(3R)-Piperidin-3-amine--hydrogen chloride (1/2) → 2-[[6-(3-Aminopiperidin-1-yl)-3-methyl-2,4-dioxopyrimidin-1-yl]methyl]-4-fluorobenzonitrile

HRID 1515168Notes

Reaction equation

Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[C:6](=[O:18])[N:5]([CH3:19])[C:4](=[O:20])[CH:3]=1.Cl.Cl.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1>CC(O)C>[NH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:2]2[N:7]([CH2:8][C:9]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:10]=3[C:11]#[N:12])[C:6](=[O:18])[N:5]([CH3:19])[C:4](=[O:20])[CH:3]=2)[CH2:25]1

Participants

Conditions

Temperature: 60 °C

Procedure

Alternatively, the free base of 34 was prepared as follows. A mixture of 33 (1212 g), IPA (10.8 L), (R)-3-amino-piperidine dihydrochloride (785 g), purified water (78 mL) and potassium carbonate (2.5 kg, powder, 325 mesh) was heated at 60° C. until completion (e.g., for >20 hours) as determined, for example, by HPLC. Acetonitrile (3.6 L) was then added at 60° C. and the mixture was allowed to cool to <25° C. The resultant slurry was filtered under vacuum and the filter cake was washed with acetonitrile (2×3.6 L). The filtrate was concentrated at 45° C. under vacuum (for >3 hours) to afford 2.6 kg of the free base of 34.

Workup

custompurified water (78 mL) and potassium carbonate (2.5 kg, powder, 325 mesh)
additionAcetonitrile (3.6 L) was then added at 60° C.
temperatureto cool to <25° C
filtrationThe resultant slurry was filtered under vacuum
washthe filter cake was washed with acetonitrile (2×3.6 L)
concentrationThe filtrate was concentrated at 45° C. under vacuum (for >3 hours)

Sources & evidence

ORD record: ord-82eb31b8e17f4ee6969d06187868ceb8
Source dataset: uspto-grants-2012_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08222411B2

Reaction notes

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