Lithium diisopropylamide → HCID 131731735, compound

HRID 2402389Notes

Reaction equation

HRID 2402389 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.C([N-]C(C)C)(C)C.[Li+].[F:32][C:33]1[C:34]([C:44]([O:46][CH3:47])=[O:45])=[CH:35][C:36]2[CH2:37][CH2:38][CH2:39][C:40](=[O:43])[C:41]=2[CH:42]=1.[OH2:48].C(#N)C>C1COCC1>[C:18]([OH:43])([C:20]([F:23])([F:22])[F:21])=[O:48].[F:21][C:20]([F:23])([F:22])[C:18]([OH:43])=[O:48].[F:32][C:33]1[C:34]([C:44]([O:46][CH3:47])=[O:45])=[CH:35][C:36]2[CH2:37][CH2:38][CH2:39][C:40]([OH:43])([C:11]3[S:12][C:8]([C:6]4[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([NH:13][C:14]5[CH:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][N:15]=5)[N:5]=4)=[CH:9][N:10]=3)[C:41]=2[CH:42]=1

Participants

7

Reactant 4

HCID 2724682Lithium diisopropylamideHCID 18373917Acetonitrile--water (1/1)HCID 67170158HCID 67170158, compoundHCID 709773814-methyl-6-(1,3-thiazol-5-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine

Product 2

HCID 6422Trifluoroacetic acidHCID 131731735HCID 131731735, compoundYield 30%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 4-methyl-6-(1,3-thiazol-5-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine (600 mg, 1.78 mmol) in THF (5.9 mL) under argon at −78° C. was slowly added lithium diisopropylamide (2.0 M in THF, 2.68 mL, 5.35 mmol), and the resulting mixture was stirred for 30 minutes at that temperature. A solution of methyl 3-fluoro-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (496 mg, 2.230 mmol) in THF (2 mL) was added, and the reaction mixture was allowed to warm to rt over 2 h. After an additional 12 h, the reaction was quenched with methanol (10 mL) and concentrated under reduced pressure. Reverse-phase HPLC (C18 column, water-acetonitrile, TFA modifier) afforded (rac)-methyl 3-fluoro-5-hydroxy-5-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]-5,6,7,8-tetrahydronaphthalene-2-carboxylate, trifluoroacetate salt (355.1 mg, 0.528 mmol, 30% yield) as a yellow solid. MS ESI calcd for C27H22F4N4O3S [M+H]+ 559, found 559. 1H NMR (500 MHz, DMSO) δ 10.22 (s, 1H), 8.65 (s, 1H), 8.48 (d, J=5.2 Hz, 1H), 8.26 (s, 1H), 7.69 (d, J=7.4 Hz, 1H), 7.37 (s, 1H), 7.21 (d, J=5.2 Hz, 1H), 7.14-7.06 (m, 2H), 3.82 (s, 3H), 2.89-2.77 (m, 2H), 2.41-2.32 (m, 1H), 2.30 (s, 3H), 2.13-2.06 (m, 1H), 2.00-1.85 (m, 2H) ppm.

Workup

  1. customat −78° C.
  2. waitAfter an additional 12 h
  3. customthe reaction was quenched with methanol (10 mL)
  4. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-7e5853565a6b44cd8a7ffd79674fa799
Source dataset
uspto-grants-2014_08
Patent number
US08796310B2

Reaction notes

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