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Propylphosphonic anhydride → (2R)-2-amino-2-methyl-N-[6-[(2,4,4-trimethyl-3,1-benzoxazin-5-yl)oxy]-3-pyridyl]butanamide

HRID 527663
Notes
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Reaction equation

HRID 527663 reaction equation
[CH3:1][C:2]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]2[C:10]([O:14][C:15]3[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]=1.Cl.[NH2:23][C@:24]([CH3:30])([CH2:28][CH3:29])[C:25](O)=[O:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(OCC)(=O)C.CC#N.C(OCC)(=O)C.O>[NH2:23][C@:24]([CH3:30])([CH2:28][CH3:29])[C:25]([NH:21][C:18]1[CH:19]=[N:20][C:15]([O:14][C:10]2[C:5]3[C:6]([CH3:8])([CH3:9])[O:7][C:2]([CH3:1])=[N:3][C:4]=3[CH:13]=[CH:12][CH:11]=2)=[CH:16][CH:17]=1)=[O:26]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 3

HCID 111923Propylphosphonic anhydrideHCID 17998883(R)-2-Amino-2-methylbutanoic acid hydrochlorideHCID 679602016-[(2,4,4-Trimethyl-3,1-benzoxazin-5-yl)oxy]pyridin-3-amine2×

Product 1

HCID 67959970(2R)-2-amino-2-methyl-N-[6-[(2,4,4-trimethyl-3,1-benzoxazin-5-yl)oxy]-3-pyridyl]butanamideYield 57.5%

Reagents, catalysts & solvents 3

HCID 962
Water
Solvent
HCID 8857Ethyl AcetateSolvent2×
HCID 21930812Acetonitrile ethyl acetateSolvent

Conditions

Temperature
80 °C

Procedure

To a suspension of 6-[(2,4,4-trimethyl-3,1-benzoxazin-5-yl)oxy]pyridin-3-amine (Intermediate 204, 185 mg, 0.65 mmol) and (R)-2-amino-2-methyl-butanoic acid hydrochloride (100 mg, 0.67 mmol) in ethyl acetate/MeCN (2 mL, 1:3 v/v mixture), a 50% w/w solution in ethyl acetate of T3P (0.43 mL) was added drop wise at 0° C. The mixture was then heated at 60° C. for 3 hours and at 80° C. for 4.5 hours. The mixture was cooled to room temperature diluted with water (5 mL) and ethyl acetate (10 mL), Two phases were separated and the aqueous one was treated with a saturated solution of NaHCO3 (pH=8) and back-extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated and the residue was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate 20:80 as eluent affording the title compound (143 mg) as a yellow foam.

Workup

  1. temperatureThe mixture was cooled to room temperature
  2. customwere separated
  3. additionthe aqueous one was treated with a saturated solution of NaHCO3 (pH=8)
  4. extractionback-extracted with ethyl acetate (2×10 mL)
  5. dry with materialThe combined organic layers were dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customthe residue was purified by flash chromatography on silica gel

Sources & evidence

ORD record
ord-e35ce4eb4320490882673310fd91ddb7
Source dataset
uspto-grants-2016_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09346790B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes