Diisopropylethylamine → 4-Amino-6-[1-(6-fluoro-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2-yl)ethylamino]pyrimidine-5-carbonitrile

HRID 243508Notes

Reaction equation

HRID 243508 reaction equation
[F:1][C:2]1[CH:12]=[CH:11][C:10]2=[C:13]3[C:3]=1[O:4][CH2:5][CH2:6][N:7]3[C:8]([CH:14]([NH2:16])[CH3:15])=[N:9]2.[NH2:17][C:18]1[C:23]([C:24]#[N:25])=[C:22](Cl)[N:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:17][C:18]1[C:23]([C:24]#[N:25])=[C:22]([NH:16][CH:14]([C:8]2[N:7]3[C:13]4[C:3]([O:4][CH2:5][CH2:6]3)=[C:2]([F:1])[CH:12]=[CH:11][C:10]=4[N:9]=2)[CH3:15])[N:21]=[CH:20][N:19]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 122782624-Amino-6-chloropyrimidine-5-carbonitrileHCID 681570071-(6-Fluoro-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2-yl)ethylamine

Product 1

HCID 681581874-Amino-6-[1-(6-fluoro-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2-yl)ethylamino]pyrimidine-5-carbonitrileYield 75.2%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 1-(6-fluoro-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2-yl)ethylamine (108 mg, 0.49 mmol), 4-amino-6-chloro-5-cyanopyrimidine (75 mg, 0.49 mmol) and DIPEA (171 μL, 0.98 mmol) in IPA (1 mL) was heated for 18 h at 100° C. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was taken up in MeOH and acidified with TFA, at which point the solution became homogenous. The reaction mixture was passed through a 2 g Isolute® SCX-2 cartridge, eluting with 2M NH3/MeOH. The basic fraction was concentrated in vacuo and the resulting brown residue was purified by column chromatography (Si—PPC, gradient 0-8% 2M NH3/MeOH in DCM) to afford 434 as a pale yellow solid (125 mg, 75%). LCMS (Method K): RT 2.49 min [M+H]+ 340.1. 1H NMR (DMSO, 400 MHz): δ 8.02 (1H, s), 7.74 (1H, d, J=7.4 Hz), 7.27 (2H, br s), 7.09 (1H, dd, J=8.7, 3.3 Hz), 6.95 (1H, dd, J=12.3, 8.8 Hz), 5.60 (1H, dq, J=7.4, 6.8 Hz), 4.50-4.41 (2H, m), 4.36-4.27 (2H, m), 1.58 (3H, d, J=6.8 Hz)

Workup

  1. temperatureAfter cooling to RT
  2. customthe volatiles were removed in vacuo
  3. washeluting with 2M NH3/MeOH
  4. concentrationThe basic fraction was concentrated in vacuo
  5. customthe resulting brown residue was purified by column chromatography (Si—PPC, gradient 0-8% 2M NH3/MeOH in DCM)

Sources & evidence

ORD record
ord-000ba4bf000c473b9cba00569f031292
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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