monovalent anion Z-r is selected from a halide, more preferably from chloride or bromide is most preferably chloride.
In yet another preferred embodiment, the monovalent anion 2.2 is selected from a halide, hy- droxide, hydrogen sulfate and monomethyl sulfate, more preferably from chloride, bromide, io- dideand hydroxide, even more preferably from chloride or bromide and is most preferably chlo- ride.
In still another preferred embodiment, the monovalent anion Z2 is selected from a halide, more preferably from chloride or bromide and is most preferably chloride.
In a preferred embodiment, the phase transfer catalyst is selected from quaternary ammonium salts of the general formula (V) wherein R4, R5, R6 and R7 are the same or different and are each independently selected from the group consisting of Ci-C2o-alkyl, C6-C2o-aryl and C6-C20- aryl-C-i-C4-alkyk
More preferably, the phase transfer catalyst is selected from quaternary ammonium salts of the general formula (V) wherein R4, R5, R6 and R7 are the same or different and are each inde- pendently selected from Ci-C2o-alkyl, even more preferably Ci-Ci2-alkyl and still more preferably C-i-Cs-alkyl and yet more preferably Ci-C4-alkyl.
Particularly preferred phase transfer catalysts useful for the process of this invention are tetra-n- Ci-Ci2-alkyl-ammonium chlorides, bromides, iodides, hydroxides, hydrogen sulfate or monome- thyl sulfate (in particular chlorides), preferably tetra-n-C-i-Cs-alkyl-ammonium chlorides, bro- mides, iodides, hydroxides, hydrogen sulfate or monomethyl sulfate (in particular chlorides), e.g. tetramethylammonium chloride, bromide, iodide, hydroxide, hydrogen sulfate or monomethyl sulfate (in particular chloride), tetraethylammonium chloride, bromide, iodide, hydroxide, hydro- gen sulfate or monomethyl sulfate, tetra-n-propylammonium chloride, bromide, iodide, hydrox- ide, hydrogen sulfate or monomethyl sulfate, tetra-n-butylammonium chloride, bromide, iodide, hydroxide, hydrogen sulfate or monomethyl sulfate (in particular chloride), tetra-n- pentylammonium chloride, bromide, iodide, hydroxide, hydrogen sulfate or monomethyl sulfate (in particular chloride), tetra-n-hexylammonium chloride, bromide, iodide, hydroxide, hydrogen sulfate or monomethyl sulfate (in particular chloride), tetra-n-heptylammonium chloride, bro- mide, iodide, hydroxide, hydrogen sulfate or monomethyl sulfate (in particular chloride), tetra-n- octylammonium chloride, bromide, iodide, hydroxide, hydrogen sulfate or monomethyl sulfate (in particular chloride), methyl-tri-n-butylammonium chloride, bromide, iodide, hydroxide, hydro- gen sulfate or monomethyl sulfate (in particular chloride), ethyl-tri-methylammonium chloride, bromide, iodide, hydroxide, hydrogen sulfate or monomethyl sulfate (in particular chloride), n- propyl-trimethyl ammonium chloride, bromide, iodide, hydroxide, hydrogen sulfate or monome- thyl sulfate (in particular chloride), methyl-triethyl ammonium chloride, bromide, iodide, hydrox- ide, hydrogen sulfate or monomethyl sulfate (in particular chloride), n-butyl-triethylammonium chloride, bromide, iodide, hydroxide, hydrogen sulfate or monomethyl sulfate (in particular chlo- ride), tri-n-octylmethylammonium chloride, bromide, iodide, hydroxide, hydrogen sulfate or monomethyl sulfate (in particular chloride) and n-dodecyltrimethylammonium chloride, bromide, iodide, hydroxide, hydrogen sulfate or monomethyl sulfate (in particular chloride). Of these, the use of tetra-n-Ci-C4-alkyl-ammonium chlorides, bromides, iodides, hydroxides, hydrogen sul- fates or monomethyl sulfates (in particular chlorides) is preferred, in particular tetra-n- butylammonium chloride, bromide, iodide, hydroxide, hydrogen sulfate or monomethyl sulfate (more specifically chloride) and methyl-tri-n-butylammonium chloride, bromide, iodide, hydrox- ide, hydrogen sulfate or monomethyl sulfate (more specifically chloride).
Even more preferably, the phase transfer catalyst is selected from tetra-n-butylammonium chlo- ride, tri-n-octylmethylammonium chloride, n-dodecyltrimethylammonium chloride, benzyl(tri-n- butyl)ammonium chloride, tetrakis(1-piperidyl)phosphonium chloride and any combination thereof. The phase-transfer catalyst, which is usually solid in pure form, can be used as such or, prefer- ably, in dissolved form. For example, a solution of the phase transfer catalyst in any of the aforementioned substantially anhydrous (preferably anhydrous) inert organic solvents such as e.g. aromatic or aliphatic hydrocarbons.
According to the one further embodiment of the invention the fluorinating reaction is carried out in the presence of a polar solvent. It was found that the use of catalytic amounts of a polar sol- vent accelerates the fluorination reaction.
Suitable organic solvents for the reaction are , aprotic polar solvents, for example cyclic or acy- clic ethers such as diethyl ether, diisopropyl ether, n-butyl methyl ether, isobutyl methyl ether, sec-butyl methyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, methyl-tetrahydrofuran, tetrahydrofuran, 1 ,4-dioxane, cyclic or acyclic amides such as dimethylformamide, diethylfor- mamide, dimethylacetamide, diethylacetamide, N-methylpyrrolidone, DMI (dimethylimidazoli- dinone) or tetramethylurea, or aliphatic nitriles such as acetonitrile or propionitrile, and mixtures of the aforementioned solvents. The preference is given to DMF, NMP, DMI.
Preferably the polar solvent is DMF.
Typical reaction times are in the range of from 1 to 24 hours, preferably from 2 to 16 hours and more preferably from 3 to 15 hours, most preferably 4 to 12 hours.
The reaction of the halogen exchange is carried our between 70°C and 180°C, preferably be- tween 80°C and 160°C
According to the one further embodiment the mono-F-substituted pyridine can be prepared ana- log.
The terms "compounds I", "compounds II", "compounds lla" and "compounds III" refer to corn- pounds of formulae I, II, lla and III, respectively. In the definitions of the variables given above, collective terms are used which are generally representative for the substituents in question.
In the definitions of the variables given herein, collective terms are used which are generally representative for the substituents in question. The term "Cn-Cm" indicates the number of carbon atoms possible in each case in the substituent or substituent moiety in question.
The term "halogen" refers to fluorine, chlorine, bromine and iodine.
