Sodium hydride → tert-Butyl 4-(6-bromothiazolo[4,5-b]pyridin-2-yloxy)piperidine-1-carboxylate

HRID 1429537Notes

Reaction equation

HRID 1429537 reaction equation
[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Cl.[Br:18][C:19]1[CH:20]=[C:21]2[S:27][C:26](Cl)=[N:25][C:22]2=[N:23][CH:24]=1.[Na]>CN(C=O)C>[Br:18][C:19]1[CH:20]=[C:21]2[S:27][C:26]([O:1][CH:2]3[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)=[N:25][C:22]2=[N:23][CH:24]=1

Participants

6

Reactant 4

HCID 24758Sodium hydrideHCID 643502Tert-butyl 4-hydroxypiperidine-1-carboxylateHCID 5360545SodiumHCID 674627556-Bromo-2-chlorothiazolo[4,5-b]pyridine hydrochloride

Product 1

HCID 68208481tert-Butyl 4-(6-bromothiazolo[4,5-b]pyridin-2-yloxy)piperidine-1-carboxylateYield 21%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (0.88 g, 4.37 mmol) in DMF (8.7 mL) was added NaH (0.121 g, 4.81 mmol) at 0° C. Upon completion of addition, the mixture was warmed to rt until the mixture became a clear solution. In a separate flask, 6-bromo-2-chlorothiazolo[4,5-b]pyridine hydrochloride (0.5 g, 1.748 mmol) was suspended in DMF (8.74 mL) and the above sodium salt solution was transferred into the thiazolepyridine suspension via cannulation. The resulting mixture was then heated in a 50° C. oil bath. After 4 h, the reaction mixture was analyzed by HPLC, which indicated the reaction was complete. The reaction mixture was cooled to rt, and then quenched with NaHCO3 (saturated aq, 10 mL). The resulting mixture was extracted with EtOAc (3×5 mL) and the combined organic layers were dried (Na2SO4), filtered, and concentrated to yield the crude product. The crude product was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 50% EtOAc) to give Compound 21B as a white solid (150 mg, 21% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 8.54 (d, J=2.2 Hz, 1H), 8.08 (d, J=2.2 Hz, 1H), 5.43-5.52 (m, J=8.0, 8.0, 4.0, 3.9 Hz, 1H), 3.70-3.84 (m, 2H), 3.24-3.34 (m, 2H), 2.07-2.17 (m, 2H), 1.80-1.92 (m, J=12.7, 8.5, 8.5, 4.1 Hz, 2H), 1.46 (s, 9H). LC/MS (m/z)=415 (M+H)+.

Workup

  1. additionUpon completion of addition
  2. temperatureThe resulting mixture was then heated in a 50° C. oil bath
  3. temperatureThe reaction mixture was cooled to rt
  4. customquenched with NaHCO3 (saturated aq, 10 mL)
  5. extractionThe resulting mixture was extracted with EtOAc (3×5 mL)
  6. dry with materialthe combined organic layers were dried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto yield the crude product
  10. customThe crude product was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 50% EtOAc)

Sources & evidence

ORD record
ord-59aed915244e42648205d1dc11d5a118
Source dataset
uspto-grants-2015_01
Patent number
US08940716B2

Reaction notes

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