Preparation of optionally substituted dihydroisoquinolines

Abstract

The present invention relates to a process for the preparation of an optionally substituted dihydroisoquinoline of formula I.

Description

[0001] This invention relates to a method for preparing optionally substituted dihydroisoquinoline of formula I:

[0002]

[0003] WO 2016 / 145153 describes a method for preparing optionally substituted dihydroisoquinolines. A drawback of the method described in the aforementioned literature is that it involves numerous steps in the preparation of this type of dihydroisoquinoline.

[0004] Org. Lett. 11(3), 729-732 also describes a multi-step method for preparing substituted dihydroisoquinolines. Furthermore, NaN3 is used as a reagent in the reaction, which can be explosive, especially at high temperatures, and is unsuitable for large-scale industrial production.

[0005] Therefore, the object of this invention is to find a new method for preparing optionally substituted dihydroisoquinolines of formula I, which will be efficient and suitable for large-scale production.

[0006] It has now been discovered that dihydroisoquinoline derivatives of formula I can be obtained through a one-step reaction of a compound of formula II with a compound of formula III:

[0007]

[0008] in

[0009] R 3 R 4 It is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl and C2-C6 haloalkynyl;

[0010] R 78 It is independently selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, and C1-C6 haloalkoxy groups;

[0011] o can be 0, 1, 2, or 3;

[0012] Y is selected from C1-C6 alkyl, C1-C6 haloalkyl, phenyl, and benzyl, wherein the phenyl and benzyl groups are unsubstituted or substituted by CN, NO2, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy groups.

[0013]

[0014] Where R 3 R 4 o and R 78 As defined above,

[0015]

[0016] Y is defined as above.

[0017] The method of the present invention is effective because it involves only one reaction step. Furthermore, instead of NaN3, compound III is used, which is non-explosive. These advantages make the method according to the invention suitable for large-scale production.

[0018] According to one embodiment of the invention, the reaction is carried out in the presence of an acid.

[0019] 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, and organic acids, such as trifluoromethanesulfonic acid, methanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, and mixtures thereof.

[0020] As acids, sulfuric acid, fuming sulfuric acid, and trifluoroacetic acid are preferred.

[0021] Sulfuric acid is the preferred choice. The preferred amount of acid relative to the alcohol II used is 1-10 equivalents, more preferably 2-8 equivalents, and even more preferably 2.5-5 equivalents.

[0022] According to an embodiment of the invention, the reaction between II and III is carried out in an inert solvent.

[0023] "Inert organic solvent" refers to an organic solvent that does not react significantly with the reactants or products under the reaction conditions of the method of this invention.

[0024] 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.

[0025] Examples of suitable non-halogenated aliphatic hydrocarbons include pentane, hexane, heptane, and petroleum ether. Saturated aliphatic hydrocarbons with 5-10 carbon atoms are preferred.

[0026] 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.

[0027] 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 (mesotrimethylbenzene). Toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 1,3,5-trimethylbenzene (mesotrimethylbenzene), 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.

[0028] 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.

[0029] Examples of suitable halogenated aromatic hydrocarbons include chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, α,α,α-trifluorotoluene (trifluorotoluene), and any combination thereof.

[0030] Examples of suitable amides include N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, N-methylpyrrolidone, and any combination thereof.

[0031] 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.

[0032] Examples of suitable esters include ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate, and any combination thereof.

[0033] Examples of suitable ketones include acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, cyclopropyl methyl ketone, and any combination thereof.

[0034] Examples of suitable nitriles include acetonitrile, benzyl nitrile, and any combination thereof.

[0035] 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-butylmethyl ether (MTBE), tert-butylethyl ether, methylcyclopentyl ether, tetrahydrofuran (THF), methyltetrahydrofuran (methylTHF), or diethyl ether. Alkanes, nitriles, such as acetonitrile and propionitrile, aliphatic halogenated hydrocarbons, such as dichloromethane, dichloroethane, trichloromethane and mixtures thereof.

[0036] More preferably, the inert solvent is chlorobenzene, cyclohexane, heptane, or petroleum ether.

[0037] Compound III is commercially available or can be synthesized according to known procedures. 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 & Biomolecular Chemistry, 2(13), 1921-1933; 2004; Tetrahedron Letters, (27), 2517-20; 1979.

[0038] Compound II is commercially available or can be synthesized according to a known procedure. For details, 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 Labeled Compounds & Radiopharmaceuticals, 43(14), 1321-1326; 2000; Organic Chemistry, 47(7), 1193-6; 1982; Chemische Berichte, 114(12), 3813-30; 1981; Russian ChemicalBulletin, 55(1), 123-136; 2006; Comptes Rendus des Seances de l'Academie desSciences, 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 Chimiquede France, (5), 787-93; 1985;Chemical Communications, 52(82), 12147-12150; 2016; European Journal of Medicinal Chemistry, 14(2), 165-70; 1979. ;

[0039] Preferably, the amount of compound III is 0.8-3 equivalents, particularly 1.05-2.5 equivalents, and more specifically 1.05-1.8 equivalents, relative to 1 equivalent of compound II.

[0040] The substituted dihydroisoquinoline of formula I obtained according to the method of the present invention can be further converted into a compound of formula IV:

[0041]

[0042] in

[0043] R 3 R 4 It is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl and C2-C6 haloalkynyl;

[0044] R 78 It is independently selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, and C1-C6 haloalkoxy groups;

[0045] o can be 0, 1, 2, or 3;

[0046] Y is selected from C1-C6 alkyl, C1-C6 haloalkyl, phenyl and benzyl, wherein the phenyl and benzyl are not substituted or are substituted by CN, NO2, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy.

[0047] Therefore, the present invention further relates to a method comprising the following steps:

[0048] (i) Providing a compound of formula I by the method according to any one of claims 1-3;

[0049] (ii) React the compound of formula I with a brominating agent.

[0050] According to one embodiment of the present invention, the brominating agent in the method according to the present invention 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.

[0051] Preferably, the brominating agent is N-bromosuccinimide (NBS).

[0052] Preferably, the brominating agent is 1,3-dibromo-5,5-dimethylhydantoin (DBDMH).

[0053] Preferably, the brominating agent is used in an amount of 1.5-5 equivalents, particularly 2.0-3.0 equivalents, relative to 1 equivalent of compound I.

[0054] The reaction time is typically 10 minutes to 12 hours, preferably 30 minutes to 8 hours, and even more preferably 1 to 4 hours.

[0055] Typically, bromination is carried out under conditions that generate free radicals. Preferred conditions for generating free radicals include the use of UV light or free radical initiators such as azo compounds or peroxides. The use of a free radical initiator is particularly preferred. The properties of the free radical initiator depend on the applied reaction temperature; benzoyl peroxide or AIBN (azobisisobutyronitrile) is most preferred. The amount of free radical initiator used relative to compound I is 0.001-0.5 equivalents, preferably 0.005-0.3 equivalents, and even more preferably 0.01-0.2 equivalents.

[0056] Typically, the reaction is carried out in an inert solvent as defined above. Preferred inert solvents for this bromination step are chlorobenzene, cyclohexane, heptane, chloroform, carbon tetrachloride, ethyl acetate, butyl acetate, or acetonitrile. Preferably, the solvent used is chlorobenzene, cyclohexane, ethyl acetate, or butyl acetate.

[0057] The method of this invention can prepare pyridine derivatives of formula I in high yield. Preferably, the yield is at least 60%, more preferably 70%, even more preferably at least 75%, and even more preferably at least 80%.

[0058] The dihydroisoquinoline bromide obtained according to the method of the present invention can be further converted into a compound of formula V.

[0059]

[0060] in

[0061] R 3 R 4 It is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl and C2-C6 haloalkynyl.

[0062] R 78 It is independently selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, and C1-C6 haloalkoxy groups;

[0063] o can be 0, 1, 2, or 3;

[0064] Y is selected from C1-C6 alkyl, C1-C6 haloalkyl, phenyl and benzyl, wherein the phenyl and benzyl are not substituted or are substituted by CN, NO2, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy.

[0065] Therefore, the present invention further relates to a method comprising the following steps:

[0066] (i) Providing a compound of formula I by the method according to any one of claims 1-3;

[0067] (ii) Providing a compound of formula IV by the method according to any one of claims 4-6;

[0068] (iii) Reacting compound IV with a fluorinating agent to provide compound V.

[0069] According to another embodiment of the invention, the fluorinating agent is selected from the group consisting of: NaF, CsF, KF, KHF2, Olah reagent, HF, polyhydrofluoride complex of trialkylamine, or a mixture of HF in trialkylamine (C1-C6 alkyl)3N.

[0070] According to another preferred embodiment, the fluorinating agent is anhydrous HF.

[0071] Trialkylamine polyhydrofluoride complexes can be described by (C1-C6 alkyl)3NxnHF, where n = 1-5, for example: (C2H5)3Nx3HF, (C4H9)3Nx3HF.

