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4-Methylmorpholine → (S)-N-[(1-butyl-2-pyrrolidinyl)methyl]-6-chloro-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide

HRID 2081560
Notes
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Reaction equation

HRID 2081560 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][N:7]([CH3:13])[C:6]=2[CH:14]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:33][CH2:34][C@@H:35]1[CH2:39][CH2:38][CH2:37][N:36]1[CH2:40][CH2:41][CH2:42][CH3:43]>O1CCCC1.CN(C)C=O>[CH2:40]([N:36]1[CH2:37][CH2:38][CH2:39][C@H:35]1[CH2:34][NH:33][C:15]([C:4]1[C:5]2[O:10][C:9]([CH3:11])([CH3:12])[CH2:8][N:7]([CH3:13])[C:6]=2[CH:14]=[C:2]([Cl:1])[CH:3]=1)=[O:17])[CH2:41][CH2:42][CH3:43]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 12829008[(2S)-1-butylpyrrolidin-2-yl]methanamineHCID 152635426-chloro-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid

Product 1

HCID 54033459(S)-N-[(1-butyl-2-pyrrolidinyl)methyl]-6-chloro-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 1.03 g of 6-chloro-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid in a mixed solvent of 5 ml of dimethylformamide and 10 ml of tetrahydrofuran was added 0.6 g N-methylmorpholine, and 0.55 g of isobutyl chloroformate was added dropwise thereto at -10° to -5° C. under ice-cooling. After stirring for 20 minutes at the same temperature, 0.63 g of (S)-(-)-2-aminomethyl-1-butylpyrrolidine was added at -10° to -5° C. and the mixture was stirred at room temperature for three hours. The resultant mixture was concentrated under reduced pressure, and to the residue were added an aqueous potassium carbonate solution and ethyl acetate. The organic layer was separated and washed with water and then dried over magnesium sulfate. The solvent was distilled off and the residue was recrystallized from isopropyl ether to give (S)-N-[(1-butyl-2-pyrrolidinyl)methyl]-6-chloro-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide as white crystals, melting at 110° to 112° C. [α]D =-61.7° (c=1, methanol)

Workup

  1. additionwas added dropwise
  2. temperatureat -10° to -5° C. under ice-cooling
  3. additionwas added at -10° to -5° C.
  4. concentrationThe resultant mixture was concentrated under reduced pressure
  5. additionto the residue were added an aqueous potassium carbonate solution and ethyl acetate
  6. customThe organic layer was separated
  7. washwashed with water
  8. dry with materialdried over magnesium sulfate
  9. distillationThe solvent was distilled off
  10. customthe residue was recrystallized from isopropyl ether

Sources & evidence

ORD record
ord-d1233f7cdcb549cf9fce6e90fc7655e6
Source dataset
uspto-grants-1993_02
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US05185333

Reaction notes

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