Diisopropylethylamine → 1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid [4-amino-5-(3-hydroxy-3-methyl-butyl)-2'-trifluoromethyl-biphenyl-3-yl]-amide

HRID 1518166Notes

Reaction equation

HRID 1518166 reaction equation
[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])=[CH:4][C:3]=1[CH2:19][CH2:20][C:21]([CH3:24])([OH:23])[CH3:22].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[O:58]1[C:62]2([CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]2)[CH2:61][C:60]([C:68](O)=[O:69])=[N:59]1>C(Cl)Cl>[NH2:1][C:2]1[C:3]([CH2:19][CH2:20][C:21]([OH:23])([CH3:24])[CH3:22])=[CH:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:16])([F:17])[F:18])=[CH:6][C:7]=1[NH:8][C:68]([C:60]1[CH2:61][C:62]2([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]2)[O:58][N:59]=1)=[O:69]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733179PyBroPHCID 509941141-Oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acidHCID 592801034-(4,5-Diamino-2'-trifluoromethyl-biphenyl-3-yl)-2-methyl-butan-2-ol

Product 1

HCID 592800921-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid [4-amino-5-(3-hydroxy-3-methyl-butyl)-2'-trifluoromethyl-biphenyl-3-yl]-amideYield 40%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

4-(4,5-Diamino-2′-trifluoromethyl-biphenyl-3-yl)-2-methyl-butan-2-ol (57.5 mg, 0.170 mmol, as prepared in the previous step) was placed in a 50 mL round-bottom flask equipped with a magnetic stir bar. DCM (15 mL), PyBrOP (95.0 mg, 0.204 mmol), and DIPEA (36.0 μL, 0.204 mmol) were added via syringe. 1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (31.0 mg, 0.170 mmol, as prepared in Example 1, step B) in DCM (10 mL) was placed in an addition funnel and added dropwise over 2 h. After completion of the addition, the mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure. The residue was chromatographed on a 40-g pre-packed SiO2 column eluting with EtOAc/heptane, 0:1 to 3:7, v/v over 20 min, yielding 34.4 mg (40%) of the title compound. Mass Spectrum (LCMS, ESI pos.) Calcd. for C27H32F3N3O3: 504.2 (M+H). Found 504.1.

Workup

  1. customwas placed in a 50 mL round-bottom flask
  2. customequipped with a magnetic stir bar
  3. additionadded dropwise over 2 h
  4. additionAfter completion of the addition
  5. customThe solvent was removed under reduced pressure
  6. customThe residue was chromatographed on a 40-g pre-packed SiO2 column
  7. washeluting with EtOAc/heptane, 0:1 to 3:7, v/v over 20 min

Sources & evidence

ORD record
ord-82dcf6b65a1f4dfa83b4737565601857
Source dataset
uspto-grants-2012_07
Patent number
US08232409B2

Reaction notes

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