[0072] The mixture of HF in trialkylamine (C1-C6 alkyl)3N has an HF content of 5-95%, preferably 10-60%, and more preferably 20-40% of the trialkylamine (C1-C6 alkyl)3N.

[0073] Preferably, the fluorinating agent is a triethylamine solution of HF, preferably (C2H5)3Nx3HF, optionally diluted with (C2H5)3N or a mixture of (C2H5)3N and a polar solvent such as acetonitrile, dimethylformamide or N-methylpyrrolidone.

[0074] Preferably, the amount of fluorinating agent used is 1.2-10 equivalents relative to 1 equivalent of compound IV, particularly 2.2-7.8 equivalents, and more specifically 4.4-5.6 equivalents.

[0075] According to another embodiment of the invention, 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 1-4 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, or non-protic 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 diisopropyl ether. Alkane, 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 nitrile, such as acetonitrile or propionitrile; and mixtures of the above solvents. Preferably, water, acetonitrile, 3-methylbutanone, butyl acetate, dimethylformamide, ethanol, or toluene are preferred.

[0076] Preferably, the polar solvent is acetonitrile or triethylamine.

[0077] Further preferred solvent systems are (C2H5)3Nx3HF alone or (C2H5)3Nx3HF with added triethylamine, acetonitrile or dimethylformamide.

[0078] The reaction is typically carried out at 10-150°C, preferably 20-100°C, and particularly preferably 50-90°C.

[0079] Typical reaction times are 0.5-18 hours, preferably 1-5 hours, and most preferably 1-3 hours.

[0080] The dihydroisoquinoline fluoride of formula V obtained according to the method of the present invention can be further converted into a compound of formula VI:

[0081]

[0082] in

[0083] R 3 R 4 It is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl and C2-C6 haloalkynyl;

[0084] R 78 It is independently selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, and C1-C6 haloalkoxy groups;

[0085] o can be 0, 1, 2, or 3;

[0086] X is a metal ion.

[0087] Therefore, the present invention further relates to a method comprising the following steps:

[0088] (i) Providing a compound of formula I by the method according to any one of claims 1-3;

[0089] (il) Provides a compound of formula IV by the method according to any one of claims 4-6;

[0090] (iii) Providing a compound of formula V by the method according to any one of claims 7-8;

[0091] (iv) Reacting compound V with a metal hydride to provide compound VI.

[0092] According to one embodiment of the present invention, X is selected from the group consisting of Li, Na, K, and Cs. Li is the most preferred.

[0093] The compound of formula I obtained according to the method of the present invention can be further converted into a 2,3-disubstituted pyridine compound of formula VII:

[0094]

[0095] in

[0096] R 1 In each case, the components are independently selected from hydrogen, halogen, C1-C6 alkyl, and C1-C6 haloalkyl;

[0097] R 2 In each case, it is independently selected from hydrogen and halogens;

[0098] R 3 R 4 It is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl and C2-C6 haloalkynyl;

[0099] R 5 It is a halogen;

[0100] R 6 It is a halogen;

[0101] R 7 R 8 Together 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

[0102] o is 0, 1, 2, or 3; and

[0103] R 78 It is independently selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, and C1-C6 haloalkoxy groups;

[0104] R 9 In each case, it is independently selected from CH3, CH2F, and CHF2;

[0105] R 10 In each case, it is independently selected from H, halogen, O(R) 95 ), C1-C6 alkyl and C1-C6 haloalkyl; wherein

[0106] R 95 It is a C1-C6 alkyl or a C1-C6 haloalkyl.

[0107] Therefore, the present invention further relates to a method comprising the following steps:

[0108] (i) Providing a compound of formula I by the method according to any one of claims 1-2;

[0109] (ii) Providing a compound of formula IV by the method according to any one of claims 4-6;

[0110] (iii) Providing a compound of formula V by the method according to any one of claims 7-8;

[0111] (iv) Providing a compound of formula VI by the method according to claim 9;

[0112] (v) Reacting compound VI with compound VIII to provide compound VII:

[0113]

[0114] Where R 1 R 2 R 9 and R 10 As defined above.

[0115] According to one embodiment, step (v) is carried out in the presence of a catalyst comprising a Cu source, a Pd source, and an optional ligand.

[0116] During the reaction, the catalyst system (Pd+ ligand) can be added together or separately at room temperature or elevated temperatures. This system can be prepared separately by combining the Pd salt and ligand immediately before the reaction, or it can be previously synthesized or purchased in pure or solution form. Alternatively, the ligand and palladium source can be added directly to the batch (in-situ process). Alternatively, the reaction can be carried out using only the palladium source without the addition of additional ligand.

[0117] The palladium catalysts used are optionally produced in situ from at least one palladium(II) salt or palladium(O) compound and the corresponding phosphine ligand. However, they can also be used directly as palladium(O) or palladium(II) compounds without reducing the initial catalytic activity.

[0118] According to one embodiment of the present invention, the Pd source is selected from the group consisting of: Pd(OAc)2, Pd(II)Cl2, 1,2-bis(diphenylphosphino)ethane palladium(II) chloride, 1,3-bis(diphenylphosphino)propane palladium(II) chloride, 1,4-bis(diphenylphosphino)butane palladium(II) chloride, 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride, tetra(triphenylphosphine)palladium(O), bis(triphenylphosphine)palladium(II) chloride, 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.

[0119] According to one embodiment of the present invention, the ligand is a monodentate or bidentate phosphorus-containing ligand.

[0120] The following are preferred as monodentate phosphorus-containing ligands:

[0121] Monodentate phosphorus-containing ligands of formula P:

[0122]

[0123] in

[0124] P′, P″, P″′ are independently selected from unsubstituted or substituted C1-C6 alkyl, C3-C6 cycloalkyl, aryl, and heteroaryl groups.

[0125] More preferably, monodentate phosphorus-containing ligands 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-sulfonylphenyl)phosphine, diphenyl(2-sulfonylphenyl)phosphine, tri(1-naphthyl)phosphine, di-tert-butyl-phenylphosphine, XPhos, SPhos, RuPhos, and diphenyl-2-pyridylphosphine. Most preferably, triphenylphosphine, tri(p-tolyl)phosphine, and tri(cyclohexyl)phosphine.

[0126] The following are preferred bidentate phosphorus-containing ligands: 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-dixantphosphonium (Xantphos), 1,2-bis(di-tert-butylphosphinomethyl)benzene, 1,2-bis(di-tert-pentylphosphinomethyl)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. The 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).

[0127] The molar ratio of palladium to phosphine ligand should be 4:1-1:100, preferably 1:1-1:5, and particularly preferably 1:1-1:2.

[0128] During the reaction, the catalyst system (Pd+ ligand) can be added together or separately at room temperature or elevated temperatures. This system can be prepared separately by combining the Pd salt and ligand immediately before the reaction, or it can be purchased or synthesized in pure or solution form. Alternatively, the ligand and palladium source can be added directly to the batch (in-situ process).

[0129] According to one embodiment of the present invention, the Cu salt is selected from the group consisting of: CuI, CuBr, CuCl, CuF, Cu2O, Cu(OAc), Cu2(CO3)(OH)2, CuSO4, CuO, Cu(O trifluoromethanesulfonate)2, and Cu(OAc)2. Most preferably, CuBr, CuCl, Cu2O, CuSO4, and CuO are used.

[0130] The molar ratio of palladium to copper salt should be 0.01-50, preferably 0.05-20, and more preferably 0.1-5.

[0131] Suitable organic solvents for the reaction are aprotic solvents, such as aromatic hydrocarbons like benzene, toluene, xylene, cumene, chlorobenzene, dichlorobenzene, nitrobenzene, or tert-butylbenzene, and aprotic polar solvents, such as cyclic or acyclic ethers like diethyl ether, diisopropyl ether, tert-butylmethyl ether (MTBE), tert-butylethyl ether, tetrahydrofuran (THF), or diethyl ether. Alkanes, 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, or 1,1,2-trichloroethylene; or aliphatic nitriles such as acetonitrile or propionitrile; and mixtures of the above solvents. Preferred are acetonitrile, 3-methylbutanone, 4-methylpentanone-2, ethyl acetate, butyl acetate, N-methylpyrrolidone, dimethylformamide, toluene, xylene, and even more preferably toluene, N-methylpyrrolidone, or butyl acetate.

[0132] Where R 9 Compounds of formula VIII (CH3) are prepared by reacting compounds of formula IX with brominating agents selected from, for example, N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), or systems consisting of HBr / H2O2, in the presence of 65% fuming sulfuric acid.

[0133]

[0134] in

[0135] R 1 In each case, the components are independently selected from hydrogen, halogen, C1-C6 alkyl, and C1-C6 haloalkyl;

[0136] R 2 In each case, it is independently selected from hydrogen and halogens;

[0137] R 10 In each case, it is independently selected from H, halogen, O(R) 95 ), C1-C6 alkyl and C1-C6 haloalkyl; wherein

[0138] R 95 It is a C1-C6 alkyl or a C1-C6 haloalkyl.

