Process for preparing a cot inhibitor compound

A process for preparing Compound 2B, the process comprising:

• (6a) contacting Compound 1E:
• with a copper catalyst, an amine ligand, and an iodide additive in a solvent at a temperature sufficient to provide Compound 2O:
• (6b) contacting Compound 2O with an alkylating agent in a solvent at a temperature sufficient to provide Compound 2P:
• wherein X is iodide, chloride, bromide, methylsulfate, sulfate, methylcarbonate, carbonate, methanesulfonate, trifluoromethanesulfonate, toluenesulfonate, or tetrafluoroborate;
• (6c) contacting Compound 2P with an oxidant and a base in a solvent at a temperature sufficient to provide Compound 2B:

The process of claim 0, wherein for step (6a):

• (i) the copper catalyst comprises copper(I) iodide, copper(I) bromide, copper(I) chloride, copper(I) oxide, copper(I) acetate, copper(I) bromide dimethyl sulfide complex, copper(I) triflate, copper(I) iodide tetrabutylammonium iodide complex, tetrakis(acetonitrile)copper(I) hexafluorophosphate, copper(I) iodide triethylphosphite complex, or copper(I) bromide triphenylphosphine complex;
• (ii) the amine ligand comprises trans-N,N′-dimethylcyclohexane-1,2-diamine, N1,N2-dimethylethane-1,2-diamine, N1,N3-dimethylpropane-1,3-diamine, or N1-(2-aminoethyl)ethane-1,2-diamine;
• (iii) the iodide additive comprises sodium iodide, lithium iodide, or potassium iodide;
• (iv) the solvent comprises diethylene glycol dimethylether, diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, dibutyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, toluene, trifluorotoluene, cyclohexane, n-heptane, xylenes, acetonitrile, propionitrile, butyronitrile, dichloromethane, chloroform, dichloroethane, chlorobenzene, or dibromoethane;
• and/or
• (v) the temperature is from about 50° C. to about 150° C.

The process of claim 0, wherein for step (6a):

• (i) the copper catalyst comprises copper(I) iodide;
• (ii) the amine ligand comprises trans-N,N′-dimethylcyclohexane-1,2-diamine;
• (iii) the iodide additive comprises sodium iodide;
• (iv) the solvent comprises diethylene glycol dimethylether;
• and/or
• (v) the temperature is from about 80° C. to about 130° C.

The process of claim 0, wherein for step (6b):

• (i) the alkylating agent comprises iodomethane, trimethylsulfoxonium iodide, diazomethane, dimethylsulfate, 2,2-dimethoxypropane, dimethylcarbonate, dimethyldicarbonate, methyl fluorosulfonate, methyl methanesulfonate, chloromethane, bromomethane, or trimethyloxonium tetrafluoroborate;
• (ii) the solvent comprises acetonitrile, methanol, ethanol, isopropanol, tert-butanol, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, acetone, methyl ethyl ketone, diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, dibutyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, toluene, trifluorotoluene, cyclohexane, n-heptane, xylenes, propionitrile, butyronitrile, dichloromethane, chloroform, dichloroethane, or chlorobenzene;
• and/or
• (iii) the temperature is from about 0° C. to about 100° C.

The process of claim 0, wherein for step (6b):

• (i) the alkylating agent comprises iodomethane;
• (ii) the solvent comprises acetonitrile;
• and/or
• (iii) the temperature is from about 20° C. to about 40° C.;
• and/or
• (iv) X is iodide.

The process of claim 0, wherein for step (6c):

• (i) the oxidant comprises potassium ferricyanide, oxone, lead tetraacetate, peracetic acid, hydrogen peroxide, molecular oxygen, air, sodium hypochlorite, sodium chlorite, sodium periodate, potassium peroxymonosulfate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, 1,4-benzoquinone, periodic acid, potassium bromate, meta-chloroperoxybenzoic acid, or magnesium monoperoxypthalate;
• (ii) the base comprises potassium hydroxide, lithium hydroxide, potassium hydroxide, or ammonium hydroxide;
• (iii) the solvent comprises water, methanol, ethanol, isopropanol, tert-butanol, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, acetone, methyl ethyl ketone, diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, dibutyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, toluene, trifluorotoluene, cyclohexane, n-heptane, xylenes, acetonitrile, propionitrile, butyronitrile, dichloromethane, chloroform, dichloroethane, chlorobenzene, or dibromoethane;
• and/or
• (iv) the temperature is from about 0° C. to about 70° C.

The process of claim 0, wherein for step (6c):

• (i) the oxidant comprises potassium ferricyanide;
• (ii) the base comprises potassium hydroxide;
• (iii) the solvent comprises water;
• and/or
• (iv) the temperature is from about 5° C. to about 20° C.

A process for preparing Compound 1, the process comprising:

• (3s) contacting Compound 10A:
• with a chlorinating reagent, optionally an amine catalyst, and optionally an acidic additive in an optional solvent at a temperature sufficient to provide Compound 10B:
• (3t) contacting Compound 10B with TsHNNH2 in a solvent at a temperature sufficient to provide Compound 10C:
• (3u) contacting Compound 10C with Compound 2K:
• in the presence of a base in a solvent at a temperature sufficient to provide Compound 10D:
• (3v) contacting Compound 10D with a base in a solvent at a temperature sufficient to provide Compound 2M:
• (3a) contacting Compound 2M with a chlorinating reagent and an additive in a solvent at a temperature sufficient to provide Compound 3A:
• (3b) contacting Compound 3A with Compound 2B:
• in the presence of an organometallic reagent, then followed by the addition of a copper or palladium catalyst, optionally, a zinc additive, and optionally, a Lewis base in a solvent at a temperature sufficient to provide Compound 2C:
• (3c) contacting Compound 2C with
• in the presence of a titanium-based or zirconium-based reagent in a solvent at a temperature sufficient to provide Compound 3B:
• (3d) contacting Compound 3B with a reducing agent, and optionally a ruthenium, palladium, or platinum catalyst in a solvent at a temperature sufficient to provide Compound 3C:
• (3e) contacting Compound 3C with an acid in a solvent at a temperature sufficient to provide Compound 2F:
• and
• (3f) contacting Compound 2F with Compound 2G:
• in the presence of a palladium catalyst and a base in a solvent at a temperature sufficient to provide Compound 1: