Bromination of pyridine derivatives

Abstract

The present invention relates to a process for the preparation of a pyridine derivative of formula (I).

Description

[0001] The present invention relates to a process for the preparation of pyridine derivatives of formula I:

[0002]

[0003] Bromination of analogous pyridine derivatives is known from US 20140194386 and WO 2008 / 070740. One of the disadvantages of the reactions described in the above mentioned documents is the use of bromine in the presence of fuming sulfuric acid.

[0004] It is known from Z. Chem 1988 28 2 50 to use 65% fuming sulfuric acid and Br2 for bromination. One of the disadvantages of using Br2 as brominating agent is that the reaction is very slow and requires high temperatures. Furthermore, the use of Br2 as brominating agent leads to a mixture of mono- and dibromo isomers which are often very difficult to purify.

[0005] It was therefore an object of the present invention to overcome the disadvantages of the known processes and to provide an improved, selective and more economic process which is equipment friendly.

[0006] It was found that pyridine derivatives of formula I can be obtained by reacting a compound of formula II with a brominating agent selected from the group consisting of e.g. N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) or a system consisting of HBr / H2O2 in the presence of 65% fuming sulfuric acid:

[0007]

[0008] wherein

[0009] R 1 is, in each case independently, selected from the group consisting of hydrogen, halogen, Ci-C6-alkyl and Ci-C6-haloalkyl;

[0010] R 2 is, in each case independently, selected from the group consisting of hydrogen and halogen;

[0011] R 10 is, in each case independently, selected from the group consisting of H, halogen, O(R 95 ), Ci-C6-alkyl and Ci-C6-haloalkyl; wherein

[0012] R 95 is Ci-C6-alkyl, Ci-C6-haloalkyl;

[0013]

[0014] wherein R 1 , R 2 and R 10 are as defined above.

[0015] The process according to the present application is very selective as it leads to the desired pyridines with low content of by-products, which is desirable from an economic point of view, and the process is suitable for large scale production.

[0016] Preferably, the brominating agent in the process according to the present application is selected from the group consisting of, for example, N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) or a system consisting of HBr / H2O2. Preferred brominating agents are NBS and DBDMH. The most preferred brominating agent is 1,3-dibromo-5,5-dimethylhydantoin (DBDMH).

[0017] Typically, the reaction time is in the range of 1 to 20 hours, preferably in the range of 2 to 15 hours, more preferably in the range of 3 to 10 hours, most preferably in the range of 3 to 5 hours.

[0018] Typically, the product will be extracted using an inert organic solvent.

[0019] "Inert organic solvent" means an organic solvent which does not undergo any significant reaction with the reactants or products under the reaction conditions of the process according to the present application.

[0020] In one embodiment, the inert organic solvent is selected from non-halogenated inert organic solvents; preferably non-halogenated aliphatic hydrocarbons, non-halogenated cycloaliphatic hydrocarbons, non-halogenated aromatic hydrocarbons, halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons, ethers, esters, ketones and any combination thereof.

[0021] Examples of suitable non-halogenated aliphatic hydrocarbons include pentane, hexane, heptane and the like. Preferably, saturated aliphatic hydrocarbons having 5 to 10 carbon atoms are used.

[0022] Examples of suitable non-halogenated cycloaliphatic hydrocarbons include cyclopentane, cyclohexane, cycloheptane and the like. Preferably, non-halogenated saturated cycloaliphatic hydrocarbons having 5 to 10 carbon atoms are used. Cyclohexane is particularly preferred.

[0023] Examples of suitable non-halogenated aromatic hydrocarbons include toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 2-propylbenzene (cymene), 2-isopropyltoluene (o-cymene), 3-isopropyltoluene (m-cymene), 4-isopropyltoluene (p-cymene), 1,3,5-trimethylbenzene (mesitylene) and the like. Preferably, toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 1,3,5-trimethylbenzene (mesitylene) and any combination thereof are used. Particularly preferred among the non-halogenated aromatic hydrocarbons are toluene, o-xylene, m-xylene, p-xylene and any combination thereof, with toluene being most preferred.

[0024] 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, and any combination thereof. Dichloromethane and 1,2-dichloroethane and any combination thereof are preferred.

[0025] Examples of suitable halogenated aromatic hydrocarbons include chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, a,a,a-trifluorotoluene (trifluoromethylbenzene) and the like, and any combination thereof.

[0026] 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, 2-methy!tetrahydrofuran and the like, and any combination thereof.

[0027] Examples of suitable esters include ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, tert-butyl acetate and the like, and any combination thereof.

[0028] 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.

[0029] After the extraction, the inert solvent is evaporated and the crude product is purified by distillation.

[0030] The bromination agent DBDMH is used in a molar ratio to the pyridine derivative of formula I, wherein R 1 = H and R 2 = H, which can vary widely and depends on the reaction conditions used, but is typically 0.40:1.1 - 1.5:1, preferably 0.40:1 - 1.2:1, more preferably 0.40:1 - 1.1 :1, even more preferably 0.50:1 - 1.0:1. In order to avoid side products, it is preferred to use less than 1 eq of the bromination agent compared to the pyridine. Thus, the molar ratio of the bromination agent DBDMH to the pyridine derivative of formula I, wherein R 1 = H and R 2 = H, is preferably 0.4 - 1.1, more preferably 0.4 - 0.9.

[0031] Preferably, the bromination of the compound of formula I, wherein R 1 = H and R 2 = H, is carried out. The preferred bromination agent is 1,3-dibromo-5,5-dimethylhydantoin (DBDMH). In this case, the bromination is preferably carried out without additional solvent.

[0032] In this case, the reaction temperature is preferably 0 - 150°C, in particular 80 - 125°C, and the reaction time is 2 - 10 hours, more preferably 2 - 5 hours. In this case, the reaction temperature is preferably 0 - 150°C, in particular 80 - 125°C, and the reaction time is 2 - 10 hours, more preferably 2 - 5 hours.

[0033] Preferably, the purification is distillation under reduced pressure (50-55 °C; 1.6-2.0 mbar).

[0034] The brominated pyridine obtained according to the process of the present application (step (i)) can be further converted to a 2,3-disubstituted pyridine compound of formula III:

[0035]

[0036] wherein

[0037] R 1 independently at each occurrence, is selected from the group consisting of hydrogen, halogen, Ci-C6-alkyl and Ci-C6-haloalkyl;

[0038] R 2 independently at each occurrence, is selected from the group consisting of hydrogen and halogen;

[0039] R 3 , R 4 are independently selected from the group consisting of Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-haloalkyl, C2-C6-haloalkenyl and C2-C6-haloalkynyl;

[0040] R 5 is halogen;

[0041] R 6 is halogen;

[0042] R 7 , R 8 together with the carbon atom to which they are bound form a ring A, wherein ring A is phenyl and wherein ring A is substituted with (R 78 )o, wherein

[0043] o is 0, 1, 2 or 3; and

[0044] R 78 are independently selected from the group consisting of halogen, Ci-C6-alkyl, Ci-C6-alkoxy, Ci-C6-haloalkyl and

[0045] Ci-C6-haloalkoxy;

[0046] R 10 independently at each occurrence, is selected from the group consisting of H, halogen, O(R 95 ), Ci-C6-alkyl and Ci-C6-haloalkyl; wherein

[0047] R 95 is Ci-C6-alkyl, Ci-C6-haloalkyl.

[0048] Accordingly, the present application further relates to a process comprising the following steps:

[0049] (i) providing a compound of formula I as described above;

[0050] (ii) reacting a compound of formula I with a compound of formula IV:

[0051]

[0052] wherein R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each as defined for formula III, and X is a metal ion.

[0053] Step (ii) is carried out in the presence of a catalyst.

[0054] According to one embodiment of the present application, the catalyst comprises: a Cu source, a Pd source and optionally a ligand.

[0055] When the reaction is carried out, the catalyst system (Pd + ligand) can be added together or separately at room temperature or at elevated temperature. The system can be prepared separately immediately prior to carrying out the reaction by combining the Pd salt and the ligand, or it can be synthesized beforehand or purchased in pure form or in solution. It is also possible to add the ligand and the palladium source directly to the batch (in situ process). As an alternative, the reaction can be carried out using the palladium source alone without the addition of an additional ligand.

[0056] The palladium catalysts used are optionally produced in situ from at least one palladium (II) salt or palladium (0) compound and the corresponding phosphine ligand. However, they can also be used directly as palladium (0) or palladium (II) compounds without reducing the initial catalytic activity.

[0057] According to one embodiment of the present application, the Pd source is selected from the group consisting of Pd(OAc)2, Pd(II)Cl2, 1,2-bis(diphenylphosphino)ethane palladium (II) dichloride, 1,3-bis(diphenylphosphino)propane palladium (II) dichloride, 1,4-bis(diphenylphosphino)butane palladium (II) dichloride, 1,1 '-bis(diphenylphosphino)ferrocene palladium (II) dichloride, tetrakis(triphenylphosphine) palladium (0), bis(triphenylphosphine) palladium (II) dichloride, Pd(P(t-Bu)3)2, Pd(acac)2, Pd(iPr)2Ph2, Pd(P(t-Bu)2Ph)2Cl2, Pd(dba)2, PdI2, PdBr2 or Pd(TFA)2.

[0058] According to one embodiment of the present application, the ligand is a mono- or bidentate phosphorus-containing ligand.

[0059] As mono-dentate phosphorus-containing ligand, the following are preferred:

[0060] monodentate phosphorus-containing ligand of the formula P:

[0061]

[0062] wherein

[0063] P', P", P'" are independently selected from the group consisting of unsubstituted or substituted C1-C6-alkyl, C3-C6-cycloalkyl, aryl and heteroaryl.

[0064] More preferably, the monodentate phosphorus-containing ligand is selected from the group consisting of triethylphosphine, tri-n-butylphosphine, tri-tert-butylphosphine, tribenzylphosphine, tri(cyclopentyl)phosphine, tri(cyclohexyl)phosphine, triphenylphosphine, tri(p-tolyl)phosphine, tri(m-tolyl)phosphine, tri(o-tolyl)phosphine, tri(p-methoxyphenyl)phosphine, tri(p-dimethylaminophenyl)phosphine, tri(sodium-m-sulfophenyl)phosphine, diphenyl(2-sulfophenyl)phosphine, tri(1-naphthyl)phosphine, di-tert-butyl-phenylphosphine, XPhos, SPhos, RuPhos and diphenyl-2-pyridylphosphine. Most preferred are triphenylphosphine, tri(p-tolyl)phosphine and tri(cyclohexyl)phosphine.

[0065] As bidentate phosphorus-containing ligand, the following are preferred: 2,2'-bis(diphenylphosphino)-1,1 '-binaphthyl (BINAP), 1,1 -bis(diphenylphosphino)methane (DPPM), 1,2-bis(diphenylphosphino)ethane (DPPE), 1,3-bis(diphenylphosphino)propane (DPPP), 1,4-bis(diphenylphosphino)butane (DPPB), 1,1 '-bis(diphenylphosphino)ferrocene (DPPF), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), 1,2-bis(di-tert-butylphosphinomethyl)benzene, 1,2-bis(di-tert-amylphosphinomethyl)benzene, 1,3-bis(diphenylphosphino)-2,2-dimethylpropane, 1,3-bis(diphenylphosphino)-2-methyl-2-butyl-propane and 1,2-bis(di-tert-butylphosphinomethyl)naphthalene. Most preferred are 1,2-bis(diphenylphosphino)ethane (DPPE), 1,3-bis(diphenylphosphino)propane (DPPP), 1,4-bis(diphenylphosphino)butane (DPPB and 1,1 '-bis(diphenylphosphino)ferrocene (DPPF).

[0066] The molar ratio of palladium to phosphine ligand should be 4:1 to 1 :100, preferably 1 :1 to 1 :5, particularly preferably 1 :1 to 1 :2.

[0067] When the reaction is carried out, the catalyst system (Pd + ligand) can be added together or separately at room temperature or at elevated temperature. The system can be prepared separately immediately prior to the reaction by combining the Pd salt and the ligand, or it can be purchased or synthesized in pure form or in solution. It is also possible to add the ligand and the palladium source directly to the batch (in situ process).

[0068] According to one embodiment of the present application, the Cu salt is selected from the group consisting of Cul, CuBr, CuCl, CuF, Cu2O, Cu(OAc), Cu2(C03)(OH)2, CuS04, CuO, Cu(Otriflate)2, Cu(OAc)2. Most preferred are Cul, CuCl, Cu2O, CuS04and CuO.

[0069] The molar ratio of palladium to copper salt should be 0.01 to 50, preferably 0.05 to 20, preferably 0.1 to 5.

[0070] Suitable organic solvents for the reaction are aprotic solvents, for example aromatic hydrocarbons such as benzene, toluene, xylene, cumene, chlorobenzene, dichlorobenzene, nitrobenzene 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, tetrahydrofuran (THF) or dioxane, cyclic or acyclic amides such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone or tetramethylurea, aliphatic esters such as ethyl acetate, butyl acetate or methyl propionate, cyclic or acyclic ketones such as cyclohexanone, acetone, 3-methylbutanone or 4-methylpentanone-2, aliphatic chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,2-trichloroethene, or aliphatic nitriles such as acetonitrile or propionitrile, and mixtures of the aforementioned solvents. Preferred are acetonitrile, 3-methylbutanone, 4-methylpentanone-2, ethyl acetate, butyl acetate, N-methylpyrrolidone, dimethylformamide, toluene, xylene, even more preferred are toluene, N-methylpyrrolidone or butyl acetate.

[0071] The reaction is usually carried out at temperatures between 50 °C and 200 °C, preferably between 70 °C and 150 °C, particularly preferably between 90 °C and 130 °C.

[0072] In the compound of formula IV, X is selected from the group consisting of Li, Na, K and Cs. Most preferred is Li.

[0073] The compound of formula IV can be obtained from a compound of formula V:

[0074]

[0075] wherein

[0076] R 3 , R​4 independently selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl and C1-C6haloalkoxy;

[0077] R 78 independently selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl and C1-C6haloalkoxy;

[0078] o is 0, 1, 2 or 3;

[0079] Y is selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, phenyl and benzyl, wherein phenyl and benzyl are unsubstituted or substituted by CN, NO2, halogen, C1-C6alkyl, C1-C6haloalkyl or C1-C6alkoxy, said compound of formula V can be obtained by a one-step reaction of a compound of formula VI with a compound of formula VII:

[0080]

[0081] wherein R 3 , R 4 , o and R 78 are as defined above,

[0082]

[0083] wherein Y is as defined above.

[0084] According to one embodiment of the present application, the reaction is carried out in the presence of an acid.

[0085] Preferably, the acid is selected from the group consisting of mineral acids, such as sulfuric acid, oleum, nitric acid, phosphoric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, organic acids, such as trifluoromethanesulfonic acid, methanesulfonic acid, trifluoroacetic acid, trichloroacetic acid and mixtures thereof.

[0086] More preferably, as acid, sulfuric acid, oleum and trifluoroacetic acid are used.

[0087] Most preferably, sulfuric acid is used. The preferred amount of acid used is 1 to 10 equivalents, more preferably 2 to 8 equivalents, even more preferably 2.5 to 5 equivalents, relative to the alcohol VI used.

[0088] According to an embodiment of the present application, the reaction between VI and VII is carried out in an inert solvent.

[0089] "Inert organic solvent" means an organic solvent which does not undergo any significant reaction with the reactants or products under the reaction conditions of the process of the present application.

[0090] In one embodiment, the inert organic solvent is selected from non-halogenated inert organic solvents; preferably, non-halogenated aliphatic hydrocarbons, non-halogenated alicyclic hydrocarbons, non-halogenated aromatic hydrocarbons, halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons, amides, ethers, esters, ketones, nitriles, and any combination thereof.

[0091] Examples of suitable non-halogenated aliphatic hydrocarbons include pentane, hexane, heptane, and petroleum ether. Saturated aliphatic hydrocarbons with 5-10 carbon atoms are preferred.

[0092] Examples of suitable non-halogenated alicyclic hydrocarbons include cyclopentane, cyclohexane, and cycloheptane. Non-halogenated saturated alicyclic hydrocarbons having 5-10 carbon atoms are preferred. Cyclohexane is particularly preferred.

[0093] 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), and 1,3,5-trimethylbenzene (mesutrixylene). Toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 1,3,5-trimethylbenzene (mesutrixylene), and any combination thereof are preferred. Among non-halogenated aromatic hydrocarbons, toluene, o-xylene, m-xylene, p-xylene, and any combination thereof are particularly preferred, with toluene being the most preferred.

[0094] Examples of suitable haloalliparaffins include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,1,2-tetrachloroethane, 1,1,2,2-tetrachloroethane, 1,1-dichloroethylene, 1,2-dichloroethylene, etc. Dichloromethane and 1,2-dichloroethane, and any combination thereof are preferred.

[0095] Examples of suitable halogenated aromatic hydrocarbons include chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, α,α,α-trifluorotoluene (trifluorotoluene), and any combination thereof.

[0096] Examples of suitable amides include N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, N-methylpyrrolidone, and any combination thereof.

[0097] Examples of suitable ethers include cyclic and non-cyclic 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, and 1,4-diethyl ether. Alkanes and any combination thereof.

[0098] Examples of suitable esters include ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate, and any combination thereof.

[0099] 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.

[0100] Examples of suitable nitriles include acetonitrile, benzonitrile and the like and any combination thereof.

[0101] Preferably, the inert solvent is selected from the group consisting of aliphatic and aromatic hydrocarbons and halogenated hydrocarbons such as cyclohexane, heptane, benzene, toluene, xylene, cumene, mesitylene, chlorobenzene, dichlorobenzene and tert-butylbenzene, cyclic or acyclic ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether (MTBE), tert-butyl ethyl ether, methylcyclopentyl ether, tetrahydrofuran (THF), methyltetrahydrofuran (methyl THF) or dioxane, nitriles such as acetonitrile and propionitrile, aliphatic halogenated hydrocarbons such as dichloromethane, dichloroethane, trichloromethane and mixtures thereof. Examples of suitable nitriles include acetonitrile, benzonitrile and the like and any combination thereof.

[0102] More preferably, the inert solvent is chlorobenzene, cyclohexane, heptane or petroleum ether.

[0103] Compound VII is commercially available or can be synthesized according to known procedures. For further 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 & Biomolecular Chemistry, 2(13), 1921-1933; 2004; Tetrahedron Letters, (27), 2517-20; 1979.

[0104] Compounds VI are commercially available or can be synthesized according to known procedures. For detailed information see: Tetrahedron, 42(11), 2931-5; 1986; Journal of the Indian Chemical Society, 87(5), 595-600; 2010; Chemistry Letters, 37(7), 800-801; 2008; Journal of Labelled Compounds & Radiopharmaceuticals, 43(14), 1321-1326; 2000; Organic Chemistry, 47(7), 1193-6; 1982; Chemische Berichte, 114(12), 3813-30; 1981; Russian Chemical Bulletin, 55(1), 123-136; 2006; Comptes Rendus des Seances de l'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 Society, 110(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.

[0105] Preferably, compound VI is used in an amount of 0.8 to 3 equivalents, in particular 1.05 to 2.5 equivalents, more specifically 1.05 to 1.8 equivalents, relative to 1 equivalent of compound VII.

[0106] The substituted dihydroisoquinoline of the formula V obtained according to the process of the present application can be further converted into a compound of the formula VIII:

[0107]

[0108] wherein

[0109] R 3 , R 4 are independently selected from the group consisting of Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-haloalkyl, C2-C6-haloalkenyl and C2-C6-haloalkynyl;

[0110] R 78 are independently selected from the group consisting of halogen, Ci-C6-alkyl, Ci-C6-alkoxy, Ci-C6-haloalkyl and Ci-C6-haloalkoxy;

[0111] o is 0, 1, 2 or 3;

[0112] Y is selected from the group consisting of Ci-C6-alkyl, Ci-C6-haloalkyl, phenyl and benzyl, wherein phenyl and benzyl are unsubstituted or substituted by CN, NO2, halogen, Ci-C6-alkyl, Ci-C6-haloalkyl or Ci-C6-alkoxy.

