Lithium diisopropylamide → HCID 89485583, compound

HRID 2402396Notes

Reaction equation

HRID 2402396 reaction equation
[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[N:5]=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:3]=1.[Li+].CC([N-]C(C)C)C.[O:32]=[C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([C:42]([O:44][CH3:45])=[O:43])[CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[OH:32][C:33]1([C:11]2[S:12][C:8]([C:6]3[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([NH:13][C:14]4[CH:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][N:15]=4)[N:5]=3)=[CH:9][N:10]=2)[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([C:42]([O:44][CH3:45])=[O:43])[CH:40]=2)[CH2:35][CH2:34]1

Participants

5

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 10081226Methyl 3-oxo-2,3-dihydro-1H-indene-5-carboxylateHCID 709773814-methyl-6-(1,3-thiazol-5-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine

Product 1

HCID 89485583HCID 89485583, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of 4-methyl-6-(thiazol-5-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine (380 mg, 1.13 mmol) in 10 mL THF was cooled to −78° C., then LDA (2.5 mmol, freshly prepared) was added and the resulting mixture was stirred at the same temperature for 30 min. Then a solution of methyl 3-oxo-2,3-dihydro-1H-indene-5-carboxylate (1.13 mmol) in THF (3 mL) was added and the reaction was warmed to rt over a period of 4 h, then stirred for an additional 15 h at rt. The reaction was quenched by addition of saturated aqueous NH4Cl (10 mL) and the resulting mixture was extracted with EtOAc (2×20 mL). The combined organic phases were dried (MgSO4), filtered and concentrated, and the residue was purified by silica gel chromatography to afford racemic methyl 3-hydroxy-3-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-2,3-dihydro-1H-indene-5-carboxylate, which was resolved by chiral SFC (Column: Chiralcel OD-H 150×4.6 mm I.D., 5 um; Mobile phase: ethanol (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 2.35 mL/min; Wavelength: 220 nm) to give each enantiomer. MS ESI calcd for C26H21F3N4O3S [M+H]+ 527, found 527.

Workup

  1. additionwas added
  2. stirringstirred for an additional 15 h at rt
  3. customThe reaction was quenched by addition of saturated aqueous NH4Cl (10 mL)
  4. extractionthe resulting mixture was extracted with EtOAc (2×20 mL)
  5. dry with materialThe combined organic phases were dried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customthe residue was purified by silica gel chromatography

Sources & evidence

ORD record
ord-eaff1e6b1afb4602b49ebdd11d4e0d93
Source dataset
uspto-grants-2014_08
Patent number
US08796310B2

Reaction notes

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