Alkylation / deprotection / alkylation

Step A (Alkylation):

 

A solution of benzyl (5R,7S)-7-methyl-2-oxo-1-8-diazasρiro[4.5]dec-3-ene-8-carboxylate (45 mg, 0,15 mmol) and N,N-dimethylethylenediamine (5 equivalents) in dioxane (0.92 mL) was added to a mixture of the heteroaryl iodide or bromide (3 equivalents), copper(l) iodide (4 equivalents) and either cesium carbonate or potassium phosphate (3 equivalents) in a 1-dram hial. The resulting suspension was sealed and heated at 80-90°C for 18- 66 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, and flushed through an MCX cartridge containing a small amount of Celite on top of the packing material. Additional ethyl acetate (5-10 mL) was eluted through the cartridge, and the combined filtrates were concentrated in vacuo to afford the product, which was taken directly into the next step.

 

Step B (Cbz deprotection):

 

The 1-heteroaryl-substituted benzyl (5R,7S)-7-methyl-2-oxo-1,8-diazaspiro[4.5]dec-3-ene-8-carboxylate from the previous step was dissolved in a freshly prepared solution of trimethylsilyl iodide (0.3 M in acetonitrile, 2 equivalents), and the resulting solution was stirred at room temperature for 18 hours. Purification was carried out by loading the reaction mixture directly onto an MCX column. The column was flushed with dichloromethane (5 mL), and the product was then eluted using a 2 M solution of ammonia in methanol (5 mL). The eluant was concentrated in vacuo to afford the deprotected intermediate.

 

Step C (Alkylation): 

 

 

This material was mixed with acetonitrile (1 ml) and potassium carbonate (3 equivalents). After addition of 1-(bromomethyl)-3- isopropoxybenzene (2 equivalents), the mixture was stirred at room temperature for 18 hours, then loaded onto an MCX cartridge containing a small amount of Celite on top of the packing material. The cartridge was flushed with dichloromethane (5 mL). and the filtered solids and Celite were manually removed from the cartridge. The product was eluted using a 2 M solution of ammonia in methanol {5 mL), and the filtrate was concentrated in vacuo.

Purification was carried by preparative HPLC. 

 

Patent reference: WO2010058333 (Pfizer)

 

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