2-Fluoro-N-methoxy-N-methylnicotinamide → Tert-butyl 4-(5-(2-fluoronicotinoyl)thiazol-2-yl)-1,4-diazepane-1-carboxylate

HRID 1929365Notes

Reaction equation

HRID 1929365 reaction equation
C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[F:25][C:26]1[N:37]=[CH:36][CH:35]=[CH:34][C:27]=1[C:28](N(OC)C)=[O:29]>O1CCCC1>[F:25][C:26]1[N:37]=[CH:36][CH:35]=[CH:34][C:27]=1[C:28]([C:22]1[S:21][C:20]([N:16]2[CH2:17][CH2:18][CH2:19][N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:12])[CH2:14][CH2:15]2)=[N:24][CH:23]=1)=[O:29]

Participants

5

Reactant 3

HCID 534170672-Fluoro-N-methoxy-N-methylnicotinamideHCID 57690677Tert-butyl 4-(thiazol-2-yl)-1,4-diazepane-1-carboxylateHCID 178418339Butyllithium

Product 1

HCID 57690516Tert-butyl 4-(5-(2-fluoronicotinoyl)thiazol-2-yl)-1,4-diazepane-1-carboxylateYield 38%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

A 2.5M n-butyl lithium in tetrahydrofuran solution (0.9 ml, 2.25 mmol) was added dropwise to a solution of tert-butyl-4-(thiazol-2-yl)-1,4-diazepane-1-carboxylate (570 mg, 2 mmol) in tetrahydrofuran (7 ml), cooled to −78° C. Thirty minutes later, a solution of 2-fluoro-N-methoxy-N-methylnicotinamide (370 mg, 2 mmol) in tetrahydrofuran (2 ml) added dropwise. The reaction mixture was stirred at −78° C. for one hour, then at 0° C. for an extra hour. It was quenched with a saturated sodium bicarbonate aqueous solution. The reaction mixture was diluted with ethyl acetate, then washed with brine. The organic was dried over magnesium sulfate, then concentrated in vacuo. The residue was purified by flash chromatography (40 g silica gel, pentane/ethyl acetate) to afford the title compound (300 mg, 38%). 1H NMR (CD3OD): 1.42 (9H, s), 1.90-2.00 (2H, M0, 3.45-3.50 (2H, m), 3.65-6.75 (2H, m), 3.80-3.90 (2H, m), 7.46-7.49 (1H, t), 7.67-7.69 (1H, d), 8.10-8.15 (1H, t), 8.39-8.40 (1H, d). MS (ES+): 407.

Workup

  1. waitat 0° C. for an extra hour
  2. customIt was quenched with a saturated sodium bicarbonate aqueous solution
  3. additionThe reaction mixture was diluted with ethyl acetate
  4. washwashed with brine
  5. dry with materialThe organic was dried over magnesium sulfate
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by flash chromatography (40 g silica gel, pentane/ethyl acetate)

Sources & evidence

ORD record
ord-6a8c0b69666c4d04a5d2824e2093bb47
Source dataset
uspto-grants-2012_05
Patent number
US08188071B2

Reaction notes

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