Piperazine azaspiro derivaves
A technology of compounds and oxides, which is applied in the field of piperazine azaspiro derivatives, can solve problems such as responsive noncompliance
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[0319] Scheme 3 shows the preparation of compounds of formula Ia. Using, for example, a copper catalyst such as copper(I) iodide, a ligand such as (1R,2R)-N,N'-dimethylcyclohexane-1,2-diamine and a base such as potassium phosphate, in a suitable solvent Such as in NMP, compound II (wherein X of formula II can be made by Ullman coupling 1 、X 2 and R 2 Substituents should be represented by the same moieties expected in the final product or protected variant thereof) with XI (where R 4 is a small alkyl or alkoxy) coupled to form compound XII. Remove the protecting group P 1 , resulting in compound XIII. P 1 In this case means the groups well known to the person skilled in the art for the protection of amines. For example, P 1 It can be tert-butoxycarbonyl (BOC), which can be cleaved by acidic conditions in a suitable solvent, including, but not limited to, HCl in 1,4-bis Solution processing in alkanes. By chiral sulfonate compound VI (where R 3 is an aryl or an alkyl ...
Embodiment 1、2 and 3
[0370] 6-{4-[3-(5-Methoxypyrazin-2-yl)pyridin-2-yl]piperazin-1-yl}-2-azaspiro[3.4]octane-2-carboxylic acid ethyl Ester (1), 6-{4-[3-(5-methoxypyrazin-2-yl)pyridin-2-yl]piperazin-1-yl}-2-azaspiro[3.4]octane -Ethyl 2-carboxylate, ENT-1(2) and 6-{4-[3-(5-methoxypyrazin-2-yl)pyridin-2-yl]piperazin-1-yl}-2 -ethyl azaspiro[3.4]octane-2-carboxylate ENT-2(3)
[0371]
[0372] Step 1. Synthesis of tert-butyl 4-[3-(5-methoxypyrazin-2-yl)pyridin-2-yl]piperazine-1-carboxylate (C5).
[0373] A solution of tetrakis(triphenylphosphine)palladium(0) (89 mg, 77 μmol) in toluene (5 mL) and ethanol (2 mL) was added to 4-[3-(4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan (dioxaborolan)-2-yl)pyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (300mg, 0.771mmol), 2-bromo-5-methyl In a mixture of oxypyrazine (146mg, 0.772mmol) and aqueous sodium carbonate (2M, 10mL). The reaction mixture was stirred at 100° C. for 3 hours under microwave irradiation, after which it was concentrated in vacuo. ...
Embodiment 4
[0382] (6R)-6-{4-[3-(1,3-Thiazol-4-yl)pyridin-2-yl]piperazin-1-yl}-2-azaspiro[3.4]octane-2- Ethyl formate (4)
[0383]
[0384] Step 1. Synthesis of tert-butyl 4-[3-(1,3-thiazol-4-yl)pyridin-2-yl]piperazine-1-carboxylate (C7).
[0385]A solution of ethanol (30 mL) and sodium carbonate (8.85 g, 83.5 mmol) in water (33 mL) was added to 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxo Borolan-2-yl)pyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (13.0g, 33.4mmol) and 4-bromo-1,3-thiazole (6.57g, 40.1mmol) in a mixture in toluene (180 mL). Then tetrakis(triphenylphosphine)palladium(0) (2.69 g, 2.33 mmol) was added, and the reaction mixture was stirred at 90° C. for 12 hours. After removing the solvent in vacuo, the residue was purified using silica gel chromatography (Gradient: 0% to 60% ethyl acetate in petroleum ether) to give the product as a pale yellow solid. Yield: 7.00 g, 20.2 mmol, 60%. LCMS m / z 347.1[M+H] + .
[0386] Step 2. Synthesis of 1-[3-(1,3-thiazol-4-yl)p...
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