Diisopropylethylamine → N-[(4aR,7aR)-6-[5-Fluoro-4-(1-hydroxy-1-methyl-ethyl)-6-methyl-pyrimidin-2-yl]-7a-isothiazol-5-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide

HRID 338150Notes

Reaction equation

HRID 338150 reaction equation
Cl[C:2]1[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[C:5]([F:12])=[C:4]([CH3:13])[N:3]=1.[S:14]1[C:18]([C@:19]23[CH2:27][NH:26][CH2:25][C@H:24]2[CH2:23][S:22][C:21]([NH:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:20]3)=[CH:17][CH:16]=[N:15]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:12][C:5]1[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])=[N:7][C:2]([N:26]2[CH2:25][C@@H:24]3[C@@:19]([C:18]4[S:14][N:15]=[CH:16][CH:17]=4)([N:20]=[C:21]([NH:28][C:29](=[O:36])[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[S:22][CH2:23]3)[CH2:27]2)=[N:3][C:4]=1[CH3:13]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 86762225N-[(4aR,7aR)-7a-Isothiazol-5-yl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamideHCID 867624932-(2-Chloro-5-fluoro-6-methylpyrimidin-4-yl)propan-2-ol

Product 1

HCID 86762241N-[(4aR,7aR)-6-[5-Fluoro-4-(1-hydroxy-1-methyl-ethyl)-6-methyl-pyrimidin-2-yl]-7a-isothiazol-5-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamideYield 17.8%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

2-(2-Chloro-5-fluoro-6-methyl-pyrimidin-4-yl)propan-2-ol (104 mg, 0.51 mmol) is dissolved in 1,4-dioxane (3 mL). N-[(4aR,7aR)-7a-Isothiazol-5-yl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (125 mg, 0.36 mmol) is added followed by diisopropylethylamine (158 μL, 0.91 mmol). The reaction is heated via microwave irradiation in a sealed microwave vessel to 110° C. for 1 hr. The reaction is concentrated to give the crude product. The crude product is purified via HPLC using a Waters XBridge 5 μm C18 OBD 30×75 mm column and eluted with a gradient of: 36% β isocratic for 3 min followed by 36-51% B over 5 min where solvent A is 10 mM ammonium bicarbonate in water with 5% MeOH and solvent B is acetonitrile. The desired fractions are combined and diluted with saturated NaHCO3 (aq, 100 mL). The mixture is extracted with 4:1 CHCl3: isopropanol (3×100 mL). The organic layers are combined, washed with brine (1×50 mL), dried over MgSO4, filtered and concentrated to give the title compound (33 mg, 0.064 mmol): EZ/MS (m/z): 513 (M+H).

Workup

  1. concentrationThe reaction is concentrated
  2. customto give the crude product
  3. customThe crude product is purified via HPLC
  4. washeluted with a gradient of: 36%
  5. waitfollowed by 36-51% B over 5 min
  6. additiondiluted with saturated NaHCO3 (aq, 100 mL)
  7. extractionThe mixture is extracted with 4:1 CHCl3
  8. washwashed with brine (1×50 mL)
  9. dry with materialdried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-49f0567d85ce401ea28ceff091ac3874
Source dataset
uspto-grants-2014_11
Patent number
US08889856B2

Reaction notes

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