Cesium carbonate → (S)-7'-(6-chloropyridin-2-yloxy)-2'-(3,6-dihydro-2H-pyran-4-yl)-4'-fluoro-5H-spiro[oxazole-4,9'-xanthen]-2-amine

HRID 335986Notes

Reaction equation

[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:15][C:16]1[O:17][CH2:18][C@@:19]2([N:41]=1)[C:32]1[CH:31]=[C:30]([C:33]3[CH2:34][CH2:35][O:36][CH2:37][CH:38]=3)[CH:29]=[C:28]([F:39])[C:27]=1[O:26][C:25]1[C:20]2=[CH:21][C:22]([OH:40])=[CH:23][CH:24]=1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([O:40][C:22]2[CH:21]=[C:20]3[C:25]([O:26][C:27]4[C:28]([F:39])=[CH:29][C:30]([C:33]5[CH2:34][CH2:35][O:36][CH2:37][CH:38]=5)=[CH:31][C:32]=4[C@@:19]43[CH2:18][O:17][C:16]([NH2:15])=[N:41]4)=[CH:24][CH:23]=2)[CH:5]=[CH:6][CH:7]=1

Participants

Conditions

Temperature: 100 °C

Procedure

A glass microwave reaction vessel was charged with 2-chloro-6-fluoropyridine (88 mg, 0.67 mmol), cesium carbonate (0.027 mL, 0.33 mmol) and (S)-2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-7′-ol (82 mg, 0.22 mmol, prepared as described in Method BB40 and Example 2 but using 4-bromo-2-fluorophenol and 2-bromo-5-methoxybenzoic acid) in DMF (0.8 mL). The reaction mixture was stirred and heated in a Initiator microwave reactor at 100° C. for 35 min. Then it was heated at 120° C. for 5 min. The crude material was purified by reverse-phase preparative HPLC using 0.1% TFA in CH3CN/H2O, gradient 35% to 65% to provide (S)-7′-(6-chloropyridin-2-yloxy)-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2-amine (36 mg, 0.075 mmol, 33.7% yield) as a off-white solid.

Workup

customA glass microwave reaction vessel
temperatureThen it was heated at 120° C. for 5 min
customThe crude material was purified by reverse-phase preparative HPLC

Sources & evidence

ORD record: ord-61f168a65986453abafeb6ee18546549
Source dataset: uspto-grants-2014_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08883782B2

Reaction notes

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