2-Fluoro-N-methoxy-N-methylnicotinamide → Tert-butyl (25)-4-[4-(2-fluoropyridine-3-carbonyl)-5-methyl-thiazol-2-yl]-2-isobutyl-piperazine-1-carboxylate

HRID 1044031Notes

Reaction equation

HRID 1044031 reaction equation
Br[C:2]1[N:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:9]2)[S:5][C:6]=1[CH3:7].[Li]CCCC.[F:30][C:31]1[C:36]([C:37](N(OC)C)=[O:38])=[CH:35][CH:34]=[CH:33][N:32]=1>C1COCC1>[F:30][C:31]1[C:36]([C:37]([C:2]2[N:3]=[C:4]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:9]3)[S:5][C:6]=2[CH3:7])=[O:38])=[CH:35][CH:34]=[CH:33][N:32]=1

Participants

5

Reactant 3

HCID 534170672-Fluoro-N-methoxy-N-methylnicotinamideHCID 70371764tert-butyl (2S)-4-(4-bromo-5-methyl-thiazol-2-yl)-2-isobutyl-piperazine-1-carboxylateHCID 178418339Butyllithium

Product 1

HCID 70371583Tert-butyl (25)-4-[4-(2-fluoropyridine-3-carbonyl)-5-methyl-thiazol-2-yl]-2-isobutyl-piperazine-1-carboxylateYield 26%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

tert-butyl (25)-4-(4-bromo-5-methyl-thiazol-2-yl)-2-isobutyl-piperazine-1-carboxylate (921 mg, 1.737 mmol) in THF (10 mL) was cooled to −78° C. before BuLi (729.6 μL, 2.5 M in hexanes, 1.824 mmol) was added dropwise over approx. 10 mins (temperature kept below −70° C. during addition). Once added, mixture stirred at −78° C. for 30 mins before a solution of 2-fluoro-N-methoxy-N-methyl-pyridine-3-carboxamide (319.9 mg, 1.737 mmol) in THF (3 mL) was added dropwise at −78° C. at such a rate that temperature did not exceed −70° C. (−5 mins). Mixture then stirred at −78° C. for 2 h allowed to warm to room temperature over the weekend (3.5 days). Reaction quenched with water, diluted with EtOAc and organic layer separated, washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Crude product purified by flash chromatography (80 g SiO2, 0 to 15% EtOAc/petrol) to leave product as a yellow solid (208 mg, 26%); 1H NMR DMSO-d6 δ 0.85 (d, 6H), 1.40-1.35 (m, 12H), 2.63 (s, 3H), 2.97-2.94 (m, 2H), 3.10 (dd, 1H), 3.58 (d, 2H), 3.87-3.80 (m, 1H), 4.20-4.13 (m, 1H), 7.49-7.46 (m, 1H), 8.17-8.12 (m, 1H), 8.39 (dd, 1H); ES+ 463.22.

Workup

  1. additionwas added dropwise over approx. 10 mins
  2. addition(temperature kept below −70° C. during addition)
  3. additionOnce added
  4. additionwas added dropwise at −78° C. at such a rate that temperature
  5. customdid not exceed −70° C.
  6. custom(−5 mins)
  7. temperatureto warm to room temperature over the weekend (3.5 days)
  8. customReaction
  9. customquenched with water
  10. additiondiluted with EtOAc and organic layer
  11. customseparated
  12. washwashed with brine
  13. dry with materialdried (MgSO4)
  14. filtrationfiltered
  15. concentrationconcentrated in vacuo
  16. customCrude product purified by flash chromatography (80 g SiO2, 0 to 15% EtOAc/petrol)

Sources & evidence

ORD record
ord-a29ff30c73c041c89b80f44267ebd6d1
Source dataset
uspto-grants-2013_10
Patent number
US08563576B2

Reaction notes

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