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Sulfuric Acid → (4S,6S)-4-(5-((3-chloro-1,7-naphthyridin-8-yl)amino)-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine

HRID 930284
Notes
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Reaction equation

HRID 930284 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[N:28][C:27]=2Cl.CC(O)C.S(=O)(=O)(O)O>O.CCOC(C)=O>[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[N:28][C:27]=2[NH:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:15])[F:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 1118Sulfuric AcidHCID 3776IsopropanolHCID 722135953,8-Dichloro-1,7-naphthyridine2×HCID 86732112(4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine

Product 1

HCID 86732113(4S,6S)-4-(5-((3-chloro-1,7-naphthyridin-8-yl)amino)-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine
Yield 24.85%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
55 °C

Procedure

A sealable vial was charged with crude (4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (345 mg, 1.116 mmol, step 1) and 3,8-dichloro-1,7-naphthyridine (Intermediate 2; 233 mg, 1.171 mmol). iPrOH (8 mL) was added and the suspension was briefly sonicated. Sulfuric acid (0.059 mL, 1.116 mmol, Aldrich) was added and the vial was sealed. The reaction was heated to 55° C. in an oil bath for one hour then cooled to RT and stirred for additional 16 hours. The reaction was diluted with water and EtOAc. The aqueous layer separated was basified to pH=12 by the addition of 1N NaOH. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude material was purified via silica gel chromatography using a gradient of 0-50% EtOAc:Hexanes to afford the title compound as a white solid. (130.8 mg, 0.277 mmol, 24.85% yield). MS m/z=472.0 [M+H]+. Calculated for C20H15ClF5N5O: 471.811

Workup

  1. customthe suspension was briefly sonicated
  2. customthe vial was sealed
  3. temperaturethen cooled to RT
  4. customThe aqueous layer separated
  5. additionwas basified to pH=12 by the addition of 1N NaOH
  6. extractionThe aqueous layer was extracted with EtOAc (3×)
  7. washThe combined organic layers were washed with brine
  8. dry with materialdried over magnesium sulfate
  9. concentrationconcentrated under reduced pressure
  10. customThe crude material was purified via silica gel chromatography

Sources & evidence

ORD record
ord-a191cc72fb4444da98eb33c4ad6cc16b
Source dataset
uspto-grants-2016_03
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09296734B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes