Ether hydrochloride → (2-Fluoro-4-methanesulfonyl-phenyl)-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methyl-pyrimidin-4-yl}-amine

HRID 1036777Notes

Reaction equation

HRID 1036777 reaction equation
Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:10]=2[F:19])[C:3]=1[CH3:20].[CH:21]([C:24]1[N:28]=[C:27]([N:29]2[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]2)[O:26][N:25]=1)([CH3:23])[CH3:22].CC(C)([O-])C.[K+].Cl.CCOCC>C1COCC1.C(Cl)Cl>[F:19][C:10]1[CH:11]=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[NH:8][C:4]1[C:3]([CH3:20])=[C:2]([O:35][CH:32]2[CH2:33][CH2:34][N:29]([C:27]3[O:26][N:25]=[C:24]([CH:21]([CH3:23])[CH3:22])[N:28]=3)[CH2:30][CH2:31]2)[N:7]=[CH:6][N:5]=1

Participants

7

Reactant 4

HCID 10953452Ether hydrochlorideHCID 218977441-(3-Isopropyl-1,2,4-oxadiazol-5-YL)piperidin-4-OLHCID 23665647Potassium tert-butoxideHCID 86597362(6-Chloro-5-methyl-pyrimidin-4-yl)-(2-fluoro-4-methanesulfonyl-phenyl)-amine

Product 1

HCID 59856820(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methyl-pyrimidin-4-yl}-amineYield 30%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

A mixture of (6-chloro-5-methyl-pyrimidin-4-yl)-(2-fluoro-4-methanesulfonyl-phenyl)-amine (HCl salt, 1.76 g, 5.0 mmol) and 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol (1.05 g, 5.0 mmol) in anhydrous THF (10 mL) was treated with potassium t-butoxide (20 mL, 20 mmol), placed under inert atmosphere, and refluxed for 4 hours, at which point the reaction had stalled at 60% conversion. The reaction mixture was cooled, quenched with water (30 mL), and extracted with ether (2×50 mL). The combined organic extract was rinsed with water (20 mL), followed by brine (20 mL), and was dried over MgSO4. After solvent removal, the residue was rinsed with boiling ether (2×20 mL), and the combined rinses were set aside to cool. Crystallization yielded a white solid (91% pure by LCMS) which was triturated in hot ether and filtered hot to furnish Compound A93 as a white solid in >95% purity (731 mg, 30% yield). This material was taken up in CH2Cl2 (10 mL), to which was added 1 N HCl/ether (1.5 mL). Upon solvent removal, a light gray foam was obtained (800 mg): 1H NMR (DMSO-d6) δ 10.26 (brs, 1 H), 8.77 (s, 1 H), 8.22 (s, 1 H), 7.83-7.71 (m, 3 H), 5.33 (m, 1 H), 3.75 (m, 2 H), 3.57 (m, 2 H), 3.37 (s, 3 H), 2.83 (m 1 H), 2.13 (s, 3 H), 2.04 (m, 2 H), 1.78 (m, 2 H), 1.20 (d, 6 H, J=6.9 Hz), MS m/z 491.2 (M+).

Workup

  1. temperaturerefluxed for 4 hours, at which
  2. temperatureThe reaction mixture was cooled
  3. customquenched with water (30 mL)
  4. extractionextracted with ether (2×50 mL)
  5. extractionThe combined organic extract
  6. washwas rinsed with water (20 mL)
  7. dry with materialwas dried over MgSO4
  8. customAfter solvent removal
  9. washthe residue was rinsed with boiling ether (2×20 mL)
  10. temperatureto cool
  11. customCrystallization
  12. customyielded a white solid (91% pure by LCMS) which
  13. customwas triturated in hot ether
  14. filtrationfiltered hot
  15. customto furnish Compound A93 as a white solid in >95% purity (731 mg, 30% yield)
  16. customUpon solvent removal
  17. customa light gray foam was obtained (800 mg)

Sources & evidence

ORD record
ord-b2bf461b0066401d90b866ab98f7b75f
Source dataset
uspto-grants-2013_10
Patent number
US08546429B2

Reaction notes

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