1,2-Dimethoxyethane → 1,1,1,3,3,3-Hexafluoro-2-(2-(4-(phenylsulfonyl)phenyl)-5-pyrimidinyl)-2-propanol

HRID 1972682Notes

Reaction equation

HRID 1972682 reaction equation
CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)O1.Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([OH:41])([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34])=[CH:28][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[F:36][C:33]([F:34])([F:35])[C:32]([C:29]1[CH:30]=[N:31][C:26]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[N:27][CH:28]=1)([OH:41])[C:37]([F:40])([F:39])[F:38]

Participants

6

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10796Cesium carbonateHCID 665825054,4,5,5-Tetramethyl-2-(4-(phenylsulfonyl)phenyl)-1,3,2-dioxaborolaneHCID 866703482-(2-Chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol2×

Product 1

HCID 866704351,1,1,3,3,3-Hexafluoro-2-(2-(4-(phenylsulfonyl)phenyl)-5-pyrimidinyl)-2-propanolYield 71.1%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

A glass microwave reaction vessel was charged with 4,4,5,5-tetramethyl-2-(4-(phenylsulfonyl)phenyl)-1,3,2-dioxaborolane (196 mg, 0.57 mmol, Example 17, Step 2), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (145 mg, 0.52 mmol, Intermediate D), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (24 mg, 0.03 mmol, Strem Chemical Inc, Newburyport, Mass.), cesium carbonate (0.51 g, 1.56 mmol, Sigma-Aldrich, St. Louis, Mo.), DME (1 mL), and water (0.1 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 30 min. The reaction was diluted with EtOAc (about 10 mL) and water (about 10 mL). The organic layer was taken and the solvent was removed under vacuum. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of 10% to 20% EtOAc in hexane, to provide 1,1,1,3,3,3-hexafluoro-2-(2-(4-(phenylsulfonyl)phenyl)-5-pyrimidinyl)-2-propanol (171 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.28 (s, 2H), 8.69 (d, J=8.61 Hz, 2H), 8.22 (d, J=8.61 Hz, 2H), 8.04-8.10 (m, 2H), 7.68-7.82 (m, 4H); m/z (ESI, +ve ion) 463.1 (M+H)+. GK-GKRP IC50 (Binding)=0.484 μM. GKRP EC50 (LC MS/MS-2)=0.478 μM.

Workup

  1. customA glass microwave reaction vessel
  2. customThe reaction mixture was purged with nitrogen for several minutes
  3. additionThe reaction was diluted with EtOAc (about 10 mL) and water (about 10 mL)
  4. customthe solvent was removed under vacuum
  5. customThe crude material was absorbed onto a plug of silica gel
  6. custompurified by chromatography through a silica gel column (12 g)
  7. washeluting with a gradient of 10% to 20% EtOAc in hexane

Sources & evidence

ORD record
ord-974c3b92a26a405e84c809cf3aebf5ef
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

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