N-Methylisobutylamine → HCID 67278681, compound

HRID 1694418Notes

Reaction equation

HRID 1694418 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18]([OH:20])=O)[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:22][NH:23][CH2:24][CH:25]([CH3:27])[CH3:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[CH2:24]([N:23]([CH3:22])[C:18]([CH:16]1[CH2:17][C:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)=[C:2]([Cl:1])[CH:3]=2)([OH:21])[CH2:15]1)=[O:20])[CH:25]([CH3:27])[CH3:26]

Participants

6

Reactant 4

HCID 12249N-MethylisobutylamineHCID 14798Sodium HydroxideHCID 111923Propylphosphonic anhydrideHCID 574858713-(3-Chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid

Product 1

HCID 67278681HCID 67278681, compoundYield 44%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of crude intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜4.3 mL ˜0.65 mmol) was added N-methylisobutylamine (0.15 ml, 1.29 mmol) and T3P (50 wt % solution in EtOAc, 0.62 ml, 0.97 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 25 ml of 1N NaOH and 100 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×60 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 40 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (108 mg, 44% yield). Rf=0.80 (20% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C21H31ClN2O2, 378.9, found, 379.1 (M+1) APCI; 400 MHz 1H NMR (CDCl3) 1:1 mixture of rotomers, δ 7.47-7.45 (m, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.36-7.30 (m, 1H), 3.71 (s, 2H), 3.20-3.02 (m, 3H), 2.92 & 2.90 (2 s, 3H total), 2.80-2.70 (m, 2H), 2.60-2.50 (m, 6H), 1.95-1.80 (m, 1H), 1.78-1.70 (m, 4H), 0.76-0.58 (m, 6H); 100 MHz 13C NMR (CDCl3) 1:1 mixture of rotomers, line list δ 176.6, 175.8, 146.4, 135.2, 135.1, 134.0, 130.9, 130.8, 126.4, 123.7, 123.6, 73.5, 73.3, 57.9, 56.7, 55.6, 54.3, 41.4, 41.0, 36.1, 35.0, 29.0, 28.2, 27.9, 26.9, 23.7, 20.2, 20.1.

Workup

  1. customThe resulting reaction mixture
  2. customthe layers were separated
  3. extractionThe aqueous layer was subjected to EtOAc extraction (2×60 ml) again
  4. dry with materialthe combined organic layers were dried over MgSO4
  5. customevaporated
  6. customThe residue was purified by flash column chromatography
  7. washeluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH
  8. additionThe product containing fractions
  9. customwere collected
  10. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-0d0c16c8508b4493829730d78aedd407
Source dataset
uspto-grants-2012_04
Patent number
US08158673B2

Reaction notes

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