Lithium Hexamethyldisilazide → 6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-[3-(quinolin-2-yl)propoxy]pyrimidin-4-amine

HRID 1626368Notes

Reaction equation

HRID 1626368 reaction equation
[Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([NH:12][CH2:13][C:14]2[S:18][C:17]([CH3:19])=[N:16][C:15]=2[CH3:20])[C:3]=1[CH3:21].[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[CH2:32][CH2:33][CH2:34][OH:35].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([O:35][CH2:34][CH2:33][CH2:32][C:23]2[CH:24]=[CH:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:22]=2)[N:5]=[C:4]([NH:12][CH2:13][C:14]2[S:18][C:17]([CH3:19])=[N:16][C:15]=2[CH3:20])[C:3]=1[CH3:21]

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 218061343-(Quinolin-2-yl)propan-1-olHCID 866881616-chloro-N-[(2,4-dimethylthiazol-5-yl)methyl]-5-methyl-2-methylsulfonyl-pyrimidin-4-amine

Product 1

HCID 569494516-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-[3-(quinolin-2-yl)propoxy]pyrimidin-4-amine

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 6-chloro-N-[(2,4-dimethylthiazol-5-yl)methyl]-5-methyl-2-methylsulfonyl-pyrimidin-4-amine F5 (51 mg, 0.15 mmol) and 3-(quinolin-2-yl)propan-1-ol G6 (25 mg, 0.13 mmol) in 3 mL of THF was added LiHMDS (200 μL of a 1M solution in THF, 0.20 mmol). After stirring for 2 hours, the reaction was quenched by the addition of a saturated ammonium chloride solution. The mixture was partitioned between a saturated solution of NaHCO3 and EtOAc, the layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated by rotary evaporation. The residue was purified by silica gel flash column chromatography (EtOAc/hexanes gradient) to provide 17 mg (28%) of G7 as an off-white solid. 1H NMR δ (400 MHz, CDCl3): 8.1-8.0 (2H, m), 7.75 (1H, m), 7.65 (1H, m), 7.5 (1H, m), 7.35 (1H, m), 4.9 (1H, m), 4.7 (2H, d), 4.4 (2H, t), 3.15 (2H, t), 2.6 (3H, s), 2.35 (5H, m), 2.0 (3H, s). HRMS (ES) calculated M+H for C23H24ClN5OS: 454.1463. Found. 454.1455.

Workup

  1. customthe reaction was quenched by the addition of a saturated ammonium chloride solution
  2. customThe mixture was partitioned between a saturated solution of NaHCO3 and EtOAc
  3. customthe layers were separated
  4. extractionthe aqueous layer was extracted twice with EtOAc
  5. washThe combined organic layers were washed with brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated by rotary evaporation
  8. customThe residue was purified by silica gel flash column chromatography (EtOAc/hexanes gradient)
  9. customto provide 17 mg (28%) of G7 as an off-white solid

Sources & evidence

ORD record
ord-896c2e93c73947f095dc833fd99be430
Source dataset
uspto-grants-2014_07
Patent number
US08785467B2

Reaction notes

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