[0139] Preferably, the brominating agent in the method according to the invention 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).

[0140] Typical reaction times are 1-20 hours, preferably 2-15 hours, more preferably 3-10 hours, and most preferably 3-5 hours.

[0141] Typically, inert organic solvents are used to extract the product.

[0142] "Inert organic solvent" refers to an organic solvent that does not react significantly with the reactants or products under the reaction conditions of the method of this invention.

[0143] 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, ethers, esters, ketones, and any combination thereof.

[0144] Examples of suitable non-halogenated aliphatic hydrocarbons include pentane, hexane, and heptane. Saturated aliphatic hydrocarbons with 5-10 carbon atoms are preferred.

[0145] 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.

[0146] Examples of suitable non-halogenated aromatic hydrocarbons include toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 2-propylbenzene (cumene), 2-isopropyltoluene (o-cymene), 3-isopropyltoluene (m-cymene), 4-isopropyltoluene (p-cymene), and 1,3,5-trimethylbenzene (mesotrimethylbenzene). Toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 1,3,5-trimethylbenzene (mesotrimethylbenzene), 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.

[0147] 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.

[0148] Examples of suitable halogenated aromatic hydrocarbons include chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, α,α,α-trifluorotoluene (trifluorotoluene), and any combination thereof.

[0149] 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, methyltetrahydrofuran, tetrahydrofuran, and 1,4-diethyl ether. Alkanes and any combination thereof.

[0150] Examples of suitable esters include ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, tert-butyl acetate, and any combination thereof.

[0151] Examples of suitable ketones include acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, cyclopropyl methyl ketone, and any combination thereof.

[0152] After extraction, the inert solvent is evaporated and the crude product is purified by distillation.

[0153] The brominating agent DBDMH and R in it 1 =H and R 2 The molar ratio of the pyridine derivative of formula I with H 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, and even more preferably 0.50:1-1.0:1. To avoid byproducts, it is preferable to use a brominating agent of less than 1 eq compared to pyridine. Therefore, the brominating agent DBDMH and R in which... 1 =H and R 2 The molar ratio of the pyridine derivative of formula I with H is preferably 0.4-1.1, more preferably 0.4-0.9.

[0154] Preferably, R is performed. 1 =H and R 2 Bromination of compounds of formula I with the =H symbol. A preferred brominating agent is 1,3-dibromo-5,5-dimethylhydantoin (DBDMH). In this case, bromination is preferably carried out without additional solvent.

[0155] In this case, the reaction temperature is preferably 0-150°C, especially 80-125°C, and the reaction time is 2-10 hours, more preferably 2-5 hours.

[0156] Preferably, the purification is carried out by vacuum distillation (50-55°C; 1.6-2.0 mbar).

[0157] Where R 9 For compounds of formula VIII, CH2F or CHF2, R is used where 9 Compound VIII of formula CH3 is prepared by chlorination and fluorination reactions.

[0158] According to one embodiment of the invention, the chlorination step is carried out in an inert solvent.

[0159] "Inert organic solvent" refers to an organic solvent that does not react significantly with the reactants or products under the reaction conditions of the method of this invention.

[0160] 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, nitriles, and any combination thereof.

[0161] Examples of suitable non-halogenated aliphatic hydrocarbons include pentane, hexane, and heptane. Saturated aliphatic hydrocarbons with 5-10 carbon atoms are preferred.

[0162] 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.

[0163] Examples of suitable non-halogenated aromatic hydrocarbons include toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 2-propylbenzene (cumene), 2-isopropyltoluene (o-cymene), 3-isopropyltoluene (m-cymene), 4-isopropyltoluene (p-cymene), and 1,3,5-trimethylbenzene (mesotrimethylbenzene). Toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 1,3,5-trimethylbenzene (mesotrimethylbenzene), 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.

[0164] 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.

[0165] Examples of suitable halogenated aromatic hydrocarbons include chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, α,α,α-trifluorotoluene (trifluorotoluene), and any combination thereof.

[0166] Examples of suitable amides include N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, N-methylpyrrolidone, DMI (dimethylimidazolinone) or tetramethylurea, and any combination thereof.

[0167] 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, methyltetrahydrofuran, and 1,4-diethyl ether. Alkanes and any combination thereof.

[0168] Examples of suitable esters include ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate, and any combination thereof.

[0169] Examples of suitable nitriles include acetonitrile, propionitrile, benzyl nitrile, and any combination thereof.

[0170] 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-butylmethyl ether (MTBE), tert-butylethyl ether, methylcyclopentyl ether, tetrahydrofuran (THF), methyltetrahydrofuran (methylTHF), or diethyl ether. Alkanes, nitriles, such as acetonitrile and propionitrile, aliphatic halogenated hydrocarbons, such as dichloromethane, dichloroethane, trichloromethane and mixtures thereof.

[0171] More preferably, the inert solvent is chlorobenzene.

[0172] According to another embodiment of the invention, the chlorinating agent is selected from the group consisting of: N-chlorosuccinimide (NCS), sulfonyl chloride, Cl2, trichloroisocyanuric acid, and 1,3-dichloro-5,5-dimethylhydantoin.

[0173] Preferably, the chlorinating agent is trichloroisocyanuric acid.

[0174] Preferably, the amount of chlorinating agent used is 0.5-2 equivalents, particularly 0.6-1.2 equivalents, and more specifically 0.7-0.8 equivalents, relative to 1 equivalent of compound VIII.

[0175] According to another embodiment of the invention, the chlorination step is carried out in the presence of an organic carboxylic acid and in the absence of an alkali metal salt of said carboxylic acid (which leads to a reduction in waste).

[0176] Preferably, the organic acid is selected from the group consisting of formic acid, acetic acid, propionic acid, or butyric acid; and the aliphatic sulfonic acid is selected from the group consisting of methanesulfonic acid, ethanesulfonic acid, and trifluoromethanesulfonic acid. More preferably, it is selected from the group consisting of acetic acid and trifluoroacetic acid. Most preferably, it is acetic acid.

[0177] Typical reaction times are 1-20 hours, preferably 2-15 hours, more preferably 3-10 hours, and most preferably 3-5 hours.

[0178] In a next step according to the invention, dichloro-substituted pyridine is converted to difluoro-substituted pyridine in the presence of a fluorinating agent.

[0179] According to another embodiment of the invention, the fluorinating agent is selected from the group consisting of: KF, KHF2, NaF, CaF2, Olah reagent, and trialkylamine polyhydrofluoride complexes.

[0180] Trialkylamine polyhydrofluoride complexes can be described by formula (C1-C6 alkyl)3NxnHF, where n = 1-3, for example (C2H5)3Nx3HF.

[0181] Preferably, the fluorinating agent is (C2H5)3Nx3HF.

[0182] Preferably, the amount of fluorinating agent used is 2.0-10 equivalents, particularly 2.5-8.0 equivalents, and more specifically 3.0-6.0 equivalents, relative to 1 equivalent of compound III.

[0183] According to another embodiment of the invention, the fluorination reaction is carried out in the presence of an amine.

[0184] Suitable amines are tertiary amines, such as tri(C1-C6 alkyl)amines, such as trimethylamine, triethylamine, or diisopropylethylamine, N-methylpiperidine, pyridine, substituted pyridines, such as 2,4,6-trimethylpyridine (corridin), 2,6-dimethylpyridine (rutidine), 2-methylpyridine (α-methylpyridine), 3-methylpyridine (β-methylpyridine), 4-methylpyridine (γ-methylpyridine), and 4-dimethylaminopyridine, and bicyclic amines, such as 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, or 1,5-diazabicyclo[4.3.0]non-5-ene. Triethylamine, pyridine, or 1,8-diazabicyclo[5.4.0]undec-7-ene are particularly preferred. Triethylamine is the most preferred. Preferably, the amount of amine used is 1.0-10 equivalents, particularly 1.5-8.0 equivalents, and even more particularly 2.0-6.0 equivalents, relative to 1 equivalent of compound III.

[0185] According to another embodiment of the invention, the fluorination reaction is carried out in the presence of a phase transfer catalyst.

[0186] The phase transfer catalysts suitable for the method of the present invention are those well known in the art. Preferred phase transfer catalysts are selected from quaternary ammonium salts and quaternary pyridines. Salt, Season Salts and any combination thereof, more preferably selected from quaternary ammonium salts, ... and quaternary ammonium salts. Salt and any combination thereof.

[0187] More preferably, the phase transfer catalyst is selected from quaternary ammonium salts of the following general formulas and quaternary ammonium salts of the following general formulas. Salt and any combination thereof:

[0188] (R′R″R″′R″″N) + Z1 - ,

[0189] Among them, R′, R″, R″′, and R″″ are either the same or different, and each is independently selected from the following groups: C1-C 20 Alkyl, C3-C 10 cycloalkyl, C6-C 20 Aryl C6-C 20 Aryl-C1-C4 alkyl, and Z1- It is a monovalent anion.