[0113] Accordingly, the present application further relates to a process comprising the following steps:

[0114] (i) providing a compound of the formula V;

[0115] (ii) reacting the compound of the formula V with a brominating agent.

[0116] According to one embodiment of the present application, the brominating agent in the process according to the present application is selected from the group consisting of Br2, N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) or a system consisting of HBr / H2O2.

[0117] Preferably, the brominating agent is N-bromosuccinimide (NBS).

[0118] Preferably, the brominating agent is 1,3-dibromo-5,5-dimethylhydantoin (DBDMH).

[0119] Preferably, the brominating agent is used in an amount of 1.5 to 5 equivalents, in particular 2.0 to 3.0 equivalents, relative to 1 equivalent of compound V.

[0120] Typically, the reaction time is 10 minutes to 12 hours, preferably 30 minutes to 8 hours, and further preferably 1 to 4 hours.

[0121] Typically, the bromination is carried out under radical-generating conditions. Preferred radical-generating conditions are the use of UV light or the use of a radical initiator such as an azo compound or a peroxide. Preferred conditions are the use of a radical initiator. The nature of the radical initiator depends on the reaction temperature applied, most preferably benzoyl peroxide or AIBN (azoisobutyro dinitrile). The amount of radical initiator used is 0.001 to 0.5 equivalents, preferably 0.005 to 0.3 equivalents, and further preferably 0.01 to 0.2 equivalents, relative to the compound V used.

[0122] 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, carbon tetrachloride, ethyl acetate, butyl acetate or acetonitrile. Preferably, the solvent used is chlorobenzene, cyclohexane, ethyl acetate or butyl acetate.

[0123] By the process according to the application, pyridine derivatives of formula I can be prepared in high yields. Preferably, the yield is at least 60%, more preferably 70%, even more preferably at least 75%, and even more preferably at least 80%.

[0124] The brominated dihydroisoquinoline of formula VIII obtained according to the process of the application can be further converted into a compound of formula IX

[0125]

[0126] wherein

[0127] R 3 , R 4 are independently selected from the group consisting of Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-haloalkyl, C2-C6-haloalkenyl and C2-C6-haloalkynyl.

[0128] R 78 are independently selected from the group consisting of halogen, Ci-C6-alkyl, Ci-C6-alkoxy, Ci-C6-haloalkyl and Ci-C6-haloalkoxy;

[0129] o is 0, 1, 2 or 3;

[0130] Y is selected from the group consisting of Ci-C6-alkyl, Ci-C6-haloalkyl, phenyl and benzyl, wherein phenyl and benzyl are unsubstituted or substituted by CN, NO2, halogen, Ci-C6-alkyl, Ci-C6-haloalkyl or Ci-C6-alkoxy.

[0131] Accordingly, the present application further relates to a process comprising the following steps:

[0132] (i) providing a compound of formula V;

[0133] (ii) providing a compound of formula VIII;

[0134] (iii) reacting the compound of formula VIII with a fluorinating agent to provide a compound of formula IX.

[0135] According to another embodiment of the present application, the fluorinating agent is selected from the group consisting of NaF, CsF, KF, KHF2, Olah's reagent, HF, a polyhydrofluoride complex of a trialkylamine or a mixture of HF in a trialkylamine (Ci-C6-alkyl)3N.

[0136] The polyhydrofluoride complex of a trialkylamine can be described by the formula (Ci-C6-alkyl)3NxnHF, wherein (n = 1-5), for example: (C2H5)3Nx3HF, (C4H9)3Nx3HF.

[0137] The mixture of HF in a trialkylamine (Ci-C6-alkyl)3N is a mixture of a trialkylamine (Ci-C6-alkyl)3N with a HF content of 5-95 %, preferably 10-60 %, further preferably 20-40 %.

[0138] Preferably, the fluorinating agent is a solution of HF in triethylamine, preferably (C2H5)3Nx3HF, optionally diluted with (C2H5)3N or with a mixture of (C2H5)3N and a polar solvent such as acetonitrile, dimethylformamide or N-methylpyrrolidone.

[0139] Preferably, the fluorinating agent is used in an amount of 1.2-10 equivalents, in particular 2.2-7.8 equivalents, more in particular 4.4-5.6 equivalents, relative to 1 equivalent of the compound VIII.

[0140] According to a further embodiment of the present application, the fluorination reaction is carried out in the presence of a solvent, preferably a polar solvent. Suitable organic solvents for the reaction are protic polar solvents, such as water, preferably aliphatic alcohols having 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, toluene, xylene, cumene, chlorobenzene, nitrobenzene or tert-butylbenzene, aprotic polar solvents, such as cyclic or acyclic ethers, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether (MTBE), tert-butyl ethyl ether, tetrahydrofuran (THF) or dioxane, cyclic or acyclic amides, such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone or tetramethylurea, aliphatic esters, such as ethyl acetate, butyl acetate or methyl propionate, cyclic or acyclic ketones, such as cyclohexanone, acetone, 3-methylbutanone or 4-methylpentanone-2, aliphatic tertiary amines, such as triethylamine, tributylamine or diisopropylethylamine, or aliphatic nitriles, such as acetonitrile or propionitrile, and mixtures of the above-mentioned solvents. Preferred are water, acetonitrile, 3-methylbutanone, butyl acetate, dimethylformamide, ethanol, toluene.

[0141]

[0142]

[0143] The reaction is generally carried out at temperatures of from 10 to 150°C, preferably from 20 to 100°C, particularly preferably from 50 to 90°C.

[0144] Typical reaction times are from 0.5 to 18 hours, preferably from 1 to 5 hours, preferably from 1 to 3 hours.

[0145] The terms "compound I", "compound II", "compound Ila" and "compound III" mean the compounds of the formulae I, II, Ila and III, respectively. In the definitions of the variables given above, collective terms are used which are generally representatives of the substituents mentioned.

[0146] In the definitions of the variables given herein, collective terms are used which are generally representatives of the substituents mentioned. The term "C n -C m " denotes the number of carbon atoms which can be present in each case in the substituents or substituent moieties mentioned.

[0147] The term "halogen" means fluorine, chlorine, bromine and iodine.

[0148] ​​​The term "C1-C6alkyl" refers to a straight or branched chain saturated hydrocarbon group having from 1 to 6 carbon atoms, for example 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-C4alkyl" refers to a straight or branched chain alkyl group having from 2 to 4 carbon atoms, for example ethyl, propyl (n-propyl), 1-methylethyl (i-propyl), butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (i-butyl), 1,1-dimethylethyl (tert-butyl).

