Hydrochloric Acid → (S)-2-(5-amino-3-(3-chloro-2-fluoro-6-morpholinopyridin-4-yl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-bromophenol

HRID 455693Notes

Reaction equation

HRID 455693 reaction equation
Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([O:36]COC)=[C:7]([C@:9]([NH:29][S@](C(C)(C)C)=O)([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=[C:17]([F:27])[C:16]=2[Cl:28])[CH2:10][O:11][CH2:12][C:13]#[N:14])[CH:8]=1.C[Al](C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1.CCOC(C)=O>[NH2:14][C:13]1[CH2:12][O:11][CH2:10][C@:9]([C:7]2[CH:8]=[C:3]([Br:2])[CH:4]=[CH:5][C:6]=2[OH:36])([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=[C:17]([F:27])[C:16]=2[Cl:28])[N:29]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 9855836Potassium sodium tartarateHCID 16682925TrimethylaluminumHCID 67438635(S)-N-((S)-1-(5-bromo-2-(methoxymethoxy)phenyl)-1-(3-chloro-2-fluoro-6-morpholinopyridin-4-yl)-2-(cyanomethoxy)ethyl)-2-methylpropane-2-sulfinamide

Product 1

HCID 67438929(S)-2-(5-amino-3-(3-chloro-2-fluoro-6-morpholinopyridin-4-yl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-bromophenolYield 47%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of hydrogen chloride (5-6N in iPrOH; 1.025 mL, 5.12 mmol) was added to a solution of (S)—N—((S)-1-(5-bromo-2-(methoxymethoxy)phenyl)-1-(3-chloro-2-fluoro-6-morpholinopyridin-4-yl)-2-(cyanomethoxy)ethyl)-2-methylpropane-2-sulfinamide (1083 mg, 1.708 mmol) in THF (4 mL) under nitrogen atmosphere. The reaction mixture was stirred for 10 min at RT. The solvent was removed under reduced pressure and the residue was dissolved in DCE (2 mL). A solution of AlMe3 (2M in toluene; 2.56 mL, 5.12 mmol) was added drop wise and the reaction mixture was allowed to stir at 70 C for 3 h. The reaction mixture was cooled to RT and a solution of aqueous saturated solution of potassium sodium tartrate was added, followed by EtOAc. The reaction mixture was allowed to stir vigorously for 1 h. The organic phase was separated, washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (100% EtOAc) to afford 390 mg of (S)-2-(5-amino-3-(3-chloro-2-fluoro-6-morpholinopyridin-4-yl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-bromophenol.

Workup

  1. customThe solvent was removed under reduced pressure
  2. dissolutionthe residue was dissolved in DCE (2 mL)
  3. stirringto stir at 70 C for 3 h
  4. temperatureThe reaction mixture was cooled to RT
  5. stirringto stir vigorously for 1 h
  6. customThe organic phase was separated
  7. washwashed with brine
  8. dry with materialdried over MgSO4
  9. customThe solvent was removed under reduced pressure
  10. customthe residue was purified by silica gel chromatography (100% EtOAc)

Sources & evidence

ORD record
ord-19691bccae494f20b74f8dd3e65611cb
Source dataset
uspto-grants-2013_07
Patent number
US08497264B2

Reaction notes

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