Methanol → HCID 59458529, compound

HRID 238831Notes

Reaction equation

HRID 238831 reaction equation
[F:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([NH:8][C@@:9]([C:21]2[CH:26]=[C:25]([O:27][C:28]([F:33])([F:32])[CH:29]([F:31])[F:30])[CH:24]=[C:23]([F:34])[CH:22]=2)([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][C:11]([OH:13])=[O:12])=[O:7])=[CH:4][C:3]=1[C:37]([F:40])([F:39])[F:38].[CH:41]1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CO.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([NH:8][C@@:9]([C:21]2[CH:26]=[C:25]([O:27][C:28]([F:32])([F:33])[CH:29]([F:31])[F:30])[CH:24]=[C:23]([F:34])[CH:22]=2)([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH2:10][C:11]([O:13][CH3:41])=[O:12])=[O:7])=[CH:4][C:3]=1[C:37]([F:40])([F:39])[F:38]

Participants

6

Reactant 4

HCID 887MethanolHCID 11430Potassium CarbonateHCID 199401P,P-Diphenylphosphinic azideHCID 59459112HCID 59459112, compound

Product 1

HCID 59458529HCID 59458529, compoundYield 15.2%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of (R)-3-(4-fluoro-3-(trifluoromethyl)benzamido)-3-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-3-(4-fluorophenyl)propanoic acid (32 mg, 0.055 mmol) in toluene (0.5 mL) was added DPPA (18 mg, 0.066 mmol) and TEA (7 mg, 0.066 mmol). The reaction mixture was heated at 100° C. for 1 h followed by the addition of MeOH and TEA. The reaction was heated at 65° C. overnight. Excess K2CO3 was added and the reaction was heated to reflux for 3 h. The reaction mixture was concentrated and the resulting residue was purified by preparative HPLC (phenominex 30×100 mm column, 30-100% MeOH (90% in water, 0.1% TFA) gradient over 12 min with flow rate 40 mL/min and UV detection at 220 nm) to yield (R)-methyl 3-(4-fluoro-3-(trifluoromethyl)benzamido)-3-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-3-(4-fluorophenyl)propanoate (Example 318) as a white solid (5 mg, 15% yield). LCMS: RT=3.92 min [M+H] 613.3 (4 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) ppm 3.74 (s, 3H), 3.87-4.11 (m, 2H), 4.89 (m, 1H), 5.86 (t, 1H), 6.95 (d, 1H), 6.99-7.13 (m, 5H), 7.28-7.40 (m, 3H), 8.09-8.16 (m, 1H), 8.26 (d, 1H), 8.94 (s, 1H).

Workup

  1. temperatureThe reaction was heated at 65° C. overnight
  2. temperaturethe reaction was heated
  3. temperatureto reflux for 3 h
  4. concentrationThe reaction mixture was concentrated
  5. customthe resulting residue was purified by preparative HPLC (phenominex 30×100 mm column, 30-100% MeOH (90% in water, 0.1% TFA) gradient over 12 min with flow rate 40 mL/min and UV detection at 220 nm)

Sources & evidence

ORD record
ord-0f8d84db1d424f119e4596f802c5b1d8
Source dataset
uspto-grants-2014_02
Patent number
US08642576B2

Reaction notes

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