[0149] The term "C1-C6haloalkyl" refers to an alkyl group as defined above having 1 or 6 carbon atoms, wherein some or all of the hydrogen atoms in these groups can be replaced by halogen atoms as mentioned above. Examples are "C1-C2haloalkyl" groups, such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, monochlorodifluoromethyl, 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.

[0150] The term "C2-C6alkenyl" refers to a straight or branched chain unsaturated hydrocarbon group having from 2 to 6 carbon atoms and a double bond in any position. Examples are "C2-C4alkenyl" 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.

[0151] The term "C2-C6haloalkenyl" refers to an alkenyl group as defined above having 2 or 6 carbon atoms, wherein some or all of the hydrogen atoms in these groups can be replaced by halogen atoms as mentioned above.

[0152] The term "C2-C6-alkynyl" refers to straight-chain or branched unsaturated alkyl groups 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.

[0153] The term "C2-C6-halogenalkynyl" refers to an alkynyl group as defined above having 2 or 6 carbon atoms, wherein some or all of the hydrogen atoms in these groups can be replaced by halogen atoms as mentioned above.

[0154] The term "C1-C6-alkoxy" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, which is bound by 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 -methylpropyloxy, 2-methylpropyloxy or 1,1 -dimethylethoxy.

[0155] The term "C1-C6-halogenalkoxy" refers to a C1-C6-alkoxy group as defined above, wherein some or all of the hydrogen atoms in these groups can be replaced by halogen atoms as mentioned above. Examples are "C1-C4-halogenalkoxy" groups, such as OCH2F, OCHF2, OCF3, OCH2C1, OCHC12, OCC13, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodichloromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2- difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2- difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, OC2F5, 2-fluoropropoxy, 3-fluoropropoxy, 2,2-difluoropropoxy, 2,3-difluoropropoxy, 2-chloropropoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 2-bromopropoxy, 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-bromoethoxy, 4-fluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy or nonafluorobutoxy.

[0156] The term "phenyl-C1-C6-alkyl" refers to an alkyl group having 1 to 6 carbon atoms (as defined above), wherein one of the hydrogen atoms of the alkyl group is replaced with a phenyl group. Likewise, the terms "phenyl-C2-C6-alkenyl" and "phenyl-C2-C6-alkynyl" refer to alkenyl and alkynyl groups, respectively, wherein one of the hydrogen atoms in the above groups is replaced with a phenyl group.

[0157] The variables R 1 , R2 3 4 5 6 7 78 95 10 and o have the meanings and preferred meanings indicated above apply to any of the compounds in the processes of the application and to the compounds of the formulae I, II, III and IV and to the by-products.

[0158] According to one embodiment of the present application, in the compounds of the formula I and, if applicable, II, III and IV, each of the variables independently of the other or more preferably in combination has the following meaning:

[0159] R 1 is in each case independently selected from the group consisting of hydrogen and Ci-C6-alkyl;

[0160] R 2 is in each case independently selected from the group consisting of hydrogen;

[0161] R 3 , R 4 are independently selected from the group consisting of Ci-C6-alkyl and Ci-C6-haloalkyl;

[0162] R 5 is halogen;

[0163] R 6 is halogen;

[0164] R 7 , R 8 form together with the carbon atom to which they are bound a ring A, wherein ring A is phenyl and wherein ring A is substituted with (R 78 ) o, wherein

[0165] o is 0, 1, 2 or 3; and

[0166] R 78 are independently selected from the group consisting of halogen and Ci-C6-alkyl;

[0167] R 10 are independently selected from the group consisting of Ci-C6-alkyl, Ci-C6-alkoxy and Ci-C6-haloalkyl.

[0168] According to another embodiment of the present application, in the compounds of the formula I and, if applicable, II, III and IV, each of the variables independently of the other or more preferably in combination has the following meaning:

[0169] R 1 is hydrogen;

[0170] R 2 is hydrogen; ​​​​​​​​

[0171] R 3 , R 4 are independently selected from the group consisting of Ci-C6-alkyl and Ci-C6-haloalkyl;

[0172] R 5 is halogen;

[0173] R 6 is halogen;

[0174] R 7 , R 8 together with the carbon atom to which they are bound form a ring A, wherein ring A is phenyl and wherein ring A is substituted by (R 78 )o, wherein

[0175] o is 0, 1, 2 or 3; and

[0176] R 78 is independently selected from the group consisting of halogen and Ci-C6-alkyl;

[0177] R 10 is independently selected from the group consisting of Ci-C6-alkyl and Ci-C6-haloalkyl.

[0178] According to a further embodiment of the present application, in the compounds of formula I and if applicable II, III and IV, the variables have independently of each other or more preferably in combination the following meanings:

[0179] R 1 is hydrogen;

[0180] R 2 is hydrogen;

[0181] R 3 , R 4 are independently Ci-C6-alkyl;

[0182] R 5 is halogen;

[0183] R 6 is halogen;

[0184] R 7 , R 8 together with the carbon atom to which they are bound form a ring A, wherein ring A is phenyl and wherein ring A is substituted by (R 78 )o, wherein

[0185] o is 0, 1, 2 or 3; and

[0186] R 78 is independently selected from the group consisting of halogen and Ci-C6-alkyl;

[0187] R 10independently selected from halogen and Ci-C6-alkyl;

[0188] According to a further embodiment of the present application, in the compounds of formula I and if applicable II, III and IV, each of the variables has independently from another or more preferably in combination the following meanings:

[0189] R 1 is hydrogen;

[0190] R 2 is hydrogen;

[0191] R 3 , R 4 independently is Ci-C6-alkyl;

[0192] R 5 is F;

[0193] R 6 is F;

[0194] R 7 , R 8 together with the carbon atom to which they are bound form a ring A, wherein ring A is phenyl and wherein ring A is substituted by (R 78 )o, wherein

[0195] o is 0, 1, 2 or 3; and

[0196] R 78 independently is selected from halogen and Ci-C6-alkyl;

[0197] R 10 independently is selected from Ci-C6-alkyl and Ci-C6-haloalkyl.

[0198] According to a further embodiment of the present application, in the compounds of formula I and if applicable II, III and IV, each of the variables has independently from another or more preferably in combination the following meanings:

[0199] R 1 is hydrogen;

[0200] R 2 is hydrogen;

[0201] R 3 , R 4 independently is Ci-C6-alkyl;

[0202] R 5 is F;

[0203] R 6 is F;

[0204] R 7 , R 8Together with the carbon atoms they are bonded to, they form ring A, wherein ring A is phenyl and wherein ring A is (R 78 )o replaces, among which

[0205] o is 0, 1, 2, or 3; and

[0206] R 78 Independently selected from halogens and C1-C6 alkyl groups;

[0207] R 10 It is independently selected from CH3 and CHF2.

