Lithium diisopropylamide → HCID 70977987, compound

HRID 2402397Notes

Reaction equation

HRID 2402397 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][C:38]([C:42]([O:44][CH3:45])=[O:43])=[CH:39][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][C:38]([C:42]([O:44][CH3:45])=[O:43])=[CH:39][CH:40]=2)[CH2:35][CH2:34]1

Participants

5

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 10375253methyl 1-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 70977987HCID 70977987, compoundYield 39%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

A solution of 4-methyl-6-(thiazol-5-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine (1.5 g, 4.46 mmol) in THF (35.7 mL) was cooled to −78° C. LDA (2M, 6.69 mL, 13.38 mmol) solution was slowly added, and the resulting mixture was stirred as at −78° C. for 30 minutes. In a separate dry flask, methyl 1-oxo-2,3-dihydro-1H-indene-5-carboxylate (1.06 g, 5.57 mmol) was dissolved in THF (5 mL), then this solution was added to the reaction mixture, which was then allowed to warm to rt over a period of 3 hrs, then stirred at rt for an additional 13 h. The reaction was quenched by addition of 2 mL MeOH and then loaded directly onto a silica gel chromatography column and purified with a gradient solvent system of 0-100% EtOAc/hexanes. The product-containing fractions were evaporated to give methyl 1-hydroxy-1-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-2,3-dihydro-1H-indene-5-carboxylate 16C (912 mg, 39%) as a light yellow solid. MS ESI calcd for C26H21F3N4O3S [M+H]+ 527, found 527.

Workup

  1. customIn a separate dry flask
  2. additionthis solution was added to the reaction mixture, which
  3. temperatureto warm to rt over a period of 3 hrs
  4. stirringstirred at rt for an additional 13 h
  5. customThe reaction was quenched by addition of 2 mL MeOH
  6. custompurified with a gradient solvent system of 0-100% EtOAc/hexanes
  7. customThe product-containing fractions were evaporated

Sources & evidence

ORD record
ord-f31c164f9f2645dfa863f2bc3a9f5d67
Source dataset
uspto-grants-2014_08
Patent number
US08796310B2

Reaction notes

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