Cyclopentylamine → 5-Bromo-2-chloro-N-cyclopentyl-4-pyrimidinamine

Beteiligte Stoffe

Reaktionsbedingungen

Reaktionsschritte

A nitrogen-flushed, suitably equipped 5 L 4-neck round bottom flask is charged with 250 g (1.097 mol, 140.4 mL, 1.0 eq.) of 5-bromo-2,4-dichloropyrimidine (A1h) and 1127 g, (1250 mL) of ethyl acetate. The content is stirred at 20° C. and 283.5 g (2.194 mol, 382.0 mL, 2.0 eq.) of N,N-diisopropylethylamine is added. A solution of 102.8 g (1.207 mol, 119 mL, 1.1 eq.) of cyclopentylamine (A1g) dissolved in 1127 g, (1250 mL) of ethyl acetate is added over 60 min. An 18° C. to 36° C. exotherm is observed. The solution is warmed to 40° C. This temperature is maintained for at least 6 h or until all the starting material A1h, is consumed as determined by HPLC analysis. The resulting slurry is cooled to 25° C. and 500 g (500 mL) of water is added. The content is stirred for 15 min and the phases are allowed to separate. The bottom (aqueous) layer is removed and the organic layer is washed once more with 500 g (500 mL) of water. The sample is stirred for 15 min, and the phases are allowed to separate. The bottom (aqueous) layer is removed. The organic phase is concentrated (atmospheric pressure) to a volume of 1500 mL (batch temp=82° C.). 684 g (1 L) of heptane is added and the concentration is resumed to a volume of 1500 mL (batch temp=85° C.). Again, 684 g (1 L) of heptane is added and the concentration is resumed to a volume of 1500 mL (batch temp=96° C.). The sample is cooled to 50° C. and seeded. The cooling is continued to 4° C. and the temperature is maintained at 4° C. for 1 h. The solids are filtered and the filter cake is washed once with 137 g (200 mL) of cold (4° C.) heptane. The solids are dried at 50° C. for 16 h, to afford 259.0 g (88.0%, corrected) of Compound A1f as a white, crystalline solid, mp=95-96° C.

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