[0208] The particularly preferred active compound I is selected from the group consisting of compounds IA to IZA:

[0209] IA: 1-(5,6-dimethyl-3-pyridyl)-4,4-difluoro-3,3-dimethylisoquinoline

[0210] ID: 4,4-Difluoro-1-[5-(fluoromethyl)-6-methyl-3-pyridyl]-3,3-dimethyl-isoquinoline

[0211] IE: 4,4-Difluoro-1-(5-methoxy-6-methyl-3-pyridyl)-3,3-dimethylisoquinoline

[0212] IJ: 1-(5,6-dimethyl-3-pyridyl)-4,4,5-trifluoro-3,3-dimethylisoquinoline

[0213] IK: 4,4,5,5-trifluoro-1-[5-(fluoromethyl)-6-methyl-3-pyridyl]-3,3-dimethyl-isoquinoline

[0214] IL: 4,4,5-trifluoro-1-(5-methoxy-6-methyl-3-pyridyl)-3,3-dimethylisoquinoline

[0215] IS: 1-(5,6-dimethyl-3-pyridyl)-4,4,6-trifluoro-3,3-dimethylisoquinoline

[0216] IT: 4,4,6-Trifluoro-1-[5-(fluoromethyl)-6-methyl-3-pyridyl]-3,3-dimethylisoquinoline

[0217] IU: 4,4,6-trifluoro-1-(5-methoxy-6-methyl-3-pyridyl)-3,3-dimethylisoquinoline

[0218] Furthermore, this invention also relates to compounds of formula I:

[0219]

[0220] in

[0221] If

[0222] R 1 is H and R 2 is halogen;

[0223] R 10 is Ci-C6alkyl and Ci-C6haloalkyl; and

[0224] If

[0225] R 1 is H and R 2 is H;

[0226] R 10 is Ci-C6alkyl and Ci-C6haloalkyl.

[0227] According to one embodiment of the present application,

[0228] If

[0229] R 1 is H and R 2 is halogen;

[0230] R 10 is CH3, CH2CI and CH2Br; and

[0231] If

[0232] R 1 is H and R 2 is H;

[0233] R 10 is CH2F, CH2CH3, CH2CH(CH3)2.

[0234] The present application is illustrated by the following examples:

[0235] Example 1 : Bromination of 2,3-dimethylpyridine with DBDMH

[0236] To a stirred solution of 2,3-dimethylpyridine (10 g, 0.09 mol) in 65% (30 mL) oleum was added DBDMH (14.5 g, 0,05 mol) at 10 °C. Thereafter the exothermic reaction started. The reaction mixture was then heated at 105 °C for 2 hours. After cooling to room temperature, the mixture was poured into ice (150 g) and the pH was adjusted to 12 with aqueous sodium hydroxide solution. The product was extracted into MTBE (3 x 100 mL), the organic phase was dried over MgS04and evaporated under reduced pressure to give 5-bromo-2,3-dimethylpyridine as a yellow oil (purity according to GC 87.3%; yield 83.3%).

[0237] Example 2: Bromination of 2,3-dimethylpyridine with DBDMH

[0238] To a stirred solution of 2,3-dimethylpyridine (20 g, 0.185 mol) in 65% (60 mL) oleum was added DBDMH (31.7 g, 0,11 mol) at 10 °C. Thereafter, an exothermic reaction started. The reaction mixture was then heated at 105 °C for 2 hours. After cooling to room temperature, the mixture was poured into ice (250 g) and the pH was adjusted to 12 with aqueous sodium hydroxide solution. The product was extracted into MTBE (3 x 100 mL), the organic phase was dried over MgS04and evaporated under reduced pressure to give 5-bromo-2,3-dimethylpyridine as a yellow oil (34.3 g). Purity according to GC was 87.0%; yield was 86.7%.

[0239] Example 3: 3,3-dimethyl-4H-isoquinoline-1-carboxylic acid ethyl ester

[0240]

[0241] 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 was added at 15 °C under stirring to a mixture of 500 ml cyclohexane and 1899 g (19 mol) concentrated sulfuric acid. After about 15 minutes, the reaction mixture was poured into an ice / water mixture and carefully basified upon addition of a concentrated NaOH solution. The phases were separated and the aqueous layer was extracted twice with methyl tert-butyl ether. The combined organic phases were dried over sodium sulfate and the volatiles were evaporated to give 584 g (99%) 3,3-dimethyl-4H-isoquinoline-1-carboxylic acid ethyl ester as a yellow oil.

[0242] 1 H-NMR (CDC13, delta in ppm): 7,55 (d, 1H); 7,4 (t, 1H); 7,3 (t, 1H); 7,18 (d, 1H); 4,45 (q, 2H); 2,75 (s, 2H); 1,4 (t, 3H); 1,28 (s, 6H)

[0243] Example 4: 4,4-dibromo-3,3-dimethylisoquinoline-1-carboxylic acid ethyl ester

[0244]

[0245] A mixture of 20 g (86 mmol) of 3,3-dimethyl-4H-isoquinoline-1 -carboxylic acid ethyl ester, 33.8 g (190 mmol) of N-bromosuccinimide and 2.8 g of azobisisobutyronitrile (17 mmol) in 250 ml of chloroform was heated to reflux under stirring. After about 60 minutes, HPLC showed that the reaction was complete. The reaction mixture was then cooled to room temperature and diluted with 200 ml of heptane. The precipitated solid was then filtered off and the mother liquor was evaporated to give 40 g (80% purity (HPLC), 95% yield) of the title compound 4,4-dibromo-3,3-dimethyl-isoquinoline-1 -carboxylic acid ethyl ester, which was then used as crude product.

[0246] HPLC-MS: HPLC column Kinetex XB C18 1,7 μ (50 x 2,1 mm); eluent: acetonitrile / water + 0.1 TFA% (5 gradients from 5:95 to 100:0 in 1.5 min at 60°C, flow gradient 0.8-1.0 ml / min in 1.5 min). MS: Quadrupol electrospray ionization, 80 V (positive mode).

[0247] Rt = 1,034 min, M + +H = 245,9 (title compound, hydrolyzed to carbonyl compound after HPLC-MS measurement); R t = 1,275, M + +H = 389,8 (title compound 4,4-dibromo-3,3-dimethyl-isoquinoline-1 -carboxylic acid ethyl ester)

[0248] Example 5: 4,4-difluoro-3,3-dimethylisoquinoline-1 -carboxylic acid ethyl ester

[0249]

[0250] To 40 g (80% purity, 82 mmol) of 4,4-dibromo 3,3-dimethylisoquinoline-1 -carboxylic acid ethyl ester in 100 ml of acetonitrile, 79.6 g (493 mmol) of triethylamine x 3 hydrogen fluoride (NEt3x 3 HF) was added. When HPLC showed that the reaction was complete, the mixture was heated to reflux for 2 hours. The reaction mixture was then cooled to room temperature and carefully poured into an ice-cold 20% NaOH solution. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were extracted with brine. The organic phase was then dried over sodium sulfate and the volatiles evaporated to give 12 g (55%) of the title compound 4,4-difluoro-3,3-dimethyl-isoquinoline-1 -carboxylic acid ethyl ester as a brown oil.

