Methanol → HCID 86680149, compound

HRID 1915952Notes

Reaction equation

HRID 1915952 reaction equation
C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:29]=[N:28][N:27]([CH3:30])[C:26]=1[N:31]1[CH2:37][CH2:36][C@H:35](O)[C@H:34]([NH:39][C:40](=[O:46])[O:41]C(C)(C)C)[CH2:33][CH2:32]1)=[O:23])=O)(C)(C)C.[H-].[Na+].CO>CN(C=O)C.Cl.O1CCOCC1>[O:46]=[C:40]1[NH:39][C@@H:34]2[CH2:33][CH2:32][N:31]([C:26]3[N:27]([CH3:30])[N:28]=[CH:29][C:25]=3[NH:24][C:22]([C:10]3[N:11]=[C:12]([C:14]4[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=4[F:21])[S:13][C:9]=3[NH2:8])=[O:23])[CH2:37][CH2:36][C@@H:35]2[O:41]1

Participants

7

Reactant 3

HCID 887MethanolHCID 24758Sodium hydrideHCID 86680150HCID 86680150, compound

Product 1

HCID 86680149HCID 86680149, compoundYield 41%

Reagents, catalysts & solvents 3

HCID 313Hydrochloric AcidSolventHCID 6228DimethylformamideSolventHCID 312751,4-DioxaneSolvent

Procedure

To a stirred solution of tert-butyl N-((4R,5S)-1-(4-((5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carbonyl)amino)-2-methyl-pyrazol-3-yl)-5-hydroxy-azepan-4-yl)carbamate (199 mg, 0.30 mmol) in DMF (2 mL) at 0° C. was added sodium hydride (60% dispersion in oil, 26 mg, 0.66 mmol). The mixture was allowed to warm to room temperature over 2 hr, quenched with water (3 mL) and the resulting precipitate filtered off and dried under reduced pressure. The aqueous layer was extracted with EtOAc (3×3 mL) and the combined organic layers were passed through a phase separation cartridge, concentrated under reduced pressure and the residue combined with the precipitate collected earlier. A solution of this material (159 mg, 0.27 mmol) in HCl in dioxane (4 M, 10 mL) and MeOH (5 mL) was stirred at room temperature for 16 hr. The solvents were removed under reduced pressure. Purification via preparative HPLC gave 486 as a white solid (55 mg, 41% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 7.79 (s, 1H), 7.37-7.28 (m, 1H), 7.05 (t, J=8.8 Hz, 2H), 6.14 (s, 2H), 5.08-5.00 (m, 1H), 4.87 (s, 1H), 4.26 (td, J=9.3, 3.5 Hz, 1H), 3.75 (s, 3H), 3.45-3.33 (m, 2H), 3.16-3.07 (m, 2H), 2.34-2.27 (m, 2H), 2.20-2.09 (m, 1H), 2.06-1.97 (m, 1H). LCMS (ES+) m/z 490 (M+1)

Workup

  1. customquenched with water (3 mL)
  2. filtrationthe resulting precipitate filtered off
  3. customdried under reduced pressure
  4. extractionThe aqueous layer was extracted with EtOAc (3×3 mL)
  5. customthe combined organic layers were passed through a phase separation cartridge
  6. concentrationconcentrated under reduced pressure
  7. customcollected earlier
  8. customThe solvents were removed under reduced pressure
  9. customPurification via preparative HPLC

Sources & evidence

ORD record
ord-06986ddf46ab4300b01fe54452d93e3a
Source dataset
uspto-grants-2013_12
Patent number
US08614206B2

Reaction notes

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