[0190] (R′R″R″′R″″P) + Z2 - (P)

[0191] R′, R″, R″′, and R″″ may be the same or different, and each is independently selected from a 5- or 6-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from the group consisting of O, N, and S, and Z2 - It is a monovalent anion.

[0192] The term “a 5- or 6-membered heterocyclic group comprising 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-piperidinyl, morpholinyl and 4-methyl-1-piperidinyl.

[0193] In a preferred embodiment, the monovalent anion Z1 - The ions are selected from halide ions, hydroxide ions, hydrogen sulfate ions and monomethyl sulfate ions, more preferably from chloride ions, bromide ions, iodide ions and hydroxide ions, even more preferably from chloride ions or bromide ions, with chloride ions being the most preferred.

[0194] In another preferred embodiment, the monovalent anion Z1 - Selected from halide ions, more preferably from chloride ions or bromide ions, with chloride ions being the most preferred.

[0195] In yet another preferred embodiment, the monovalent anion Z2 - The ions are selected from halide ions, hydroxide ions, hydrogen sulfate ions and monomethyl sulfate hydrogen ions, more preferably from chloride ions, bromide ions, iodide ions and hydroxide ions, even more preferably from chloride ions or bromide ions, with chloride ions being the most preferred.

[0196] In another preferred embodiment, the monovalent anion Z2 - Selected from halide ions, more preferably from chloride ions or bromide ions, with chloride ions being the most preferred.

[0197] In a preferred embodiment, the phase transfer catalyst is selected from quaternary ammonium salts of general formula (P), wherein R 4 R 5 R 6 and R 7 The groups selected independently, whether identical or different, are as follows: C1-C 20 Alkyl, C6-C 20 Aryl and C1-C8 aryl-C1-C4 alkyl-.

[0198] More preferably, the phase transfer catalyst is selected from quaternary ammonium salts of general formula (P), wherein R 4 R 5R 6 and R 7 Same or different, and each independently selected from C1-C 20 Alkyl, or even more preferably C1-C 12 Alkyl, more preferably C1-C8 alkyl, and still more preferably C1-C4 alkyl.

[0199] A particularly preferred phase transfer catalyst that can be used in the method of the present invention is tetra-n-C1-C. 12Alkylammonium chlorides, bromides, iodides, hydroxides, hydrogen sulfates, or monomethyl sulfates (especially chlorides), preferably tetra-C1-C8 alkylammonium chlorides, bromides, iodides, hydroxides, hydrogen sulfates, or monomethyl sulfates (especially chlorides), such as tetramethylammonium chlorides, bromides, iodides, hydroxides, hydrogen sulfates, or monomethyl sulfates (especially chlorides), tetraethylammonium chlorides, bromides, iodides, hydroxides, hydrogen sulfates, or monomethyl sulfates, and tetra-n-propylammonium chlorides, bromides, and... Iodides, hydroxides, hydrogen sulfates, or monomethyl sulfates; chlorides, bromides, iodides, hydroxides, hydrogen sulfates, or monomethyl sulfates (especially chlorides) of tetra-n-butylammonium; chlorides, bromides, iodides, hydroxides, hydrogen sulfates, or monomethyl sulfates (especially chlorides) of tetra-n-pentylammonium; chlorides, bromides, iodides, hydroxides, hydrogen sulfates, or monomethyl sulfates (especially chlorides) of tetra-n-hexylammonium; chlorides, bromides, iodides, hydroxides, hydrogen sulfates, or monomethyl sulfates (especially chlorides) of tetra-n-heptylammonium. (especially chlorides), chlorides, bromides, iodides, hydroxides, hydrogen sulfates, or monomethyl sulfates of tetra-n-octylammonium (especially chlorides), chlorides, bromides, iodides, hydroxides, hydrogen sulfates, or monomethyl sulfates of methyltri-n-butylammonium (especially chlorides), chlorides, bromides, iodides, hydroxides, hydrogen sulfates, or monomethyl sulfates of ethyltrimethylammonium (especially chlorides), chlorides, bromides, iodides, hydroxides, hydrogen sulfates, or monomethyl sulfates of n-propyltrimethylammonium (especially chlorides) (e.g., chloride, bromide, iodide, hydroxide, hydrogen sulfate or monomethyl sulfate salt of methyltriethylammonium, especially chloride); chloride, bromide, iodide, hydroxide, hydrogen sulfate or monomethyl sulfate salt of n-butyltriethylammonium, especially chloride); chloride, bromide, iodide, hydroxide, hydrogen sulfate or monomethyl sulfate salt of tri-n-octylmethylammonium, especially chloride); and chloride, bromide, iodide, hydroxide, hydrogen sulfate or monomethyl sulfate salt of n-dodecyltrimethylammonium, especially chloride. Preferably, the chloride, bromide, iodide, hydroxide, hydrogen sulfate or monomethyl sulfate salt (especially chloride) of tetra-n-C1-C4 alkylammonium is used, especially the chloride, bromide, iodide, hydroxide, hydrogen sulfate or monomethyl sulfate salt (more specifically chloride) of tetra-n-butylammonium and the chloride, bromide, iodide, hydroxide, hydrogen sulfate or monomethyl sulfate salt (more specifically chloride) of methyltri-n-butylammonium.

[0200] Even more preferably, the phase transfer catalyst is selected from tetra-n-butylammonium chloride, tri-n-octylmethylammonium chloride, n-dodecyltrimethylammonium chloride, benzyl(tri-n-butyl)ammonium chloride, tetra(1-piperidinyl)ammonium chloride, etc. and any combination thereof.

[0201] Phase transfer catalysts, typically in pure solid form, can be used as is, or preferably 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 aromatic or aliphatic hydrocarbons.

[0202] According to another embodiment of the invention, the fluorination reaction is carried out in the presence of a polar solvent. It has been found that using a catalytic amount of polar solvent accelerates the fluorination reaction.

[0203] The suitable organic solvents for the reaction are aprotic polar solvents, such as cyclic or acyclic ethers, including 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, and 1,4-diethyl methyl ether. Alkane, cyclic or acyclic amides, such as dimethylformamide, diethylformamide, dimethylacetamide, diethylacetamide, N-methylpyrrolidone, DMI (dimethylimidazolinone), or tetramethylurea, or aliphatic nitrile, such as acetonitrile or propionitrile, and mixtures of the above solvents. DMF, NMP, and DMI are preferred.

[0204] Preferably, the polar solvent is DMF.

[0205] Typical reaction times are 1-24 hours, preferably 2-16 hours, more preferably 3-15 hours, and most preferably 4-12 hours.

[0206] The halogen exchange reaction is carried out between 70°C and 180°C, preferably between 80°C and 160°C.

[0207] The terms "compound I", "compound II", "compound IIa", and "compound III" refer to compounds of formulas I, II, IIa, and III, respectively. In the definitions of variables given above, collective terms are used, which typically represent the substituents.

[0208] In the definitions of variables given in this paper, collective terms are used, which are typically representative of the substituents. The term "C" n -C m "" indicates the number of carbon atoms that may be present in the substituent or substituent structural portion in each case.

[0209] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0210] The term "C1-C6 alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1-6 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methyl Pentyl, 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. Similarly, the term "C2-C4 alkyl" refers to a straight-chain or branched alkyl group having 2-4 carbon atoms, such as ethyl, propyl (n-propyl), 1-methylethyl (isopropyl), butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), and 1,1-dimethylethyl (tert-butyl).

[0211] The term "C1-C6 haloalkyl" refers to an alkyl group having one or six carbon atoms as defined above, wherein some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as described above. Examples are "C1-C2 haloalkyl" groups, such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichloromonofluoromethyl, 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.

[0212] The term "C2-C6 alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon group having 2-6 carbon atoms and a double bond in any position. Examples are "C2-C4 alkenyl" groups, such as vinyl, 1-propenyl, 2-propenyl (allyl), 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, and 2-methyl-2-propenyl.

[0213] The term “C2-C6 haloalkenyl” 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 described above.

[0214] The term "C2-C6 ynyl" refers to a straight-chain or branched unsaturated hydrocarbon group having 2-6 carbon atoms and containing at least one triple bond. Examples are "C2-C4 ynyl" groups, such as ethynyl, propynyl-1-ynyl, propynyl-2-ynyl (propynyl), butynyl-1-ynyl, butynyl-2-ynyl, butynyl-3-ynyl, and 1-methyl-propynyl-2-ynyl.

[0215] The term “C2-C6 haloalkynyl” 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 described above.

[0216] The term "C1-C6 alkoxy" refers to a straight-chain or branched alkyl group having 1-6 carbon atoms, bonded by oxygen at any position on the alkyl group. Examples are "C1-C4 alkoxy" groups, such as methoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, or 1,1-dimethylethoxy.

