Hydrochloric Acid → 5-Fluoro-2-(thiophen-2-ylmethoxy)pyrimidin-4-ylamine
Reaction equation
[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][OH:16].CC([O-])(C)C.[K+].Cl>>[F:8][C:7]1[C:2]([NH2:1])=[N:3][C:4]([O:16][CH2:15][C:11]2[S:10][CH:14]=[CH:13][CH:12]=2)=[N:5][CH:6]=1Participants
Conditions
- Temperature
- 100 °C
Procedure
To a mixture of 4-amino-2-chloro-5-fluoropyrimidine (2.00 g, 13.5 mmol) and thiophen-2-ylmethanol (1.92 g, 16.9 mmol) with a magnetic stir bar in a 20 mL Biotage Initiator microwave reaction vessel was added t-BuOK (17.0 mL of 1M in t-BuOH, 17.0 mmol). The resulting mixture was sealed with a Biotage Initiator microwave septa cap and heated in a Biotage Initiator microwave to 100° C. for 30 min. The heating cycle was repeated (2×) for a total reaction time of 90 min. The contents were poured into ice-water and the pH was adjusted to neutral with 2N HCl. The resulting solid was filtered and washed with water (2×) and then 20% ether/hexanes (100 mL). The remaining solid was dried overnight at 50° C. under vacuum to give 4.17 g (68%) of 5-fluoro-2-(thiophen-2-ylmethoxy)pyrimidin-4-ylamine as a pale yellow powder: mp 92-94° C.; 1H NMR (300 MHz, CDCl3) δ 7.92 (d, J=2.7 Hz, 1H), 7.29 (m, 1H), 7.13 (d, J=3.6 Hz, 1H), 6.97 (m, 1H), 5.46 (s, 2H), 5.17 (br s, 2H); MS (ESI) m/z 226 (M+H)+.
Workup
- customin a 20 mL Biotage Initiator microwave reaction vessel
- customThe resulting mixture was sealed with a Biotage Initiator microwave
- customsepta cap
- customfor a total reaction time of 90 min
- filtrationThe resulting solid was filtered
- washwashed with water (2×)
- customThe remaining solid was dried overnight at 50° C. under vacuum
Sources & evidence
- ORD record
- ord-84b4a306e45d476ead0d47b63080380b
- Source dataset
- uspto-grants-2015_12
- Patent number
- US09204653B2
Reaction notes
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