The term "Ci-C6-alkyl" refers to a straight-chained or branched saturated hydrocarbon group having 1 to 6 carbon atoms, e.g. 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, 1 ,1-dimethylpropyl, 1 ,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1 -dimethylbutyl, 1 ,2-dimethylbutyl,
1.3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,
2-ethylbutyl, 1 ,1 ,2-trimethylpropyl, 1 ,2,2-trimethylpropyl, 1 -ethyl-1 -methylpropyl and 1 -ethyl-2- methylpropyl. Likewise, the term "C2-C4-alkyl" refers to a straight-chained or branched alkyl group having 2 to 4 carbon atoms, such as ethyl, propyl (n-propyl), 1-methylethyl (iso-propoyl), butyl, 1-methylpropyl (sec. -butyl), 2-methylpropyl (iso-butyl), 1 ,1-dimethylethyl (tert. -butyl).
The term "Ci-C6-halogenalkyl" refers to an alkyl group having 1 or 6 carbon atoms as defined above, wherein some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as mentioned above. Examples are "Ci-C2-haloalkyl" groups such as chloromethyl, bro- momethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloro- fluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1- fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-
2.2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl.
The term "C2-C6-alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon radical having 2 to 6 carbon atoms and a double bond in any position. Examples are "C2-C4-alkenyl" groups, such as ethenyl, 1-propenyl, 2-propenyl (allyl), 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1 -methyl-1 -propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl.
The term " C2-C6-halogenalkenyl" refers to an alkyl group having 2 or 6 carbon atoms as defined above, wherein some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as mentioned above.
The term "C2-C6-alkynyl" refers to a straight-chain or branched unsaturated hydrocarbon radical having 2 to 6 carbon atoms and containing at least one triple bond. Examples are "C2-C4- alkynyl" groups, such as ethynyl, prop-1 -ynyl, prop-2-ynyl (propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl , 1 -methyl-prop-2 -ynyl .
The term " C2-C6-halogenalkynyl" refers to an alkyl group having 2 or 6 carbon atoms as defined above, wherein some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as mentioned above.
The term "Ci-C6-alkoxy" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms which is bonded via an oxygen, at any position in the alkyl group. Examples are "C1-C4- alkoxy" groups, such as methoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy, 1- methyhpropoxy, 2-methylpropoxy or 1 ,1-dimethylethoxy.
The term "Ci-C6-halogenalkoxy" refers to a Ci-C6-alkoxy radical as defined above, wherein some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as men- tioned above. Examples are "Ci-C4-haloalkoxy" groups, such as OCH2F, OCHF2, OCF3,
OCH2CI, OCHCI2, OCCI3, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-tri- fluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy,
2.2.2-trichloro-,ethoxy, OC2F5, 2-fluoropropoxy, 3-fluoropropoxy, 2,2-difluoropropoxy,
2,3-difluoro~,propoxy, 2 chloropropoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 2-bro- mo-'propoxy, 3 bromopropoxy, 3,3,3-trifluoropropoxy, 3,3,3-trichloropropoxy, OCH2-C2F5, OCF2-C2F5, 1-fluoromethyl-2-fluoroethoxy, 1-chloromethyl-2-chloroethoxy, 1-bromomethyl-2- bromo^ethoxy, 4-fluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy or nonafluorobutoxy.
The term "phenyl-Ci-C6-alkyl" refers to alkyl having 1 to 6 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl radical is replaced by a phenyl radical. Likewise, the terms“phenyl-C2-C6-alkenyl” and“phenyl-C2-C6-alkynyl” refer to alkenyl and alkynyl, respective- ly, wherein one hydrogen atom of the aforementioned radicals is replaced by a phenyl radical.
The meanings and preferred meanings described in the following for the variables R1, R2, R3,
R4, R5, R6, R7, R78, R95, R10 and o apply to compounds and the the compounds of the formula I, II, 111 A, MB, IIC, HID, IV, V, VI, VII and VIII and side products in any of the above detailed inventive processes.
According to one embodiment of the invention in compounds of the formula I, II, IIIA, MB, IIC, MID, IV, V, VI, VII and VIII where applicable, the variables have independently of each other or more preferably in combination the following meanings:
R1 is in each case independently selected from hydrogen and Ci-C6-alkyl;
R2 is in each case independently selected from hydrogen;
R3, R4 are independently selected from Ci-C6-alkyl and Ci-C6-halogenalkyl;
R5 is halogen;
R6 is halogen;
o is 0, 1 , 2 or 3; and
R78 are independently selected from halogen and Ci-C6-alkyl;
R9 is in each case independently selected from CH3 and CHF2;
R10 is independently selected from from Ci-C6-alkyl, Ci-C6-alkoxy, and C1-C6- halogenalkyl.
According to one further embodiment of the invention in compounds of the formula I, II, IIIA, MB, IIC, MID, IV, V, VI, VII and VIII where applicable, the variables have independently of each other or more preferably in combination the following meanings:
R1 is hydrogen;
R2 is hydrogen;
R3, R4 are independently selected from Ci-C6-alkyl and Ci-C6-halogenalkyl;
R5 is halogen;
R6 is halogen;
o is 0, 1 , 2 or 3; and
R78 are independently selected from halogen and Ci-C6-alkyl;
R9 is in each case independently selected from CH3 and CHF2;
R10 is independently selected from from Ci-C6-alkyl and Ci-C6-halogenalkyl.
According to one further embodiment of the invention in compounds of the formula I, II, IIIA, MB, IIC, MID, IV, V, VI, VII and VIII where applicable, the variables have independently of each other or more preferably in combination the following meanings:
R1 is hydrogen;
R2 is hydrogen;
R3, R4 are independently Ci-C6-alkyl;
R5 is halogen;
R6 is halogen;
o is 0, 1 , 2 or 3; and
R78 are independently selected from halogen and Ci-C6-alkyl; R9 is in each case independently selected from CH3 and CHF2;
R10 are independently selected from Ci-C6-alkyl and Ci-C6-halogenalkyl.
According to one further embodiment of the invention in compounds of the formula I, II, IMA, 11 B, IIC, HID, IV, V, VI, VII and VIII where applicable, the variables have independently of each other or more preferably in combination the following meanings:
R1 is hydrogen;
R2 is hydrogen;
R3, R4 are independently Ci-C6-alkyl;
R5 is F;
R6 is F;
R7,
o is 0, 1 , 2 or 3; and
R78 are independently selected from halogen and Ci-C6-alkyl;
R9 is in each case independently selected from CH3 and CHF2;
R10 is independently selected from Ci-C6-alkyl and Ci-C6-halogenalkyl.
According to one further embodiment of the invention in compounds of the formula I, II, IIIA, MB, IIC, MID, IV, V, VI, VII and VIII where applicable, the variables have independently of each other or more preferably in combination the following meanings:
R1 is hydrogen;
R2 is hydrogen;
R3, R4 are independently Ci-C6-alkyl;
R5 is F;
R6 is F;
o is 0, 1 , 2 or 3; and
R78 are independently selected from halogen and Ci-C6-alkyl;
R9 is in each case independently selected from CH3 and CHF2;
R10 is independently selected from CH3 and CHF2.