[0217] The term "C1-C6 haloalkoxy" refers to C1-C6 alkoxy groups as defined above, wherein some or all of the hydrogen atoms in these groups can be replaced by halogen atoms as described above. Examples are "C1-C4 haloalkoxy" groups, such as OCH2F, OCHF2, OCF3, OCH2Cl, OCHCl2, OCCl3, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 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, OC2F 5. 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.

[0218] The term "phenyl-C1-C6 alkyl" refers to an alkyl group having 1-6 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl group is replaced by a phenyl group. Similarly, the terms "phenyl-C2-C6 alkenyl" and "phenyl-C2-C6 ynyl" refer to alkenyl and ynyl groups, respectively, wherein one hydrogen atom of the aforementioned groups is replaced by a phenyl group.

[0219] The following section discusses variable R. 1 R2 R 3 R 4 R 5 R 6 R 7 R 78 R 95 R 10 The meanings and preferred meanings described above apply to compounds in any of the methods of the present invention detailed above, as well as compounds and byproducts of formulas I, II, III, IV, V and VI.

[0220] According to one embodiment of the present invention, in compounds of formulas I, II, III, IV, V, VI, VII, and VIII, if applicable, the variables, whether independent of each other or more preferably in combination, have the following meanings:

[0221] R 1 In each case, they are independently selected from hydrogen and C1-C6 alkyl groups;

[0222] R 2 In each case, it is independently selected from hydrogen;

[0223] R 3 R 4 Independently selected from C1-C6 alkyl and C1-C6 haloalkyl;

[0224] R 5 It is a halogen;

[0225] R 6 It is a halogen;

[0226] R 7 R 8 Together 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

[0227] o is 0, 1, 2, or 3; and

[0228] R 78 Independently selected from halogens and C1-C6 alkyl groups;

[0229] R 9 In each case, it is independently selected from CH3, CH2F, and CHF2;

[0230] R 10 It is independently selected from C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl.

[0231] According to another embodiment of the invention, in compounds of formulas I, II, III, IV, V, VI, VII, and VIII, if applicable, the variables, whether independent of each other or more preferably in combination, have the following meanings:

[0232] R 1 It is hydrogen;

[0233] R 2 It is hydrogen;

[0234] R 3 R 4 Independently selected from C1-C6 alkyl and C1-C6 haloalkyl;

[0235] R 5 It is a halogen;

[0236] R 6 It is a halogen;

[0237] R 7 R 8 Together 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

[0238] o is 0, 1, 2, or 3; and

[0239] R 78 Independently selected from halogens and C1-C6 alkyl groups;

[0240] R 9 In each case, it is independently selected from CH3, CH2F, and CHF2;

[0241] R 10 It is independently selected from C1-C6 alkyl and C1-C6 haloalkyl.

[0242] According to another embodiment of the invention, in compounds of formulas I, II, III, IV, V, VI, VII, and VIII, if applicable, the variables, whether independent of each other or more preferably in combination, have the following meanings:

[0243] R 1 It is hydrogen;

[0244] R 2 It is hydrogen;

[0245] R 3 R 4 Independently, it is a C1-C6 alkyl group;

[0246] R 5 It is a halogen;

[0247] R 6 It is a halogen;

[0248] R 7 R 8 Together 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

[0249] o is 0, 1, 2, or 3; and

[0250] R 78 Independently selected from halogens and C1-C6 alkyl groups;

[0251] R 9 In each case, it is independently selected from CH3 and CHF2;

[0252] R 10 It is independently selected from C1-C6 alkyl and C1-C6 haloalkyl.

[0253] According to another embodiment of the invention, in compounds of formulas I, II, III, IV, V, VI, VII, and VIII, if applicable, the variables, whether independent of each other or more preferably in combination, have the following meanings:

[0254] R 1 It is hydrogen;

[0255] R 2 It is hydrogen;

[0256] R 3 R 4 Independently, it is a C1-C6 alkyl group;

[0257] R 5 For F;

[0258] R 6 For F;

[0259] R 7 R 8 Together 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, of which

[0260] o is 0, 1, 2, or 3; and

[0261] R 78 Independently selected from halogens and C1-C6 alkyl groups;

[0262] R 9 In each case, it is independently selected from CH3 and CHF2;

[0263] R 10 It is independently selected from C1-C6 alkyl and C1-C6 haloalkyl.

[0264] According to another embodiment of the invention, in compounds of formulas I, II, III, IV, V, VI, VII, and VIII, if applicable, the variables, whether independent of each other or more preferably in combination, have the following meanings:

[0265] R 1 It is hydrogen;

[0266] R 2 It is hydrogen;

[0267] R 3 R 4 Independently, it is a C1-C6 alkyl group;

[0268] R 5 For F;

[0269] R 6 For F;

[0270] R 7 R 8 Together 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

[0271] o is 0, 1, 2, or 3; and

[0272] R 78 Independently selected from halogens and C1-C6 alkyl groups;

[0273] R 9 In each case, it is independently selected from CH3 and CHF2;

[0274] R 10 It is independently selected from CH3 and CHF2.

[0275] The particularly preferred active compound I is selected from the group consisting of compounds IA to IZA:

[0276] IA: 1-(5,6-dimethyl-3-pyridyl)-4,4-difluoro-3,3-dimethylisoquinoline

[0277] IB: 1-[6-(difluoromethyl)-5-methyl-3-pyridyl]-4,4-difluoro-3,3-dimethyl-isoquinoline

[0278] IC: 1-[6-(difluoromethyl)-5-methoxy-3-pyridyl]-4,4-difluoro-3,3-dimethyl-isoquinoline

[0279] ID: 4,4-Difluoro-1-[5-(fluoromethyl)-6-methyl-3-pyridyl]-3,3-dimethyl-isoquinoline

[0280] IE: 4,4-Difluoro-1-(5-methoxy-6-methyl-3-pyridyl)-3,3-dimethylisoquinoline

[0281] IF: 4,4-Difluoro-1-[6-(fluoromethyl)-5-methyl-3-pyridyl]-3,3-dimethyl-isoquinoline

[0282] IG: 1-[5,6-bis(fluoromethyl)-3-pyridyl]-4,4-difluoro-3,3-dimethylisoquinoline

[0283] IH: 4,4-Difluoro-1-[6-(fluoromethyl)-5-methoxy-3-pyridyl]-3,3-dimethyl-isoquinoline

[0284] II: 1-[6-(difluoromethyl)-5-(fluoromethyl)-3-pyridyl]-4,4-difluoro-3,3-dimethyl-isoquinoline

[0285] IJ: 1-(5,6-dimethyl-3-pyridyl)-4,4,5-trifluoro-3,3-dimethylisoquinoline

[0286] IK: 4,4,5,5-trifluoro-1-[5-(fluoromethyl)-6-methyl-3-pyridyl]-3,3-dimethyl-isoquinoline

[0287] IL: 4,4,5-trifluoro-1-(5-methoxy-6-methyl-3-pyridyl)-3,3-dimethylisoquinoline

[0288] IM: 4,4,5-trifluoro-1-[6-(fluoromethyl)-5-methyl-3-pyridyl]-3,3-dimethyl-isoquinoline

[0289] IN: 1-[5,6-bis(fluoromethyl)-3-pyridyl]-4,4,5-trifluoro-3,3-dimethylisoquinoline

[0290] IO: 4,4,5-trifluoro-1-[6-(fluoromethyl)-5-methoxy-3-pyridyl]-3,3-dimethyl-isoquinoline

[0291] IP: 1-[6-(difluoromethyl)-5-methyl-3-pyridyl]-4,4,5-trifluoro-3,3-dimethylisoquinoline

[0292] IQ: 1-[6-(difluoromethyl)-5-(fluoromethyl)-3-pyridyl]-4,4,5-trifluoro-3,3-dimethylisoquinoline

[0293] IR: 1-[6-(difluoromethyl)-5-methoxy-3-pyridyl]-4,4,5-trifluoro-3,3-dimethylisoquinoline

[0294] IS: 1-(5,6-dimethyl-3-pyridyl)-4,4,6-trifluoro-3,3-dimethylisoquinoline

[0295] IT: 4,4,6-Trifluoro-1-[5-(fluoromethyl)-6-methyl-3-pyridyl]-3,3-dimethylisoquinoline

[0296] IU: 4,4,6-trifluoro-1-(5-methoxy-6-methyl-3-pyridyl)-3,3-dimethylisoquinoline

[0297] IV: 4,4,6-Trifluoro-1-[6-(fluoromethyl)-5-methyl-3-pyridyl]-3,3-dimethylisoquinoline

[0298] IW: 1-[5,6-bis(fluoromethyl)-3-pyridyl]-4,4,6-trifluoro-3,3-dimethylisoquinoline

[0299] IX: 4,4,6-trifluoro-1-[6-(fluoromethyl)-5-methoxy-3-pyridyl]-3,3-dimethylisoquinoline

[0300] IY: 1-[6-(difluoromethyl)-5-methyl-3-pyridyl]-4,4,6-trifluoro-3,3-dimethylisoquinoline

[0301] IZ: 1-[6-(difluoromethyl)-5-(fluoromethyl)-3-pyridyl]-4,4,6-trifluoro-3,3-dimethylisoquinoline

[0302] I.ZA: 1-[6-(difluoromethyl)-5-methoxy-3-pyridyl]-4,4,6-trifluoro-3,3-dimethylisoquinoline.

