Triethylamine → Methyl (+/-)-3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3-cyclobutylpropanoate

HRID 1055057Notes

Reaction equation

[NH2:1][CH:2]([CH:8]1[CH2:11][CH2:10][CH2:9]1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([F:20])=[CH:15][N:14]=1.C(N(CC)CC)C>C1COCC1.C(O)C>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][CH:2]([CH:8]2[CH2:9][CH2:10][CH2:11]2)[CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:16]([F:20])=[CH:15][N:14]=1

Participants

Conditions

Temperature: 70 °C

Procedure

To a racemic solution of methyl 3-amino-3-cyclobutylpropanoate, 49a, (0.354 g, 2.252 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (0.414 g, 2.477 mmol) in THF (10 mL) and ethanol (1 mL) was added triethylamine (0.628 mL, 4.504 mmol). The reaction mixture was heated and stirred at 70° C. for 5 hours. The mixture was filtered and the filtrate was concentrated in vacuo to approximately 5 mL final volume. The crude residue was purified via silica gel chromatography (0-100% EtOAC/hexanes gradient) to afford 289 mg (45%) of the desired product: 1H NMR (300 MHz, CDCl3) δ 7.87 (s, 1H), 5.80 (s, 1H), 4.71-4.38 (m, 1H), 3.68 (s, 3H), 2.84-2.37 (m, 3H), 2.23-1.67 (m, 6H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=3.08 minutes (M+H) 287.98.

Workup

temperatureThe reaction mixture was heated
filtrationThe mixture was filtered
concentrationthe filtrate was concentrated in vacuo to approximately 5 mL final volume
customThe crude residue was purified via silica gel chromatography (0-100% EtOAC/hexanes gradient)

Sources & evidence

ORD record: ord-cd48fc43a32049bf87c4a7c642533b43
Source dataset: uspto-grants-2016_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09394302B2

Reaction notes

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