Particularly preferred active compounds I are selected from the group consisting of compounds I .A to IZA:
I .A: 1 -(5, 6-dimethyl-3-pyridyl)-4,4-difluoro-3, 3-dimethyl-isoquinoline
I.B: 1-[6-(difluoromethyl)-5-methyl-3-pyridyl]-4,4-difluoro-3, 3-dimethyl-isoquinoline
I.C: 1-[6-(difluoromethyl)-5-methoxy-3-pyridyl]-4,4-difluoro-3, 3-dimethyl-isoquinoline
I.D: 4, 4-difluoro-1-[5-(fluoromethyl)-6-methyl-3-pyridyl]-3, 3-dimethyl-isoquinoline I.E: 4, 4-difluoro-1-(5-methoxy-6-methyl-3-pyridyl)-3, 3-dimethyl-isoquinoline
.F: 4, 4-difluoro-1-[6-(fluoromethyl)-5-methyl-3-pyridyl]-3, 3-dimethyl-isoquinoline
I.G: 1 -[5, 6-bis(fluoromethyl)-3-pyridyl]-4,4-difluoro-3, 3-dimethyl-isoquinoline
I.H: 4, 4-difluoro-1-[6-(fluoromethyl)-5-methoxy-3-pyridyl]-3, 3-dimethyl-isoquinoline
1.1: 1-[6-(difluoromethyl)-5-(fluoromethyl)-3-pyridyl]-4,4-difluoro-3, 3-dimethyl-isoquinoline
I.J: 1 -(5, 6-dimethyl-3-pyridyl)-4, 4, 5-trifluoro-3, 3-dimethyl-isoquinoline
I.K: 4, 4, 5-trifluoro-1-[5-(fluoromethyl)-6-methyl-3-pyridyl]-3, 3-dimethyl-isoquinoline
I.L: 4, 4, 5-trifluoro-1-(5-methoxy-6-methyl-3-pyridyl)-3, 3-dimethyl-isoquinoline
I.M: 4, 4, 5-trifluoro-1-[6-(fluoromethyl)-5-methyl-3-pyridyl]-3, 3-dimethyl-isoquinoline
I.N: 1 -[5, 6-bis(fluoromethyl)-3-pyridyl]-4, 4, 5-trifluoro-3, 3-dimethyl-isoquinoline
I.O: 4, 4, 5-trifluoro-1-[6-(fluoromethyl)-5-methoxy-3-pyridyl]-3, 3-dimethyl-isoquinoline
I.P: 1-[6-(difluoromethyl)-5-methyl-3-pyridyl]-4, 4, 5-trifluoro-3, 3-dimethyl-isoquinoline
I.Q: 1-[6-(difluoromethyl)-5-(fluoromethyl)-3-pyridyl]-4, 4, 5-trifluoro-3, 3-dimethyl-isoquinoline
I.R: 1-[6-(difluoromethyl)-5-methoxy-3-pyridyl]-4, 4, 5-trifluoro-3, 3-dimethyl-isoquinoline
I.S: 1 -(5, 6-dimethyl-3-pyridyl)-4, 4, 6-trifluoro-3, 3-dimethyl-isoquinoline
I.T: 4, 4, 6-trifluoro-1-[5-(fluoromethyl)-6-methyl-3-pyridyl]-3, 3-dimethyl-isoquinoline
I.U: 4, 4, 6-trifluoro-1-(5-methoxy-6-methyl-3-pyridyl)-3, 3-dimethyl-isoquinoline
I.V: 4, 4, 6-trifluoro-1-[6-(fluoromethyl)-5-methyl-3-pyridyl]-3, 3-dimethyl-isoquinoline
I.W: 1 -[5, 6-bis(fluoromethyl)-3-pyridyl]-4, 4, 6-trifluoro-3, 3-dimethyl-isoquinoline
I.X: 4, 4, 6-trifluoro-1-[6-(fluoromethyl)-5-methoxy-3-pyridyl]-3, 3-dimethyl-isoquinoline
I.Y: 1-[6-(difluoromethyl)-5-methyl-3-pyridyl]-4, 4, 6-trifluoro-3, 3-dimethyl-isoquinoline
I.Z: 1-[6-(difluoromethyl)-5-(fluoromethyl)-3-pyridyl]-4, 4, 6-trifluoro-3, 3-dimethyl-isoquinoline
I.ZA: 1-[6-(difluoromethyl)-5-methoxy-3-pyridyl]-4, 4, 6-trifluoro-3, 3-dimethyl-isoquinoline.
The invention is illustrated by the following examples:
Procedures
Example 1 - (4,4-Difluoro-3,3-dimethyl-isoquinoline-1-carbonyl)oxylithium
Figure imgf000022_0001
7,3 g (26 mmol) Ethyl 4,4-difluoro-3,3-dimethyl-isoquinoline-1-carboxylate and 1 ,143 g (27 mmol) lithium hydroxide in 100 ml methanol have been stirred at room temperature. After 2,5 hours HPLC showed total conversion of the starting material. Subsequently the solvent was evaporated at room temperature and the crystalline residue was stirred with diethylether. The crystals were filtered off and dried at 50°C under vacuum to yield 6,3 g of the title compound as a light yellow solid (Mp > 200°C, decomposition).
HPLC-MS: HPLC-column Kinetex XB C18 1 ,7m (50 x 2,1 mm); eluent: acetonitrile / water + 0.1 % TFA (5 gradient from 5:95 to 100 : 0 in 1.5 min at 60°C, flow gradient from 0.8 to 1.0 ml/min in 1.5 min). MS: Quadrupol Electrospray Ionisation, 80 V (positive mode).
M++H=239.9 (Rt=0.797min)
Example 2 - 1 -(5, 6-dimethyl-3-pyridyl)-4,4-difluoro-3, 3-dimethyl-isoquinoline
Figure imgf000023_0001
2,9 g (1 1 ,8 mmol) (4,4-Difluoro-3,3-dimethyl-isoquinoline-1-carbonyl)oxylithium and 2,0 g (10,75 mmol) 5-bromo-2, 3-dimethyl-pyridine in 50 ml toluene/N-methyl-pyrrolidone 3:2 where heated at 70°C upon stirring and a light stream of argon was passed over this mixture. Subsequently 0,231 g (1 ,6 mmol) copper(l)bromide and 0,145 g (0,18 mmol) Pd(dppf)Ch x CH2CI2 ([1 ,1 bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane) were added and the mixture was heated to reflux (122°C) over night.
Afterwards the volatiles were evaporated and the residue was taken up in methyl-t-butylether This heterogenous mixture was put on top of a short silica column which was eluted with me- thyl-t-butylether. The combined fractions were extracted with diluted ammonia solution and lithi- urn chloride solution. The volatiles were evaporated to yield 3,2 g (purity (HPLC) 86 %, yield 85 %) of the title compound as a brown oil, which crystallized upon standing.
Figure imgf000023_0002
HPLC-MS: HPLC-column Kinetex XB C18 1 ,7m (50 x 2,1 mm); eluent: acetonitrile / water + 0.1 % TFA (5 gradient from 5:95 to 100 : 0 in 1.5 min at 60°C, flow gradient from 0.8 to 1.0 ml/min in 1.5 min). MS: Quadrupol Electrospray Ionisation, 80 V (positive mode).