[0303] Furthermore, this invention relates to compounds of formula I:

[0304]

[0305] in

[0306] R 3 R 4 It is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl and C2-C6 haloalkynyl;

[0307] R 78 It is independently selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, and C1-C6 haloalkoxy groups;

[0308] o can be 0, 1, 2, or 3;

[0309] Y is selected from C1-C6 alkyl, C1-C6 haloalkyl, phenyl, and benzyl, wherein the phenyl and benzyl are not substituted or are substituted by CN, NO2, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy, provided that R 3 and R 4 If CH3 is present and Y is C2H5, then o cannot be 0; and

[0310] If R 3 and R 4 If Y is CH3, and O is C2H5 with 1, then R 78 Not F.

[0311] Preferably, a compound of formula I is preferred, wherein

[0312] R 3 R 4 Independently, it is a C1-C6 alkyl group;

[0313] o is 0;

[0314] Y is a C1-C6 alkyl group;

[0315] The condition is if R 3 and R 4 If CH3 is present and Y is C2H5, then o cannot be 0.

[0316] More preferably, a compound of formula I, wherein

[0317] R 3 R 4 Independently CH3;

[0318] o is 0;

[0319] Y is a C1-C6 alkyl group;

[0320] The condition is if R 3 and R 4 If CH3 is present and Y is C2H5, then o cannot be 0.

[0321] According to another embodiment of the present invention, a compound of formula I is preferred:

[0322] R 3 R 4 Independently CH3;

[0323] o is 0; and

[0324] Y can choose from the following groups:

[0325] <![CDATA[C6H5]]> <![CDATA[4-Cl-C6H4]]> <![CDATA[4-F-C6H4]]> <![CDATA[4-CH3O-C6H4]]> <![CDATA[4-CH3-C6H4]]> <![CDATA[CH2-C6H5]]> <![CDATA[CH2-C6H4-4-F <!-- 17 -->]]> <![CDATA[CH2-C6H4-4-Cl]]> <![CDATA[CH2-C6H4-4-OCH3]]> <![CDATA[CH2-C6H4-4-CH3]]>

[0326] Furthermore, this invention relates to...

[0327] IV,

[0328]

[0329] in

[0330] R 3 R 4 It is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl and C2-C6 haloalkynyl;

[0331] R 78 It is independently selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, and C1-C6 haloalkoxy groups;

[0332] o can be 0, 1, 2, or 3;

[0333] Y is selected from C1-C6 alkyl, C1-C6 haloalkyl, phenyl and benzyl, wherein the phenyl and benzyl are not substituted or are substituted by CN, NO2, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy.

[0334] Preferably, compounds of formula IV are preferred, wherein

[0335] R 3 R 4 Independently, it is a C1-C6 alkyl group;

[0336] o is 0;

[0337] Y is a C1-C6 alkyl group;

[0338] More preferably, compounds of formula IV, wherein

[0339] R 3 R 4 Independently CH3;

[0340] o is 0;

[0341] Y is a C1-C6 alkyl group.

[0342] According to another embodiment of the invention, a compound of formula IV is preferred: R 3 R 4 Independently CH3;

[0343] o is 0; and

[0344] Y can choose from the following groups:

[0345] <![CDATA[C6H5]]> <![CDATA[4-Cl-C6H4]]> <![CDATA[4-F-C6H4]]> <![CDATA[4-CH3O-C6H4]]> <![CDATA[4-CH3-C6H4]]> <![CDATA[CH2-C6H5]]> <![CDATA[CH2-C6H4-4-F]]> <![CDATA[CH2-C6H4-4-Cl]]> <![CDATA[CH2-C6H4-4-OCH3]]> <![CDATA[CH2-C6H4-4-CH3]]>

[0346] Furthermore, this invention relates to...

[0347]

[0348] in

[0349] R 3 R 4 It is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl and C2-C6 haloalkynyl;

[0350] R 78 It is independently selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, and C1-C6 haloalkoxy groups;

[0351] o can be 0, 1, 2, or 3;

[0352] Y is selected from C1-C6 alkyl, C1-C6 haloalkyl, phenyl and benzyl, wherein the phenyl and benzyl are not substituted or are substituted by CN, NO2, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy.

[0353] Preferably, compound V is of the following formula, wherein

[0354] R 3 R 4 Independently, it is a C1-C6 alkyl group;

[0355] o is 0;

[0356] Y is a C1-C6 alkyl group.

[0357] More preferably, a compound of formula V, wherein

[0358] R 3 R 4 Independently CH3;

[0359] o is 0;

[0360] Y is a C1-C6 alkyl group.

[0361] According to another embodiment of the invention, compound V of the following formula is preferred:

[0362] R 3 R 4 Independently CH3;

[0363] o is 0; and

[0364] Y can choose from the following groups:

[0365] <![CDATA[C6H5]]> <![CDATA[4-Cl-C6H4]]> <![CDATA[4-F-C6H4]]> <![CDATA[4-CH3O-C6H4]]> <![CDATA[4-CH3-C6H4]]> <![CDATA[CH2-C6H5]]> <![CDATA[CH2-C6H4-4-F]]> <![CDATA[CH2-C6H4-4-Cl]]> <![CDATA[CH2-C6H4-4-OCH3]]> <![CDATA[CH2-C6H4-4-CH3]]>

[0366] The present invention is illustrated by the following embodiments:

[0367] program

[0368] Example 1 - Ethyl 3,3-dimethyl-4H-isoquinoline-1-carboxylate

[0369]

[0370] A solution of 380 g (2.53 mol) of 2-methyl-1-phenyl-prop-2-ol and 426 g (4.3 mol) of ethyl cyanocarboxylate in 500 mL of cyclohexane was added to a mixture of 500 mL of cyclohexane and 1899 g (19 mol) of concentrated sulfuric acid at 15 °C with stirring. After about 15 minutes, the reaction mixture was poured into an ice / water mixture and carefully alkalized with 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 evaporation was evaporated to give 584 g (99%) of ethyl 3,3-dimethyl-4H-isoquinoline-1-carboxylate as a yellow oil.

[0371] 1 H-NMR (CDCl3, δ, in ppm):

[0372] 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)

[0373] Example 2 - Ethyl 4,4-dibromo-3,3-dimethylisoquinoline-1-carboxylate

[0374]

[0375] 20 g (86 mmol) of ethyl 3,3-dimethyl-4H-isoquinoline-1-carboxylate, 33.8 g (190 mmol) of N-bromosuccinimide, and 2.8 g (17 mmol) of azobisisobutyronitrile (azobisisobutyronitrile) were heated to reflux with stirring in 250 mL of chloroform. After approximately 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 ethyl 4,4-dibromo-3,3-dimethyl-isoquinoline-1-carboxylate, which was subsequently used as the crude product.

[0376] HPLC-MS: HPLC column Kinetex XB C18 1.7μm (50x2.1mm); 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).

[0377] Rt = 1,034 minutes, M + +H = 245,9 (title compound, hydrolyzed to a carbonyl compound after HPLC-MS measurement); R t =1,275, M + +H = 389,8 (title compound ethyl 4,4-dibromo-3,3-dimethyl-isoquinoline-1-carboxylate)

[0378] Example 3 - Ethyl 4,4-difluoro-3,3-dimethylisoquinoline-1-carboxylate

[0379]

[0380] 79.6 g (493 mmol) of triethylamine x 3 fluoride (NEt3x3HF) was added to 40 g (80% purity, 82 mmol) of ethyl 4,4-dibromo-3,3-dimethylisoquinoline-1-carboxylate in 100 mL of acetonitrile. When HPLC indicated 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 were evaporated to give 12 g (55%) of the title compound ethyl 4,4-difluoro-3,3-dimethylisoquinoline-1-carboxylate as a brown oil.

[0381] 1 H-NMR (CDCl3, δ, in ppm):

[0382] 7,75(2d,2H); 7,65(2t,2H); 4,45(q,2H); 1,4(m,9H)

[0383] HPLC-MS: HPLC column Kinetex XB C18 1.7μm (50x2.1mm); 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).

[0384] Rt = 1,176 minutes, M + +H = 268.