[0251] 1 H-NMR (CDCI3, delta in ppm):

[0252] 7,75 (2d, 2H); 7,65 (2t, 2H); 4,45 (q, 2H); 1,4 (m, 9H)

[0253] HPLC-MS: HPLC column Kinetex XB C18 1,7μ (50 x 2,1 mm); eluent: acetonitrile / water + 0.1 TFA% (5 gradients from 5:95 to 100:0 in 1.5 min at 60°C, flow gradient 0.8-1.0 ml / min in 1.5 min). MS: Quadrupol electrospray ionization, 80 V (positive mode).

[0254] R t = 1,176 min, M + +H = 268.

[0255] Example 6: (4,4-difluoro-3,3-dimethyl-isoquinoline-1-carbonyl)oxy lithium

[0256]

[0257] Example 6: (4,4-difluoro-3,3-dimethyl-isoquinoline-1-carbonyl)oxy lithium

[0258] HPLC-MS: HPLC column Kinetex XB C18 1,7μ (50 x 2,1 mm); eluent: acetonitrile / water + 0.1 TFA% (5 gradients from 5:95 to 100:0 in 1.5 min at 60°C, flow gradient 0.8-1.0 ml / min in 1.5 min). MS: Quadrupol electrospray ionization, 80 V (positive mode).

[0259] M + +H = 239.9 (R t = 0.797 min)

[0260] Example 6: (4,4-difluoro-3,3-dimethyl-isoquinoline-1-carbonyl)oxy lithium

[0261]

[0262] A solution of 7,3 g (26 mmol) of 4,4-difluoro-3,3-dimethyl-isoquinoline-1- carboxylic acid ethyl ester and 1,143 g (27 mmol) of lithium hydroxide in 100 g of methanol was stirred at room temperature. After 2.5 hours, HPLC showed complete conversion of the starting material. The solvent was then evaporated at room temperature and the crystalline residue was stirred with diethyl ether. The crystals were filtered off and dried under vacuum at 50°C to give 6.3 g of the title compound as a light yellow solid (Mp > 200°C, decomposition).

[0263] HPLC-MS: HPLC column Kinetex XB C18 1,7 μ (50 x 2,1 mm); eluent: acetonitrile / water + 0.1 TFA % (5 gradients from 5:95 to 100:0 in 1.5 min at 60°C, flow gradient 0.8-1.0 ml / min in 1.5 min). MS: Quadrupol electrospray ionization, 80 V (positive mode).

[0264] M + +H = 239.9 (R t = 0.797 min)

[0265] Example 8: 1 -(5,6-dimethyl-3-pyridyl)-4,4-difluoro-3,3-dimethylisoquinoline

[0266]

[0267] A solution of 7,3 g (26 mmol) of 4,4-difluoro-3,3-dimethyl-isoquinoline-1- carboxylic acid ethyl ester and 1,143 g (27 mmol) of lithium hydroxide in 100 g of methanol was stirred at room temperature. After 2.5 hours, HPLC showed complete conversion of the starting material. The solvent was then evaporated at room temperature and the crystalline residue was stirred with diethyl ether. The crystals were filtered off and dried under vacuum at 50°C to give 6.3 g of the title compound as a light yellow solid (Mp > 200°C, decomposition).

[0268] The volatiles were then evaporated and the residue was dissolved in methyl- tert-butyl ether. The heterogeneous mixture was placed on top of a short silica gel column, which was eluted with methyl-tert-butyl ether. The combined fractions were extracted with dilute aqueous ammonia and lithium chloride solution. The volatiles were evaporated to give 3.2 g (86% purity (HPLC), 85% yield) of the title compound as a brown oil, which crystallized upon standing.

[0269] 1H-NMR (CDCl3, δ, in ppm): 8,52(s,1H); 7,83(d,1H); 7,67(s,1H); 7,62(t,1H); 7,52,(t,1H); 7,3(d,1H); 2,55(s,3H); 2,35(s,3H); 1,4(s,6H)

[0270] HPLC-MS: HPLC column Kinetex XB C18 1.7μm (50 x 2.1mm); eluent: acetonitrile / water + 0.1% TFA (5 gradients from 5:95 to 100:0 over 1.5 min at 60°C, with a flow gradient of 0.8–1.0 mL / min over 1.5 min). MS: Quadrupol electrospray ionization, 80 V (positive mode).

[0271] M + +H=301(R t =0.889min)

[0272] Example 9: 1-[6-(difluoromethyl)-5-methyl-3-pyridyl]-4,4-difluoro-3,3-dimethylisoquinoline

[0273]

[0274] 2.43 g (9.9 mmol) of (4,4-difluoro-3,3-dimethylisoquinoline-1-carbonyl)oxylithium and 2.0 g (10.75 mmol) of 5-bromo-2,3-dimethylpyridine were heated at 70 °C with stirring in 50 mL of toluene / N-methylpyrrolidone in a 3:2 ratio, and a light stream of argon was passed through the mixture. Subsequently, 0.194 g (1.35 mmol) of copper bromide (l) and 0.122 g (0.15 mmol) of Pd(dppf)Cl2xCH2Cl2 ([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexed with dichloromethane) were added, and the mixture was heated to reflux (122 °C) overnight.

[0275] The volatiles were then evaporated and the residue dissolved in methyl tert-butyl ether. The heterogeneous mixture was placed on top of a short silica gel column and eluted with methyl tert-butyl ether. The combined fractions were extracted with dilute ammonia and lithium chloride solution. The volatiles were evaporated and the residue was purified by column chromatography with a heptane / methyl tert-butyl ether mixture to give 2 g (5.9 mmol; 68% yield) of the title compound as a light brown oil.

[0276] 1H-NMR (CDC13, δ in ppm): 8,65 (s, 1H); 7,87 (d, 1H); 7,83 (s, 1H); 7,67 (t, 1H); 7,55 (t, 1H); 7,25, (d, 1H); 6,75 (t, 1H); 2,58 (s, 3H); 1,4 (s, 6H)

[0277] HPLC-MS: HPLC column Kinetex XB C18 1,7μ (50 x 2,1 mm); eluent: acetonitrile / water + 0.1 TFA% (5 gradients from 5:95 to 100:0 in 1.5 min at 60°C, flow gradient 0.8-1.0 ml / min in 1.5 min). MS: Quadrupol electrospray ionization, 80 V (positive mode).

