Potassium Phosphate, Tribasic → HCID 60164406, compound

HRID 529395Notes

Reaction equation

HRID 529395 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C:15]4([CH2:16][O:17][CH2:18][CH2:19][C:20]([NH2:22])=[N:21]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:23]1[C:24]([F:29])=[N:25][CH:26]=[CH:27][CH:28]=1)=[CH:11][CH:10]=3.[F:30][C:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33][N:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[F:29][C:24]1[C:23]([C:12]2[CH:13]=[C:14]3[C:15]4([CH2:16][O:17][CH2:18][CH2:19][C:20]([NH2:22])=[N:21]4)[C:4]4[CH:3]=[C:2]([C:35]5[CH:34]=[CH:33][N:32]=[C:31]([F:30])[CH:36]=5)[N:7]=[CH:6][C:5]=4[O:8][C:9]3=[CH:10][CH:11]=2)=[CH:28][CH:27]=[CH:26][N:25]=1

Participants

4

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 27833962-Fluoropyridine-4-boronic acidHCID 86709315HCID 86709315, compound

Product 1

HCID 60164406HCID 60164406, compound

Conditions

Temperature
110 °C

Procedure

A vial was charged with (E)-3-chloro-7-(2-fluoropyridin-3-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amine (142 mg, 0.346 mmol), 2-fluoropyridin-4-ylboronic acid (122 mg, 0.864 mmol), Pd(AmPhos)2Cl2 (12.24 mg, 0.017 mmol), and potassium phosphate (220 mg, 1.037 mmol). The vial was flushed with Ar (g), then dioxane (1296 μL) and water (432 μL) were added in sequence. The vial was sealed and heated in a microwave reactor for 30 min at 110° C. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The crude product was purified by chromatography on silica gel (10-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM) to give (E)-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amine as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.71 (d, J=0.4 Hz, 1 H), 8.38 (d, J=5.3 Hz, 1 H), 8.26 (td, J=1.5, 4.8 Hz, 1 H), 8.13 (ddd, J=1.9, 7.5, 10.4 Hz, 1 H), 8.07 (s, 1 H), 7.95 (td, J=1.8, 5.2 Hz, 1 H), 7.72 (s, 1 H), 7.69-7.59 (m, 2 H), 7.50 (ddd, J=1.9, 4.9, 7.4 Hz, 1 H), 7.42 (d, J=8.6 Hz, 1 H), 6.16 (br. s., 2 H), 3.86 (t, J=5.6 Hz, 2 H), 3.72 (q, J=12.8 Hz, 2 H), 3.09-2.90 (m, 2 H). MS m/z=472.0. Calc'd for C26H20F2N5O2: 472.2. The racemic material (104 mg) was subjected to chiral SFC separation, using 35% MeOH with diethylamine to afford 45 mg of the (R)-enantiomer (peak 1) and 44 mg of the (S)-enantiomer (peak 2) as white solids.

Workup

  1. customThe vial was flushed with Ar (g)
  2. additiondioxane (1296 μL) and water (432 μL) were added in sequence
  3. customThe vial was sealed
  4. extractionThe mixture was extracted with EtOAc (3×)
  5. concentrationthe combined organic extracts were concentrated
  6. customThe crude product was purified by chromatography on silica gel (
  7. addition10-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM)

Sources & evidence

ORD record
ord-bc18ac1d28a74a98a5c9d2d3b8fc0547
Source dataset
uspto-grants-2016_05
Patent number
US09346827B2

Reaction notes

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