[0385] Example 4 - Ethyl 4,4-difluoro-3,3-dimethylisoquinoline-1-carboxylate

[0386] 5 g (70% purity, 9 mmol) of ethyl 4,4-dibromo-3,3-dimethyl-isoquinoline-1-carboxylate was placed in a Hastelloy pressure reactor. Subsequently, 50 g of anhydrous hydrogen fluoride was condensed in the pressure reactor. The mixture was heated to 100 °C and held for 3 hours (14 bar). After cooling to 25 °C, the pressure was released and the reaction mixture was diluted with 100 mL of water. The mixture was then cooled with ice and the pH was adjusted to 10 with an aqueous KOH solution. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were extracted with brine. The organic phase was then dried over sodium sulfate, and the volatiles were evaporated to give 2.1 g (88.6% purity according to GC; yield 77.4%) of the title compound ethyl 4,4-difluoro-3,3-dimethyl-isoquinoline-1-carboxylate in the form of a brown oil.

[0387] Example 5 - (4,4-difluoro-3,3-dimethyl-isoquinoline-1-carbonyl)oxylithium

[0388]

[0389] 7.3 g (26 mmol) of ethyl 4,4-difluoro-3,3-dimethyl-isoquinoline-1-carboxylate and 1,143 g (27 mmol) of lithium hydroxide were stirred in 100 g of methanol 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 pale yellow solid (decomposes at Mp > 200 °C).

[0390] HPLC-MS: HPLC column Kinetex XB C18 1.7μm (50x2.1mm); 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).

[0391] M + +H=239.9(R t =0.797min)

[0392] Example 6-1-(5,6-dimethyl-3-pyridyl)-4,4-difluoro-3,3-dimethylisoquinoline

[0393]

[0394] 2.9 g (11.8 mmol) of (4,4-difluoro-3,3-dimethyl-isoquinoline-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, 0.231 g (1.6 mmol) of copper bromide (l) and 0.145 g (0.18 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.

[0395] The volatiles were then evaporated and the residue dissolved in methyl tert-butyl ether. This heterogeneous mixture was placed atop 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 to give 3.2 g (86% purity, 85% yield) of the title compound as a brown oil, which crystallized upon standing.

[0396] 1 H-NMR (CDCl3, δ, in ppm):

[0397] 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)

[0398] HPLC-MS: HPLC column Kinetex XB C18 1.7μm (50x2.1mm); 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).

[0399] M + +H=301(R t =0.889min)

[0400] Example 7-1-[6-(difluoromethyl)-5-methyl-3-pyridyl]-4,4-difluoro-3,3-dimethylisoquinoline

[0401]

[0402] 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.

[0403] 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.

[0404] 1 H-NMR (CDCl3, δ, in ppm):

[0405] 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)

[0406] HPLC-MS: HPLC column Kinetex XB C18 1.7μm (50x2.1mm); 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).

[0407] M + +H=337(R t =1,243min)

[0408] Example 8 - Bromination of 2,3-dimethylpyridine with DBDMH

[0409] DBDMH (14.5 g, 0.05 mol) was added to a stirred solution of 2,3-dimethylpyridine (10 g, 0.09 mol) in 65% (30 mL) fuming sulfuric acid at 10 °C. An exothermic reaction then began. 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 an aqueous sodium hydroxide solution. The product was extracted into MTBE (3 x 100 mL), and the organic phase was dried over MgSO4 and evaporated under reduced pressure to give 5-bromo-2,3-dimethylpyridine as a yellow oil (purity 87.3% according to GC; yield 83.3%).

[0410] Example 9 - Bromination of 2,3-dimethylpyridine with DBDMH

[0411] DBDMH (31.7 g, 0.11 mol) was added to a stirred solution of 2,3-dimethylpyridine (20 g, 0.185 mol) in 65% (60 mL) fuming sulfuric acid at 10 °C. An exothermic reaction then began. 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 an aqueous sodium hydroxide solution. The product was extracted into MTBE (3 x 100 mL), and the organic phase was dried over MgSO4 and evaporated under reduced pressure to give 5-bromo-2,3-dimethylpyridine (34.3 g) as a yellow oil. Purity was 87.0% according to GC; yield was 86.7%.

[0412] Example 1: Dichlorination of 10-5-bromo-2,3-dimethylpyridine

[0413] Trichloroisocyanuric acid (93.0 g, 0.4 mol) was added to a stirred solution of 5-bromo-2,3-dimethylpyridine (100 g, 0.54 mol) in acetic acid (150 mL) and chlorobenzene (1000 mL) at 25 °C. The reaction mixture was then heated at 125 °C for 3 hours. After cooling to room temperature, the mixture was poured into ice (300 g) and the pH was adjusted to 12 with an aqueous sodium hydroxide solution. The product was extracted into ethyl acetate (3 × 200 mL), and the organic phase was dried over MgSO4 and evaporated under reduced pressure to give 5-bromo-2-(dichloromethyl)-3-methylpyridine (139.3 g) as a brown oil. The purity was 57.3% according to HPLC. The yield was 58.2%.

[0414] 1 H-NMR(CDCl3): 2.6ppm(s,3H,CH3); 6.8ppm(s,1H,CHCl2); 7.7ppm(s,1H,CH); 8.5ppm(s,1H,CH)

[0415] Example 11: Dichlorination of 1,5-bromo-2,3-dimethylpyridine

[0416] Trichloroisocyanuric acid (93.0 g, 0.4 mol) was added to a stirred solution of 5-bromo-2,3-dimethylpyridine (100 g, 0.54 mol) in acetic acid (1000 mL) at 25 °C. The reaction mixture was then heated at 75 °C for 12 hours. After cooling to room temperature, the mixture was filtered. The solvent of the filtrate was evaporated under reduced pressure (70 °C, 40 mbar). Subsequently, the product was dissolved in 1000 mL of ethyl acetate and washed twice with aqueous sodium hydroxide solution. The organic phase was dried over MgSO4 and evaporated under reduced pressure to give 5-bromo-2-(dichloromethyl)-3-methylpyridine (130.0 g) as a white solid. Purity was 88.0% according to GC; yield was 84.0%.

[0417] Example 1: Fluorination of 2-5-bromo-2-(dichloromethyl)-3-methylpyridine

[0418] A triethylamine-3HF complex (63.2 g, 0.39 mol) was added to a stirred solution of 5-bromo-2-(dichloromethyl)-3-methylpyridine (20 g, 0.078 mol) in triethylamine (23.8 g, 0.24 mol) at 60 °C. The reaction mixture was then heated at 115 °C for 21 hours. After cooling to room temperature, water (20 mL) and CH2Cl2 (20 mL) were added to the reaction mixture, and the pH was adjusted to 9 with an aqueous potassium hydroxide solution. The product was extracted into CH2Cl2 (3 x 100 mL), and the organic phase was extracted with brine (1 x 100 mL), dried over Na2SO4, and evaporated under reduced pressure to give 5-bromo-2-(difluoromethyl)-3-methylpyridine (20.4 g) as a yellow oil. Purity was 71.7% according to GC; yield was 84.5%.

[0419] 1 H-NMR(CDCl3): 2.5ppm(s,3H,CH3); 6.65ppm(t,1H,CHF2); 7.75ppm(s,1H,CH); 8.5ppm(s,1H,CH).

[0420] Example 1: Fluorination of 3-5-bromo-2-(dichloromethyl)-3-methylpyridine

[0421] A triethylamine-3HF-complex (12.6 g, 0.08 mol) was added to a stirred solution of 5-bromo-2-(dichloromethyl)-3-methylpyridine (5 g, 0.0196 mol) in triethylamine (6.0 g, 0.06 mol) and DMF (0.7 g, 0.01 mol) at 60 °C. The reaction mixture was then heated at 115 °C for 18 hours. After cooling to room temperature, water (20 mL) and toluene (20 mL) were added to the reaction mixture, and the pH was adjusted to 9 with an aqueous potassium hydroxide solution. The product was extracted into toluene (3 × 100 mL), and the organic phase was extracted with brine (1 × 100 mL) and evaporated under reduced pressure to give 5-bromo-2-(difluoromethyl)-3-methylpyridine (4.3 g) as a yellow oil. Purity was 78.4% according to GC; yield was 83.2%.

[0422] Example 14: Dichlorination of 5-bromo-2,3-dimethylpyridine

[0423] Trichloroisocyanuric acid (234.2 g, 1.01 mol) was added to a stirred solution of 5-bromo-2,3-dimethylpyridine (250 g, 1.34 mol) in acetic acid (2500 mL) at 25 °C. The reaction mixture was then heated at 75 °C for 12 hours with stirring. After cooling to room temperature, the mixture was filtered. The solvent of the filtrate was evaporated under reduced pressure (70 °C, 40 mbar). The residue was then dissolved in 1000 mL of ethyl acetate and washed three times with a 10% aqueous sodium hydroxide solution. The organic phase was dried over Na₂SO₄ and evaporated under reduced pressure to give 5-bromo-2-(dichloromethyl)-3-methylpyridine (342 g) as a yellow solid.

