Diisopropylethylamine → N-{(4aR,7aR)-7a-(5-Cyanothiophen-2-yl)-6-[5-fluoro-4-(2-hydroxypropan-2-yl)pyrimidin-2-yl]-4,4a,5,6,7,7a-hexahydropyrrolo[3,4-d][1,3]thiazin-2-yl}benzamide

HRID 338147Notes

Reaction equation

HRID 338147 reaction equation
[C:1]([C:3]1[S:7][C:6]([C@:8]23[CH2:16][NH:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]3)=[CH:5][CH:4]=1)#[N:2].C(N(C(C)C)CC)(C)C.Cl[C:36]1[N:41]=[C:40]([C:42]([OH:45])([CH3:44])[CH3:43])[C:39]([F:46])=[CH:38][N:37]=1>O1CCOCC1.C(OCC)(=O)C>[C:1]([C:3]1[S:7][C:6]([C@:8]23[CH2:16][N:15]([C:36]4[N:41]=[C:40]([C:42]([OH:45])([CH3:44])[CH3:43])[C:39]([F:46])=[CH:38][N:37]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:9]3)=[CH:5][CH:4]=1)#[N:2]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 866978842-(2-Chloro-5-fluoropyrimidin-4-yl)propan-2-olHCID 86762239N-[(4aR,7aR)-7a-(5-cyanothiophen-2-yl)-4,4a,5,6,7,7a-hexahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide

Product 1

HCID 86762238N-{(4aR,7aR)-7a-(5-Cyanothiophen-2-yl)-6-[5-fluoro-4-(2-hydroxypropan-2-yl)pyrimidin-2-yl]-4,4a,5,6,7,7a-hexahydropyrrolo[3,4-d][1,3]thiazin-2-yl}benzamideYield 89%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

To a stirred clear and colorless solution of N-[(4aR,7aR)-7a-(5-cyanothiophen-2-yl)-4,4a,5,6,7,7a-hexahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (0.806 mmol) in 1,4-dioxane (16 mL) is added diisopropylethylamine (422 μL, 2.42 mmol) and 2-(2-chloro-5-fluoropyrimidin-4-yl)propan-2-ol (1.54 g, 8.06 mmol). The solution is heated to reflux for 14 hours. The pale yellow solution is allowed to cool, diluted with ethyl acetate (80 mL) and hexanes (20 mL), and washed with dilute aqueous sodium bicarbonate (30 mL, prepared from saturated aqueous sodium bicarbonate (15 mL) and water (15 mL), water (2×20 mL), and brine (20 mL). The organic phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography, eluting with a hexanes/diethyl ether, gradient from 80:20 to 0:100, to give the title compound (374 mg, 89% over two steps) as a pale yellow glass. MS/ES (m/z) 523.2 (M+H).

Workup

  1. temperatureThe solution is heated
  2. temperatureto reflux for 14 hours
  3. temperatureto cool
  4. washwashed with dilute aqueous sodium bicarbonate (30 mL
  5. customprepared from saturated aqueous sodium bicarbonate (15 mL) and water (15 mL), water (2×20 mL), and brine (20 mL)
  6. dry with materialThe organic phase is dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe residue is purified by silica gel chromatography
  10. washeluting with a hexanes/diethyl ether, gradient from 80:20 to 0:100

Sources & evidence

ORD record
ord-558edb731b4c4a13ac3804bcba552c4b
Source dataset
uspto-grants-2014_11
Patent number
US08889856B2

Reaction notes

Loading…