M++H=301 (Rt=0.889 min)
Example 3 - 1-[6-(Difluoromethyl)-5-methyl-3-pyridyl]-4,4-difluoro-3, 3-dimethyl-isoquinoline
Figure imgf000024_0001
2,43 g (9,9 mmol) (4,4-Difluoro-3,3-dimethyl-isoquinoline-1-carbonyl)oxylithium and 2,0 g (10,75 mmol) 5-bromo-2, 3-dimethyl-pyridine in 50 ml toluene/N-methyl-pyrrolidone 3:2 where heated at 70°C upon stirring and a light stream of argon was passed over this mixture. Subsequently 0,194 g (1 ,35 mmol) copper(l)bromide and 0,122 g (0,15 mmol) Pd(dppf)Cl2 x CH2CI2 ([1 ,1 bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane) were added and the mixture was heated to reflux (122°C) over night.
Afterwards the volatiles were evaporated and the residue was taken up in methyl-t-butylether This heterogenous mixture was put on top of a short silica column which was eluted with me- thyl-t-butylether. The combined fractions were extracted with diluted ammonia solution and lithi- um chloride solution. The volatiles were evaporated and the residue was purified via column chromatographie with heptane/methyl-t-butylether-mixtures to yield 2 g (5,9 mmol; yield 68 %) of the title compound as a light brown oil.
1H-NMR (CDCI3, d in ppm):
8,65 (s, 1 H); 7,87 (d, 1 H); 7,83 (s, 1 H); 7,67 (t, 1 H); 7,55 (t, 1 H); 7,25, (d, 1 H); 6,75 (t, 1 H); 2,58 (s, 3H); 1 ,4 (s, 6H)
HPLC-MS: HPLC-column Kinetex XB C18 1 ,7m (50 x 2,1 mm); eluent: acetonitrile / water +
0.1 % TFA (5 gradient from 5:95 to 100 : 0 in 1.5 min at 60°C, flow gradient from 0.8 to 1.0 ml/min in 1.5 min). MS: Quadrupol Electrospray Ionisation, 80 V (positive mode).
M++H=337 (Rt=1 ,243 min)
Example 4 - Ethyl 4,4-difluoro-3,3-dimethyl-isoquinoline-1-carboxylate
Figure imgf000024_0002
79,6 g (493 mmol) Triethylamine x 3 hydrogen fluoride (NEt3 x 3 HF) were added to 40 g (purity 80 %, 82 mmol) ethyl 4,4-dibromo-3,3-dimethyl-isoquinoline-1-carboxylate in 100 ml acetonitrile. The mixture was heated to reflux for 2 hours, when HPLC showed completion of the reaction. Subsequently the reaction mixture was cooled to room temperature and cautiously poured onto ice cold 20 % NaOH-solution. The aqueous layer was extracted twice with ethylacetate and the combined organic layers were extracted with brine. Afterwards the organic phase was dried over sodium sulfate and the volatiles were evaporated to yield 12 g (55 %) of the title compound ethyl 4,4-difluoro-3,3-dimethyl-isoquinoline-1-carboxylate as brown oil. 1H-NMR (CDCIs, d in ppm):
7,75 (2d, 2H); 7,65 (2t, 2H); 4,45 (q, 2H); 1 ,4 (m, 9H)
HPLC-MS: HPLC-column Kinetex XB C18 1 ,7m (50 x 2,1 mm); eluent: acetonitrile / water + 0.1 % TFA (5 gradient from 5:95 to 100 : 0 in 1.5 min at 60°C, flow gradient from 0.8 to 1.0 ml/min in 1.5 min). MS: Quadrupol Electrospray Ionisation, 80 V (positive mode).
Rt = 1 ,176 min, M++H=268
Example 5- Ethyl 3,3-dimethyl-4H-isoquinoline-1-carboxylate
Figure imgf000025_0001
At 15°C a solution of 380 g (2,53 mol) 2-methyl-1 -phenyl-propan-2 -ol and 426 g (4,3 mol) ethyl cyanoformate in 500 ml cyclohexane has been added to a mixture of 500 ml cyclohexane and 1899 g (19 mol) concentrated sulfuric acid upon stirring. After ca. 15 min the reaction mixture was poured onto an ice/water mixture and cautiously basified upon addition of concentrated NaOH-solution. The phases were separated and the aqeous layer was extracted twice with me- thyl-t-butylether. The combined organic phases were dried over sodium sulfate and ant volatiles were evaporated to yield 584 g (99 %) ethyl 3,3-dimethyl-4H-isoquinoline-1-carboxylate as a yellow oil.
1H-NMR (CDCIs, d in ppm):
7,55 (d, 1 H); 7,4 (t, 1 H); 7,3 (t, 1 H); 7,18 (d, 1 H); 4,45 (q, 2H); 2,75 (s, 2H); 1 ,4 (t, 3H); 1 ,28 (s, 6H)
Example 6 - Ethyl 4,4-dibromo-3,3-dimethyl-isoquinoline-1-carboxylate
Figure imgf000025_0002
20 g (86 mmol) ethyl 3,3-dimethyl-4H-isoquinoline-1-carboxylate, 33,8 g (190 mmol) N-bromo succinimide and 2,8 g azo-bis-isobutyronitrile (17 mmol) in 250 ml chloroform were heated to reflux upon stirring. After ca. 60 min HPLC showed completion of the reaction. Subsequently the reaction mixture was cooled to room temperature and diluted with 200 ml heptane. Afterwards the precipitated solid was filtered off and the mother liquor was evaporated to yield 40 g (purity 80 % (HPLC), yield 95 %) of the title compound ethyl 4,4-dibromo-3,3-dimethyl-isoquinoline-1- carboxylate, which was subsequently used as crude product.
HPLC-MS: HPLC-column Kinetex XB C18 1 ,7m (50 x 2,1 mm); eluent: acetonitrile / water + 0.1 % TFA (5 gradient from 5:95 to 100 : 0 in 1.5 min at 60°C, flow gradient from 0.8 to 1.0 ml/min in 1.5 min). MS: Quadrupol Electrospray Ionisation, 80 V (positive mode).
Rt = 1 ,034 min, M++H=245,9 (title compound, hydrolyzed to carbonyl compound upon meas- urement of HPLC-MS); Rt=1 ,275, M++H=389,8 (title compound ethyl 4,4-dibromo-3,3-dimethyl- isoquinoline-1 -carboxylate)
Example 7 - Ethyl 4, 4-difluoro-3,3-dimethyl-isoquinoline-1 -carboxylate
Figure imgf000026_0001
79,6 g (493 mmol) Triethylamine x 3 hydrogen fluoride (NEt3 x 3 HF) were added to 40 g (purity 80 %, 82 mmol) ethyl 4, 4-dibromo-3,3-dimethyl-isoquinoline-1 -carboxylate in 100 ml acetonitrile. The mixture was heated to reflux for 2 hours, when HPLC showed completion of the reaction. Subsequently the reaction mixture was cooled to room temperature and cautiously poured onto ice cold 20 % NaOH-solution. The aqueous layer was extracted twice with ethylacetate and the combined organic layers were extracted with brine. Afterwards the organic phase was dried over sodium sulfate and the volatiles were evaporated to yield 12 g (55 %) of the title compound ethyl 4, 4-difluoro-3,3-dimethyl-isoquinoline-1 -carboxylate as brown oil.