[0424] The reaction was carried out four times using a total of 1 kg (5.37 mol) of 5-bromo-2,3-dimethylpyridine, as described above. The resulting crude products were dissolved in dichloromethane and combined, and the solvent was distilled off under vacuum. The residue was dissolved in 500 mL of n-heptane, and the mixture was stirred at 60 °C until all solids dissolved. The mixture was then cooled to room temperature. The title compound crystallized out and was stirred overnight. The mixture was then cooled in an ice / water bath, and the precipitated crystals were filtered off to give 1053 g (97% (GC) purity, 4.13 mol, 75% of theoretical value) of 5-bromo-2-(dichloromethyl)-3-methylpyridine (mp = 61 °C).

[0425] The mother liquor was evaporated to obtain 283g (62% purity (GC)) of the title compound.

[0426] 1H-NMR(CDCl3): 2.6ppm(s,3H,CH3); 6.8ppm(s,1H,CHCl2); 7.7ppm(s,1H,CH); 8.5ppm(s,1H,CH

[0427] Example 15-1-(5,6-dimethyl-3-pyridyl)-4,4-difluoro-3,3-dimethylisoquinoline

[0428] Under N2, CuBr (875.6 mg; 6,104 mmol), Pd(dppf)Cl2 (664.6 mg; 0.814 mmol), and 902.4 mg (1,628 mmol) dppf x CH2Cl2 ([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexed with dichloromethane) were added to a suspension of 5-bromo-1,3-dimethylpyridine (7,805 g; 40,693 mmol) and (4,4-difluoro-3,3-dimethyl-isoquinoline-1-carbonyl)oxylithium (9,976 g; 40,693 mmol) in 100 mL of dry N-methylpyrrolidone. The reaction mixture was heated to 150 °C and stirred for 3 hours. After the reaction was complete (HPLC), the mixture was cooled to 10 °C.

[0429] Then, slowly add 100 ml of 5M hydrochloric acid through a dropping funnel. Extract the aqueous layer twice with 100 ml of n-heptane each time and discard the organic layer.

[0430] 300 mL of n-heptane was added to the aqueous layer, and the solution was alkalized to pH 10 with 50% sodium hydroxide solution at 25 °C. The precipitated solid residue was filtered off, washed with n-heptane (3 × 50 mL), and discarded. Subsequently, the layers were separated, and the aqueous layer was extracted with n-heptane (2 × 300 mL). The combined organic layers were dried on Na₂SO₄, the drying agent was filtered off, and the evaporation was evaporated to give 11.1 g of the title compound in orange crystalline form.

[0431] 8.05 g of beige crystals (purity 93.5%) were obtained by recrystallization from heptane. 1 ¹H-NMR (yield 61.6%) was used to purify 1-(5,6-dimethyl-3-pyridyl)-4,4-difluoro-3,3-dimethylisoquinoline in white crystalline form by column chromatography with a mixture of cyclohexane and ethyl acetate (mp = 10⁴–10⁵ °C). 1 H-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)

[0432] Example 16-1-[6-(difluoromethyl)-5-methyl-3-pyridyl]-4,4-difluoro-3,3-dimethylisoquinoline

[0433] Under N2, 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(II), complexed with dichloromethane) were added to a suspension of 5-bromo-2-(difluoromethyl)-3-methylpyridine (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 dried N-methylpyrrolidone. The reaction mixture was heated at 150 °C and stirred for 8 hours. After the reaction was complete (HPLC), the mixture was cooled to 10 °C and then added to a mixture of 300 mL of water and 500 mL of n-heptane. The mixture was then alkalized at 25°C with 50 ml of 25% ammonia solution (pH 11-12) and filtered through diatomaceous earth (Celite). The diatomaceous earth was washed with n-heptane, and the ammonia layer was separated from the n-hexane layer.

[0434] The combined heptane phases were washed twice with 250 ml of 5% hydrochloric acid. After the first extraction, some insoluble matter precipitated out; this was filtered off and discarded.

[0435] The organic layer was dried on Na2SO4, filtered, and evaporated to give 40.5 g of the title compound (purity ~80% (quantitative-HPLC)).

[0436] Dissolve the product in 400 ml of n-heptane. Extract the heptane phase twice with 250 ml of 15% HCl, and then discard the heptane phase.

[0437] The combined HCl layers were treated three times with 500 ml of dichloromethane to extract the product into the organic phase.

[0438] Subsequently, the combined dichloromethane layers were stirred together with 300 ml of 20% Na2CO3 solution for 1 hour.

[0439] The phases were separated, and the organic layer was dried on Na2SO4, filtered, and evaporated to obtain 33.3 g of 1-[6-(difluoromethyl)-5-methyl-3-pyridyl]-4,4-difluoro-3,3-dimethylisoquinoline (purity 92.5%). 1 H-NMR), yield 56%.

[0440] The title compound can be further purified by column chromatography using a mixture of cyclohexane and ethyl acetate.

[0441] 1 H-NMR (CDCl3, δ, in ppm):

[0442] 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).

Claims

1. A method for preparing compound of formula I: in R 3 R 4 Independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl and C2-C6 haloalkynyl; R 78 It is independently selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, and C1-C6 haloalkoxy groups; o can be 0, 1, 2, or 3; Y is selected from C1-C6 alkyl, C1-C6 haloalkyl, phenyl, and benzyl, wherein the phenyl and benzyl groups are unsubstituted or substituted by CN, NO2, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy groups. A one-step reaction involving compounds of formula II and formula III: Where R 3 R 4 o and R 78 As defined above, Y is defined as above.

2. The method according to claim 1, wherein the reaction is carried out in the presence of sulfuric acid.

3. A method for preparing compound IV: in R 3 R 4 Independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl and C2-C6 haloalkynyl; R 78 It is independently selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, and C1-C6 haloalkoxy groups; o can be 0, 1, 2, or 3; Y is selected from C1-C6 alkyl, C1-C6 haloalkyl, phenyl, and benzyl, wherein the phenyl and benzyl groups are unsubstituted or substituted by CN, NO2, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy groups. Includes the following steps: (i) Providing a compound of formula I by the method according to any one of claims 1-2, (ii) React the compound of formula I with a brominating agent.

4. The method according to claim 3, wherein the brominating agent is selected from the group consisting of N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), or a system consisting of HBr / H2O2.

5. The method according to any one of claims 3 or 4, wherein the brominating agent is N-bromosuccinimide (NBS).

6. The method according to any one of claims 3 or 4, wherein the brominating agent is 1,3-dibromo-5,5-dimethylhydantoin (DBDMH).

7. A method for preparing compound V: in R 3 R 4 Independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl and C2-C6 haloalkynyl; R 78 It is independently selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, and C1-C6 haloalkoxy groups; o can be 0, 1, 2, or 3; Y is selected from C1-C6 alkyl, C1-C6 haloalkyl, phenyl, and benzyl, wherein the phenyl and benzyl groups are unsubstituted or substituted by CN, NO2, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy groups. Includes the following steps: (i) Providing a compound of formula I by the method according to any one of claims 1-2; (ii) Providing a compound of formula IV by the method according to any one of claims 3-6; (iii) Reacting compound IV with a fluorinating agent to provide compound V.

8. The method of claim 7, wherein the fluorinating agent is selected from the group consisting of: NaF, CsF, KF, KHF2, Olah reagent, HF, polyhydrofluoride complexes of trialkylamines, or mixtures of HF in trialkylamines.

9. A method for preparing compound VI: in R 3 R 4 Independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl and C2-C6 haloalkynyl; R 78 It is independently selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, and C1-C6 haloalkoxy groups; o can be 0, 1, 2, or 3; X is a metal ion; Includes the following steps: (i) Providing a compound of formula I by the method according to any one of claims 1-2; (ii) Providing a compound of formula IV by the method according to any one of claims 3-6; (iii) Providing a compound of formula V by the method according to any one of claims 7-8; (iv) React compound V with a metal hydroxide to provide compound VI.

10. A method for preparing 5-substituted pyridine compounds of formula VII: in R 1 In each case, the components are independently selected from hydrogen, halogen, C1-C6 alkyl, and C1-C6 haloalkyl; R 2 In each case, it is independently selected from hydrogen, halogen, C1-C6 alkyl, and C1-C6 haloalkyl; R 3 R 4 Independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl and C2-C6 haloalkynyl; o can be 0, 1, 2, or 3; R 78 It is independently selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, and C1-C6 haloalkoxy groups; R 9 In each case, it is independently selected from CH3, CH2F, and CHF2; R 10 In each case, it is independently selected from H, halogen, O(R) 95 C1-C6 alkyl and C1-C6 haloalkyl; Where R 95 It is a C1-C6 alkyl or a C1-C6 haloalkyl; Including the following step: (i) Providing a compound of formula I by the method according to any one of claims 1-2; (ii) Providing a compound of formula IV by the method according to any one of claims 4-6; (iii) Providing a compound of formula V by the method according to any one of claims 7-8; (iv) Providing a compound of formula VI by the method according to claim 9; (v) Reacting compound VI with compound VIII to provide compound VI: Where R 1 R 2 R 9 and R 10 As defined above.

Images