Diisopropylethylamine → (R)-methyl-2-(5-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate

HRID 1482986Notes

Reaction equation

HRID 1482986 reaction equation
[CH3:1][O:2][C:3]([C:5]1[C:6]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:7][C:8]2[N:12]3[CH2:13][CH2:14][NH:15][C@H:16]([CH:17]([CH3:19])[CH3:18])[C:11]3=[N:10][C:9]=2[CH:20]=1)=[O:4].Cl[C:26]1[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:29]([C:36]([OH:39])([CH3:38])[CH3:37])=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:7][C:8]2[N:12]3[CH2:13][CH2:14][N:15]([C:26]4[N:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[C:29]([C:36]([OH:39])([CH3:37])[CH3:38])=[CH:28][N:27]=4)[C@H:16]([CH:17]([CH3:19])[CH3:18])[C:11]3=[N:10][C:9]=2[CH:20]=1)=[O:4]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 898155822-(2-Chloro-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-olHCID 89815671(R)-methyl 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate

Product 1

HCID 89816015(R)-methyl-2-(5-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylateYield 62%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
165 °C

Procedure

(R)-methyl-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (224 mg, 0.639 mmol) and 2-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol (192 mg, 0.799 mmol) were combined in a small vial and azeotroped with benzene to remove any residual water. A mixture of dioxane (1 mL) and iPr2NEt (0.22 mL, 1.28 mmol) was degassed with N2 for 10 minutes. This mixture was then added to the reaction vial and sealed with a Teflon® coated cap which was then wrapped with Teflon® tape. The resulting suspension was then placed in a 165° C. silicone oil bath at which point the mixture became homogeneous. The resulting solution stirred at 165° C. for 21 h. After the solvents were removed by rotovap, the mixture was purified using ISCO FCC, eluting with 50% EtOAc in Hexanes to obtain 219 mg of (R)-methyl-2-(5-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate as a white solid (62% yield, 40% ee).

Workup

  1. customazeotroped with benzene
  2. customto remove any residual water
  3. customwas degassed with N2 for 10 minutes
  4. additionThis mixture was then added to the reaction vial
  5. customsealed with a Teflon®
  6. customcoated cap which
  7. customwas then placed in a 165° C.
  8. customAfter the solvents were removed by rotovap
  9. customthe mixture was purified
  10. washeluting with 50% EtOAc in Hexanes

Sources & evidence

ORD record
ord-fd42156e1b174b5f86e6742fbcfa89a9
Source dataset
uspto-grants-2016_08
Patent number
US09416135B2

Reaction notes

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