1-Butanol → HCID 71270621, compound

HRID 2406267Notes

Reaction equation

HRID 2406267 reaction equation
[Si:1]([O:8][C@H:9]1[CH2:13][C@H:12]([O:14][C:15]2[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=2)[CH2:11][C@H:10]1[CH2:22][OH:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[NH:25][CH:26]1[C:34]2[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=2)[CH2:28][CH:27]1[O:36][CH3:37].C(O)CCC.C(N(CC)CC)C>>[Si:1]([O:8][C@H:9]1[CH2:13][C@H:12]([O:14][C:15]2[CH:20]=[C:19]([NH:25][C@@H:26]3[C:34]4[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=4)[CH2:28][C@@H:27]3[O:36][CH3:37])[N:18]=[CH:17][N:16]=2)[CH2:11][C@H:10]1[CH2:22][OH:23])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]

Participants

5

Reactant 4

HCID 2631-ButanolHCID 8471TriethylamineHCID 86686869HCID 86686869, compoundHCID 86686870HCID 86686870, compound

Product 1

HCID 71270621HCID 71270621, compoundYield 71%

Conditions

Temperature
148 °C

Procedure

To a solution of {(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-chloropyrimidin-4-yl)oxy]cyclopentyl}methanol (15) (11.2 g, 0.0312 mol) and N,5-dichloro-2-methoxy-2,3-dihydro-1H-inden-1-amine (9.00 g, 0.0384 mol) in 1-butanol (99.2 mL, 1.09 mol), in a 350 mL sealable reaction vessel, was added triethylamine (21.7 mL, 0.156 mol). The vessel was sealed and then heated with stirring to 148° C. in an oil bath for 72 hours. The vessel was cooled to room temperature and the volatiles were removed in vacuo and Et2O (200 mL) was added to the resulting residue. The solids were homogenized by sonication, filtered, and rinsed with Et2O (50 mL). To the filtrate was added Celite® (100 mL) and the volatiles were removed in vacuo. The product adsorbed onto Celite® was added to a dry load cartridge and purified via column chromatography (400 g column, eluent 0-80% EtOAc:hexanes over 80 min) to afford {(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methanol (11.5 g, 71%). LCMS: (FA) ES+ 520; 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.24-7.13 (m, 3H), 5.75 (s, 1H), 5.56 (s, 1H), 5.45 (dt, J=2.9, 5.8, 2H), 4.57 (dd, J=5.9, 11.2, 1H), 4.19 (td, J=1.3, 4.7, 1H), 3.84-3.77 (m, 1H), 3.75-3.65 (m, 1H), 3.37 (s, 3H), 3.10 (d, J=16.6, 1H), 2.97 (dd, J=4.5, 16.7, 1H), 2.58 (dd, J=4.8, 7.4, 1H), 2.43-2.32 (m, 1H), 2.23-2.06 (m, 3H), 1.90 (dd, J=8.0, 14.2, 1H), 0.91 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H).

Workup

  1. customThe vessel was sealed
  2. temperatureheated
  3. temperatureThe vessel was cooled to room temperature
  4. customthe volatiles were removed in vacuo and Et2O (200 mL)
  5. additionwas added to the resulting residue
  6. stirringThe solids were homogenized by sonication
  7. filtrationfiltered
  8. washrinsed with Et2O (50 mL)
  9. additionTo the filtrate was added Celite® (100 mL)
  10. customthe volatiles were removed in vacuo
  11. additionwas added to a dry load cartridge
  12. custompurified via column chromatography (400 g column, eluent 0-80% EtOAc:hexanes over 80 min)

Sources & evidence

ORD record
ord-f5495441e6454e06a7440db4f63c0bb9
Source dataset
uspto-grants-2014_08
Patent number
US08809356B2

Reaction notes

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