1H-NMR (CDCIs, d in ppm):
7,75 (2d, 2H); 7,65 (2t, 2H); 4,45 (q, 2H); 1 ,4 (m, 9H)
HPLC-MS: HPLC-column Kinetex XB C18 1 ,7m (50 x 2,1 mm); eluent: acetonitrile / water +
0.1 % TFA (5 gradient from 5:95 to 100 : 0 in 1.5 min at 60°C, flow gradient from 0.8 to 1.0 ml/min in 1.5 min). MS: Quadrupol Electrospray Ionisation, 80 V (positive mode).
Rt = 1 ,176 min, M++H=268
Example 8 - Bromination of 2,3-dimethylpyridine with DBDMH
To a stirred solution of 2,3-dimethylpyridine (1 Og, 0.09mol) in oleum 65% (30mL) at 10°C DBDMH (14.5g, 0,05mol) was added. There after the exothermic reactions started. The reaction mixture was then heated at 105°C for 2h. After cooling to room temperature, the mixture was poured onto ice (150g) and the ph adjusted to 12 with aqueous sodium hydroxide solution. The product was extracted into MTBE (3x100mL), the organic phases were dried with MgS04 and evaporated under reduced pressure to give 5-bromo-2,3-dimethylpyridine as yellow oil (. Purity acc. to GC 87.3%; yield: 83.3%.
Example 9 - Bromination of 2,3-dimethylpyridine with DBDMH
To a stirred solution of 2,3-dimethylpyridine (20g, 0.185mol) in oleum 65% (60mL) at 10°C DBDMH (31.7g, 0,11 mol) was added. There after the exothermic reactions started. The reaction mixture was then heated at 105°C for 2h. After cooling to room temperature, the mixture was poured onto ice (250g) and the ph adjusted to 12 with aqueous sodium hydroxide solution. The product was extracted into MTBE (3x100ml_), the organic phases were dried with MgS04 and evaporated under reduced pressure to give 5-bromo-2,3-dimethylpyridine as yellow oil (34.3g). Purity acc. to GC 87.0%; yield: 86.7%.
Example 10 - Bromination of 2,3-dimethylpyridine with DBDMH
To a stirred solution of 2,3-dimethylpyridine (20g, 0.185mol) in oleum 65% (60ml_) at 10°C DBDMH (31.7g, 0,11 mol) was added. There after the exothermic reactions started. The reaction mixture was then heated at 105°C for 2h. After cooling to room temperature, the mixture was poured onto ice (250g) and the ph adjusted to 12 with aqueous sodium hydroxide solution. The product was extracted into MTBE (3x100ml_), the organic phases were dried with MgS04 and evaporated under reduced pressure to give 5-bromo-2,3-dimethylpyridine as yellow oil (34.3g). Purity acc. to GC 87.0%; yield: 86.7%.
Example 11- Dichlorination of 5-bromo-2,3-dimethylpyridine
To a stirred solution of 5-bromo-2,3-dimethylpyridine (100g, 0.54mol) in acetic acid (150ml_) and l OOOmL chlorobenzene at 25°C trichloroisocyanuric acid (93. Og, 0.4mol) was added. The reac- tion mixture was then heated at 125°C for 3h. After cooling to room temperature, the mixture was poured onto ice (300g) and the ph adjusted to 12 with aqueous sodium hydroxide solution. The product was extracted into ethyl acetate (3x200ml_), the organic phases were dried with MgS04 and evaporated under reduced pressure to give 5-bromo-2-(dichloromethyl)-3-methyl- pyridine as brown oil (139.3g). Purity acc. to HPLC 57.3%; yield: 58.2%.
1H-NMR (CDCIs): 2.6ppm (s, 3H, CH3); 6.8ppm (s, 1 H, CHC ); 7.7ppm (s, 1 H, CH); 8.5ppm (s, 1 H, CH)
Example 12 - Dichlorination of 5-bromo-2,3-dimethylpyridine
To a stirred solution of 5-bromo-2,3-dimethylpyridine (100g, 0.54mol) in acetic acid (lOOOmL) at 25°C trichloroisocyanuric acid (93. Og, 0.4mol) was added. The reaction mixture was then heat- ed at 75°C for 12h. After cooling to room temperature, the mixture was filtrated. The solvent of the filtrate was evaporated under reduced pressure (70°C, 40mbar). Thereafter, the product was solved in l OOOmL ethyl acetetate and washed two times with aqueous sodium hydroxide solution. The organic phases were dried with MgS04 and evaporated under reduced pressure to give 5-bromo-2-(dichloromethyl)-3-methyl-pyridine as white solid (130.0g). Purity acc. to GC 88.0%; yield: 84.0%.
Example 13 - Fluorination of 5-bromo-2-(dichloromethyl)-3-methyl-pyridine
To a stirred solution of 5-bromo-2-(dichloromethyl)-3-methyl-pyridine (20g, 0.078mol) in triethyl- amine (23.8g, 0.24mol) at 60°C triethylamine -3HF-complex (63.2g, 0.39mol) was added. The reaction mixture was then heated at 115°C for 21 h. After cooling to room temperature, water (20ml_) and CH2CI2 (20ml_) were added to the reaction mixture and the ph adjusted to 9 with aqueous potassium hydroxide solution. The product was extracted into CH2CI2 (3x100ml_), the organic phases were extraction with brine (1x 100ml_) dried with Na2S04 and evaporated under reduced pressure to give 5-bromo-2-(difluoromethyl)-3-methyl-pyridine as yellow oil (20.4g). Purity acc. to GC 71.7%; yield: 84.5%.
1H-NMR (CDCI3): 2.5ppm (s, 3H, CH3); 6.65ppm (t, 1 H, CHF2); 7.75ppm (s, 1 H, CH); 8.5ppm (s, 1 H, CH).
Example 14 - Fluorination of 5-bromo-2-(dichloromethyl)-3-methyl-pyridine
To a stirred solution of 5-bromo-2-(dichloromethyl)-3-methyl-pyridine (5g, 0.0196mol) in triethyl- amine (6.0g, 0.06mol) and (0.7g, 0.01 mol) DMF at 60°C triethylamine -3HF-complex (12.6g, 0.08mol) was added. The reaction mixture was then heated at 1 15°C for 18h. After cooling to room temperature, water (20ml_) and toluene (20ml_) were added to the reaction mixture and the ph adjusted to 9 with aqueous potassium hydroxide solution. The product was extracted into toluene (3x100ml_), the organic phases were extraction with brine (1x 100ml_) and evaporated under reduced pressure to give 5-bromo-2-(difluoromethyl)-3-methyl-pyridine as yellow oil (4.3g). Purity acc. to GC 78.4%; yield: 83.2%.
Example 15 - Fluorination of 5-bromo-2-(dichloromethyl)-3-methyl-pyridine
From a stirred suspension of KF (88.8g, 1.53mol) and (21.3g, 0.11 mol) benzyltrimethyl ammo- nium chloride in sulfolane 775g (6.45mol) sulfolane 169g was distilled off at 120°C and 5mbar. After cooling to 25°C and pressure release 5-bromo-2-(dichloromethyl)-3-methyl-pyridine 97.4% purity (100g, 0.0196mol) was added to the suspension. The reaction mixture was then heated at 130°C for 12h. Therafter, the product was distilled off at 130° in a pressure range of 100-5mbar. Three fraction were obtained: 1. Fraction 66.5g contained 77.6% (quant. GC) product, 2. Frac- tion 87.5g contained 16.4% (quant. GC) and a 3. Fraction 236.6g contained 0.08% (quant. GC) product; yield: 75.8%.
Example 16 - Dichlorination of 5-bromo-2,3-dimethylpyridine
To a stirred solution of 5-bromo-2,3-dimethylpyridine (250g, 1 ,34mol) in acetic acid (2500ml_) trichloroisocyanuric acid (234, 2g, 1 ,01 mol) was added at 25°C. Afterwards the reaction mixture was heated at 75°C for 12h upon stirring. After cooling to room temperature, the mixture was filtrated. The solvent of the filtrate was evaporated under reduced pressure (70°C, 40mbar). Thereafter, the residue was solved in 1000 ml ethyl acetate and washed three times with aque- ous 10 % sodium hydroxide solution. The organic phase was dried with Na2S04 and evaporated under reduced pressure to give 5-bromo-2-(dichloromethyl)-3-methyl-pyridine as a yellow solid (342g).
This reaction was carried out four times as described above using a total of 1 kg (5,37 mol) 5- bromo-2,3-dimethylpyridin. The resulting crude products were dissolved in dichloromethane and combined and the solvent was distilled off under vacuum. The residue was taken up in 500 ml of n-heptane and the mixture was stirred at 60°C until all solids had dissolved. Afterwards the mixture was allowed to cool down to room temperature. The title compound crystallized out and stirring was continued over night. Afterwards the mixture was cooled with an ice/water-bath and the precipitated crystals were filtered off to yield 1053 g (purity 97 % (GC), 4,13 mol, 75 % of theory) of 5-bromo-2-(dichloromethyl)-3-methyl-pyridine (mp = 61 °C). The mother liquor was evaporated to yield further 283 g (purity 62 % (GC)) of the title compound.
1H-NMR (CDCIs): 2.6ppm (s, 3H, CH3); 6.8ppm (s, 1 H, CHC ); 7.7ppm (s, 1 H, CH); 8.5ppm (s, 1 H, CH
Example 17 - 1 -(5, 6-dimethyl-3-pyridyl)-4,4-difluoro-3, 3-dimethyl-isoquinoline
To a suspension of 5-brom-1 ,3-dimethylpyridin (7,805g; 40,693mmol) and (4,4-difluoro-3,3- dimethyl-isoquinoline-1-carbonyl)oxylithium (9,976g; 40,693mmol) in 100 mL of dry N-methyl- pyrrolidone under N2 was added CuBr (875, 6mg; 6,104mmol), Pd(dppf)Cl2 (664, 6mg;
0,814mmol) and 902, 4mg (1 ,628mmol) dppf x CH2CI2 ([1 , 1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane). The reaction mixture was heated to 150°C and stirred for 3h. After the reaction was complete (HPLC) the mixture was cooled to 10°C.
Subsequently 100 ml of 5 molar hydrochloric acid was slowly added via dropping funnel. The aqueous layer was extracted twice with 100 ml n-heptane each and the organic layers were discarded.
300 ml n-Heptane was added to the aqueous layer and the solution was basified with 50 % so- dium hydroxide solution to pH = 10 at 25°C. A solid residue precipitated which was filtered off, washed with n-heptane (3x50 ml) and discarded. Afterwards the layers were separated and the aqueous layer was extracted with n-heptane (2 x 300ml_). The combined organic layers were dried over Na2S04, the drying agent was filtered off and the volatiles were evaporated to obtain 1 1 ,1 g of the title compound as orange crystals.
Recrystallisation from heptane yielded 8,05g beige crystals (purity 93,5 % (quant. 1H-NMR), yield 61 ,6%). Purification via column chromatography with cyclohexane/ethyl acetate mixtures afforded 1 -(5, 6-dimethyl-3-pyridyl)-4,4-difluoro-3, 3-dimethyl-isoquinoline as white crystals, mp = 104 - 105°C.
1H-NMR (CDCI3, d in ppm):
8,52 (s, 1 H); 7,83 (d, 1 H); 7,67 (s, 1 H); 7,62 (t, 1 H); 7,52, (t, 1 H); 7,3 (d, 1 H); 2,55 (s, 3H); 2,35 (s, 3H); 1 ,4 (s, 6H)
Example 18 - 1-[6-(Difluoromethyl)-5-methyl-3-pyridyl]-4,4-difluoro-3, 3-dimethyl-isoquinoline
To a suspension of 5-bromo-2-(difluoromethyl)-3-methyl-pyridine (36,59 g; 163,16 mmol) and (4,4-difluoro-3,3-dimethyl-isoquinoline-1-carbonyl)oxylithium (40,00 g; 163,165 mmol) in 480 ml of dry N-methylpyrrolidone under N2 were added CuBr (3,51 g; 24,48 mmol), Pd(dppf)Ch x CH2CI2 (2,67 g; 3,26 mmol) and 3,62 g (6,53 mmol) dppf ([1 ,T- bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane). The reaction mixture was heated at 150°C and stirred for 8h. After the reaction was complete (HPLC) the mixture was cooled to 10°C and subsequently added to a mixture of 300 ml water and 500 ml n-heptane. Afterwards the mixture was basified with 50 ml of 25% ammonia-solution at 25°C (pH 1 1-12) and filtered over Celite. The Celite was washed with n-heptane and the aqueous ammonia layer was separated from the n-hexane layer.
The combined heptane phases were washed twice with 250 ml of 5 % hydrochloric acid. After the first extraction some insoluble material precipitated which was filtered off and discarded.
The organic layer was dried over Na2S04, filtered and evaporated to obtain 40,5 g of the title compound (purity ~ 80 % (quant. -HPLC)).
This product was dissolved in 400 ml of n-heptane. The heptane-phase was extracted twice with 250 ml of 15 % HCI and the heptane phase was discarded afterwards.
The combined HCI-layers were treated three times with 500ml of dichloromethane to extract the product into the organic phase.
Thereafter the combined dichloromethane layers were stirred for 1 h with 300 ml of 20%
Na2C03-solution.
The phases were separated and the organic layer was dried over Na2S04, filtered and evapo- rated to obtain 33,3 g 1-[6-(Difluoromethyl)-5-methyl-3-pyridyl]-4,4-difluoro-3, 3-dimethyl- isoquinoline (purity 92,5% (quant. 1H-NMR), yield 56 %).
The title compound could be further purified via column chromatography with cyclohexane/ethyl acetate mixtures.
1H-NMR (CDCIs, d in ppm):
8,65 (s, 1 H); 7,87 (d, 1 H); 7,83 (s, 1 H); 7,67 (t, 1 H); 7,55 (t, 1 H); 7,25, (d, 1 H); 6,75 (t, 1 H); 2,58 (s, 3H); 1 ,4 (s, 6H)

Claims

Claims:
1. A process for preparing compounds of formula I,
Figure imgf000031_0001
wherein
R1 is in each case independently selected from hydrogen, halogen, Ci-C6-alkyl and C1-C6- halogenalkyl;
R2 is in each case independently selected from hydrogen, halogen, Ci-C6-alkyl and C1-C6- halogenalkyl;
R3, R4 are independently selected from Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6- halogenalkyl, C2-C6-halogenalkenyl and C2-C6-halogenalkynyl;
R5 is halogen;
R6 is halogen;
o is 0, 1 , 2 or 3; and
R78 are independently selected from halogen, Ci-C6-alkyl, Ci-C6-alkoxy, Ci-C6-halogenalkyl and Ci-C6-halogenalkoxy;
R9 CHs, CHF2 and CH2F;
R10 is independently selected from H, halogen, 0(R95), Ci-C6-alkyl and Ci-C6-halogenalkyl; wherein
R95 is Ci-C6-alkyl, Ci-C6-halogenalkyl; comprising a reaction of the compound of the formula II O
X
II
Figure imgf000032_0001
,78
R o
R3, R4, R5, R6 R78 and o are as defined above and
X is a metal ion;
with the compound of the formula III
III
Figure imgf000032_0002
in which R1, R2, R9 and R10 are as defined above in the presence of a catalyst.
2. The process according to claim 1 , wherein the catalyst comprises three components: a Cu source, a Pd source and a ligand.
3. The process according to claim 1 or 2 wherein the Pd source is selected from the group consisting of: Pd(OAc)2, Pd(ll)Cl2, Palladium(ll)-1 ,2-bis(diphenylphosphino)ethan dichloride, Palladium(ll)- 1 ,3-Bis(diphenylphosphino)propan dichloride, Palladium(ll)- 1 ,4- Bis(diphenylphosphino)butan dichloride, Palladium(ll)-1 ,T-Bis(diphenylphosphino)ferrocene dichloride, Palladium(0)-tetrakis(triphenylphosphin, Palladium(ll)- bis(triphenylphosphin)dichloride, Pd(P(t-Bu)3)2, Pd(acac)2, Pd(iPr)2Ph2, Pd(P(t-Bu)2Ph)2Cl2, Pd(dba)2, Pdl2, PdBr2, or Pd(TFA)2.
4. The process according to any one of claims 1 to 3, wherein the ligand is mono- or bidentate phosphorus-containing ligand.
5. The process according to any one of claims 1 to 4, wherein the Cu salt is selected from the group consisting of: group Cul, CuBr, CuCI, CuF, CU2O, Cu(OAc), Cu2(C03)(0H)2,CuS04, CuO, Cu(Otriflate)2, Cu(OAc)2.
6. The process according to any one of claims 1 to 5, wherein X is selected from the group consisting of: Li, NA, K and Cs.
7. The process according to any one of claims 1 to 6, wherein the compound of the formula II is provided by a reaction of the compound of the formula IV IV
Figure imgf000033_0001
R3, R4, R5, R6 R78 and o are as defined above and
Y is selected from Ci-C6-alkyl, Ci-C6-halogenalkyl, phenyl and benzyl, wherein phenyl and benzyl are unsubstituted or substituted by CN, NO2, halogen, Ci-C6-alkyl, C1-C6- halogenalkyl or Ci-C6-alkoxy;
with a metal hydrodixe to provide the compound of the formula II.
8. The process as claimed in any one of claims 1 to 7, wherein the compound of the formula IV is provided by
(i) a reaction of the compound of the formula V
V
Figure imgf000033_0002
wherein
R3, R4 are independently selected from Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6- halogenalkyl, C2-C6-halogenalkenyl and C2-C6-halogenalkynyl;
R78 is independently selected from halogen, Ci-C6-alkyl, Ci-C6-alkoxy, C1-C6- halogenalkyl and Ci-C6-halogenalkoxy;
o is 0, 1 , 2 or 3;
with a compound of the formula VI
Figure imgf000033_0003
Y is selected from Ci-C6-alkyl, Ci-C6-halogenalkyl, phenyl and benzyl, wherein phenyl and benzyl are unsubstituted or substituted by CN, NO2, halogen, Ci-C6-alkyl, C1- C6-halogenalkyl or Ci-C6-alkoxy; in the presence of sulphuric acid to provide a compound of the formula VII VII
Figure imgf000034_0001
wherein R3, R4, R78, o and Y are as defined above; and
(i) a chlorination reaction in the presence of a chlorination agent or bromination reaction in the presence of a bromination agent; and
(ii) a subsequent fluorination reaction in the presence of a fluorination agent.
9. The process according to any one of claims 1 to 8, wherein the the chlorinating agent is se- lected from the group consisting of N-chlorosuccinimide (NCS), sulfuryl chloride, Ch, tri- chloroisocyanuric acid, 1 ,3-dichloro-5,5-dimethylhydantoin.
10. The process according to any one of claims 1 to 9, wherein the bromination agent is select- ed from the group consisting of N-bromosuccinimide (NBS), 1 ,3-dibromo-5,5- dimethylhydantoin (DBDMH) or a system consisting of HBr/hhC^.
1 1. The process according to any one of claims 1 to 10, wherein the compound of the formula III is provided by following steps:
(i) a selective bromination of a compound of the formula VIII
VIII
Figure imgf000034_0002
wherein
R1 is in each case independently selected from hydrogen, halogen, Ci-C6-alkyl and C1-C6- halogenalkyl;
R2 is in each case independently selected from hydrogen, halogen, Ci-C6-alkyl and C1-C6- halogenalkyl;
R10 is in each case independently selected from H, halogen, 0(R95), Ci-C6-alkyl and C1-C6- halogenalkyl; wherein
R95 is Ci-C6-alkyl, Ci-C6-halogenalkyl;
in a reaction with a brominating agent in the presence of oleum 65% to provide a compound of the formula IMA MIA
Figure imgf000035_0001
wherein R1, R2 and R10 are as defined above; and
(ii) an optionally selective chlorination of a compound of the formula IMA with a chlorinating agent to provide a compound of the formula NIB or MIC
Figure imgf000035_0003
wherein R1, R2 and R10 are as defined above; and
(iii) followed by an optionally selective fluorination of the compound of the formula NIB or MIC using a fluorination agent to provide a compound of the formula HID or HIE
Figure imgf000035_0002
wherein R1, R2 and R10 are as defined above.