[0278] M + +H = 337 (R t = 1,243 min)

[0279] Example 10: 4,4-difluoro-3,3-dimethylisoquinoline-1-carboxylic acid ethyl ester

[0280]

[0281] To 40 g (purity 80%, 82 mmol) of 4,4-dibromo 3,3-dimethylisoquinoline-1- carboxylic acid ethyl ester in 100 ml of acetonitrile was added 79,6 g (493 mmol) of triethylamine x 3 hydrogen fluoride (NEt3x 3 HF). When the HPLC showed that the reaction was complete, the mixture was heated to reflux for 2 hours. Subsequently the reaction mixture was cooled to room temperature and carefully poured into an ice-cold 20% NaOH solution. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were extracted with brine. The organic phase was then dried over sodium sulfate and the volatiles evaporated to yield 12 g (55%) of the title compound 4,4-difluoro-3,3-dimethyl-isoquinoline-1-carboxylic acid ethyl ester as a brown oil.

[0282] 1 H-NMR (CDC13, δ in ppm):

[0283] 7,75 (2d, 2H); 7,65 (2t, 2H); 4,45 (q, 2H); 1,4 (m, 9H)

[0284] HPLC-MS: HPLC column Kinetex XB C18 1,7μ (50 x 2,1 mm); eluent: acetonitrile / water + 0.1 TFA % (5 gradients from 5:95 to 100:0 in 1.5 min at 60°C, flow gradient 0.8-1.0 ml / min in 1.5 min). MS: Quadrupol electrospray ionization, 80 V (positive mode).

[0285] R t = 1,176 min, M + +H = 268

[0286] Example 11 : 1 -(5,6-Dimethyl-3-pyridinyl)-4,4-difluoro-3,3-dimethylisoquinoline

[0287] To a suspension of 5-bromo-1,3-dimethylpyridine (7,805 g; 40,693 mmol) and lithium (4,4-difluoro-3,3-dimethyl-isoquinoline-1 -carbonyl)oxy (9,976 g; 40,693 mmol) in 100 mL dry N-methylpyrrolidone under N2was added CuBr (875,6 mg; 6,104 mmol), Pd(dppf)CI2(664,6 mg; 0,814 mmol) and 902,4 mg (1,628 mmol) dppf x CH2CI2 ([1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane). The reaction mixture was heated to 150°C and stirred for 3 hours. After completion of the reaction (HPLC) the mixture was cooled to 10°C.

[0288] Subsequently 100 ml 5M hydrochloric acid was added slowly through a dropping funnel. The aqueous layer was extracted twice with 100 ml n-heptane each and the organic layer was discarded.

[0289] 300 ml n-heptane was added to the aqueous layer and the solution was basified to pH = 10 with a 50% sodium hydroxide solution at 25°C. The precipitated solid residue was filtered off, washed with n-heptane (3 x 50 ml) and discarded. Thereafter, the layers were separated and the aqueous layer was extracted with n-heptane (2 x 300 mL). The combined organic layers were dried over Na2S04, the drying agent was filtered off and the volatiles were evaporated to yield 11.1 g of the title compound in the form of orange crystals.

[0290] 8.05 g of beige crystals were obtained by recrystallization from heptane (purity 93.5% (quantitative 1 H-NMR), yield 61.6%). Purification by column chromatography with a cyclohexane / ethyl acetate mixture yielded 1 -(5,6-dimethyl-3-pyridinyl)-4,4-difluoro-3,3-dimethylisoquinoline in the form of white crystals (mp = 104-105°C).1 H-NMR (CDC13, δ in ppm): 8,52 (s, 1H); 7,83 (d, 1H); 7,67 (s, 1H); 7,62 (t, 1H); 7,52, (t, 1H); 7,3 (d, 1H); 2,55 (s, 3H); 2,35 (s, 3H); 1,4 (s, 6H)

[0291] Example 12: 1-[6-(Difluoromethyl)-5-methyl-3-pyridinyl]-4,4-difluoro-3,3- dimethylisoquinoline

[0292] To a suspension of 5-bromo-2-(difluoromethyl)-3-methylpyridine (36, 59 g; 163,16 mmol) and lithium (4,4-difluoro-3,3-dimethyl-isoquinoline-1-carbonyl)oxy (40,00 g; 163,165 mmol) in 480 ml dry N-methylpyrrolidone under N2was added CuBr (3,51 g; 24,48 mmol), Pd(dppf)Cl2xCH2Cl2(2,67 g; 3,26 mmol) and 3,62 g (6,53 mmol) dppf ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane). The reaction mixture was heated at 150 °C and stirred for 8 hours. After completion of the reaction (HPLC), the mixture was cooled to 10 °C and then a mixture of 300 ml water and 500 ml n-heptane was added. Thereafter, the mixture was basified with 50 ml 25% ammonia solution (pH 11-12) at 25 °C and filtered over Celite. The Celite was washed with n-heptane and the ammonia water layer was separated from the n- hexane layer.

[0293] 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.

[0294] The organic layer was dried over Na2SO4, filtered and evaporated to give 40.5 g of the title compound (purity ~ 80% (quantitative-HPLC)).

[0295] The product was dissolved in 400 ml n-heptane. The heptane phase was extracted twice with 250 ml 15% HC1 and the heptane phase was then discarded.

[0296] The combined HC1 layers were treated 3 times with 500 ml dichloromethane to extract the product into the organic phase.

[0297] Thereafter, the combined dichloromethane layers were stirred with 300 ml of a 20% Na2CO3solution for 1 hour.

[0298] The phases were separated and the organic layer was dried over Na2SO4, filtered and evaporated to give 33,3 g of 1-[6-(difluoromethyl)-5-methyl-3-pyridinyl]-4,4-difluoro-3,3- dimethylisoquinoline (purity 92.5% (quantitative 1 H-NMR, yield 56%).

[0299] The title compound can be further purified by column chromatography using a mixture of cyclohexane / ethyl acetate.

[0300] 1 H-NMR (CDCI3, δ in ppm):

[0301] 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

1. A process for the preparation of a compound of formula I, wherein R 1 selected from hydrogen, halogen, Ci-C6alkyl, and Ci-C6haloalkyl; R 2 selected from hydrogen and halogen; R 10 is selected from H, halogen, O(R 95 ), C1-C6alkyl and C1-C6haloalkyl; wherein R 95 Ci-C6-alkyl, d-C6-haloalkyl; comprising Step: (i) reacting a compound of formula II with a brominating agent which is 1,3- dibromo-5,5-dimethylhydantoin (DBDMH) in the presence of fuming sulfuric acid 65%: (ii) reacting the compound of formula III with a compound of formula IV: wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20 wherein R 1 , R 2 and R 10 are as defined above.

2. The method according to claim 1, wherein R 1 and R 2 are hydrogen, and R 10 is CrC6alkyl.

3. The method according to claim 1, wherein R 1 and R 2 are hydrogen, and R 10 is CH3.

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