12. The process according to claim 11 , wherein the brominating agent is 1 ,3-dibromo-5,5- dimethylhydantoin (DBDMH).
13. The process to claim 11 or 12, wherein the step (ii) is carried out in an inert solvent.
14. The process according to any one of claims 11 to 13 wherein the step (ii) is carried out in an inert solvent selected from the group consisting of aromatic hydrocarbons and halohy- drocarbons such as benzene, toluene, xylenes, cumene, chlorobenzene and tert- butylbenzene, cyclic or acyclic ethers such as diethyl ether, diisopropyl ether, tert-butyl me- thyl ether (MTBE), tert-butyl ethyl ether, tetrahydrofuran (THF) or dioxane, nitriles such as acetonitrile and propionitrile, aliphatic halohydrocarbons such as dichloromethane, dichloro- ethane, trichloromethane, carboxylic acids such as acetic acid, propionic acid, chloroacetic acid, dichloroacetic acid, trichloroactic acid or trifluoro acetic acid and mixtures thereof.
15. The process according to any one of claims 1 1 to 14, wherein the step (ii) is carried out in the presence of an organic carboxylic acid and in the absence of an alkali metal salt of said carboxylic acid.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11839214B2 (en) 2017-12-15 2023-12-12 Basf Se Fungicidal mixture comprising substituted pyridines

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH675875A5 (en) 1988-10-13 1990-11-15 Lonza Ag Cyano:formate ester prodn. from corresp. chloro:formate - by reaction with hydrogen cyanide in presence of base, intermediates for pharmaceuticals and plant protection agents
WO2008090193A2 (en) 2007-01-25 2008-07-31 Boehringer Ingelheim International Gmbh Method for producing betamimetics
EP2223919A1 (en) * 2007-12-26 2010-09-01 Nippon Soda Co., Ltd. Nitrogen-containing heterocyclic compound and bactericide for agricultural and horticultural use
DE102014008070A1 (en) 2014-05-30 2015-12-03 Johanna Martens Cyanoformyloxybenzoesäuren, process for their preparation and their use as medicaments
WO2016038628A2 (en) 2014-09-09 2016-03-17 Reddy G Pratap A process for preparing olodaterol and intermediates thereof
WO2017016915A1 (en) * 2015-07-24 2017-02-02 Basf Se Pyridine compounds useful for combating phytopathogenic fungi
WO2017059191A1 (en) 2015-09-30 2017-04-06 Quartet Medicine, Inc. Heteroaryl derivatives as sepiapterin reductase inhibitors

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH675875A5 (en) 1988-10-13 1990-11-15 Lonza Ag Cyano:formate ester prodn. from corresp. chloro:formate - by reaction with hydrogen cyanide in presence of base, intermediates for pharmaceuticals and plant protection agents
WO2008090193A2 (en) 2007-01-25 2008-07-31 Boehringer Ingelheim International Gmbh Method for producing betamimetics
EP2223919A1 (en) * 2007-12-26 2010-09-01 Nippon Soda Co., Ltd. Nitrogen-containing heterocyclic compound and bactericide for agricultural and horticultural use
DE102014008070A1 (en) 2014-05-30 2015-12-03 Johanna Martens Cyanoformyloxybenzoesäuren, process for their preparation and their use as medicaments
WO2016038628A2 (en) 2014-09-09 2016-03-17 Reddy G Pratap A process for preparing olodaterol and intermediates thereof
WO2017016915A1 (en) * 2015-07-24 2017-02-02 Basf Se Pyridine compounds useful for combating phytopathogenic fungi
WO2017059191A1 (en) 2015-09-30 2017-04-06 Quartet Medicine, Inc. Heteroaryl derivatives as sepiapterin reductase inhibitors

Non-Patent Citations (28)

* Cited by examiner, † Cited by third party
Title
"Angewandte Chemie", vol. 53, 2014, pages: 6439 - 6442
ANORGANISCHE UND ALLGEMEINE CHEMIE, vol. 510, 1984, pages 136 - 42
BIOORGANIC & MEDICINAL CHEMISTRY, vol. 23, no. 24, 2015, pages 7661 - 7670
BULLETIN DE LA SOCIETE CHIMIQUE DE FRANCE, vol. 5, 1985, pages 787 - 93
CHEMICAL COMMUNICATIONS, vol. 16, 2006, pages 1775 - 1777
CHEMICAL COMMUNICATIONS, vol. 51, no. 30, 2015, pages 6637 - 6639
CHEMICAL COMMUNICATIONS, vol. 52, no. 82, 2016, pages 12147 - 12150
CHEMISCHE BERICHTE, vol. 114, no. 12, 1981, pages 3813 - 30
CHEMISTRY LETTERS, vol. 37, no. 7, 2008, pages 800 - 801
COMPTES RENDUS DES SEANCES DE I'ACADEMIE DES SCIENCES, SERIE C: SCIENCES CHIMIQUES, vol. 283, no. 3, 1976, pages 75 - 8
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 14, no. 2, 1979, pages 165 - 70
HALEY CHRISTOPHER K ET AL: "Development of a palladium-catalyzed decarboxylative cross-coupling of (2-azaaryl)carboxylates with aryl halides", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 69, no. 27, 27 March 2013 (2013-03-27), pages 5732 - 5736, XP028558128, ISSN: 0040-4020, DOI: 10.1016/J.TET.2013.03.085 *
HETEROATOM CHEMISTRY, vol. 26, no. 4, 2015, pages 249 - 256
JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, vol. 43, no. 14, 2000, pages 1321 - 1326
JOURNAL OF MEDICINAL CHEMISTRY, vol. 14, no. 2, 1979, pages 165 - 70
JOURNAL OF ORGANIC CHEMISTRY, vol. 41, no. 21, 1976, pages 3486 - 7
JOURNAL OF ORGANIC CHEMISTRY, vol. 45, no. 19, 1980, pages 3925 - 7
JOURNAL OF ORGANOMETALLIC CHEMISTRY, vol. 328, no. 1-2, pages 81 - 6,1987
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 110, no. 23, 1988, pages 7737 - 45
JOURNAL OF THE INDIAN CHEMICAL SOCIETY, vol. 87, no. 5, 2010, pages 595 - 600
ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 2, no. 13, 2004, pages 1921 - 1933
ORGANIC CHEMISTRY, vol. 47, no. 7, 1982, pages 1193 - 6
RUSSIAN CHEMICAL BULLETIN, vol. 55, no. 1, 2006, pages 123 - 136
TETRAHEDRON LETTERS, no. 27, 1979, pages 2517 - 20
TETRAHEDRON LETTERS, vol. 27, 1979, pages 2517 - 20
TETRAHEDRON LETTERS, vol. 50, no. 20, 2009, pages 2320 - 2321
TETRAHEDRON, vol. 42, no. 11, 1986, pages 2931 - 5
TETRAHEDRON, vol. 63, no. 39, 2007, pages 9724 - 9740

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11839214B2 (en) 2017-12-15 2023-12-12 Basf Se Fungicidal mixture comprising substituted pyridines

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