Nitrogen → 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoic acid

HRID 923573Notes

Reaction equation

HRID 923573 reaction equation
[CH:1]([O-:3])=[O:2].[Li+].CCN(C(C)C)C(C)C.C(OC(=O)C)(=O)C.N#N.I[C:24]1[CH:63]=[CH:62][C:27]([CH2:28][N:29]([CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C:30](=[O:53])[C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:52])[CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=3[C:48]([F:51])([F:50])[F:49])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1>CN(C=O)C.CC(=O)OCC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:58]([O:57][C:55](=[O:56])[CH2:54][N:29]([CH2:28][C:27]1[CH:62]=[CH:63][C:24]([C:1]([OH:3])=[O:2])=[CH:25][CH:26]=1)[C:30](=[O:53])[C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:52])[CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=2[C:48]([F:51])([F:50])[F:49])=[CH:33][CH:32]=1)([CH3:61])([CH3:60])[CH3:59]

Participants

9

Reactant 5

HCID 947NitrogenHCID 7918Acetic AnhydrideHCID 81531DiisopropylethylamineHCID 23680280Lithium formateHCID 71111625tert-butyl 2-(N-(4-iodobenzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate

Product 1

HCID 710768754-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoic acidYield 60%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

To a stirring mixture of lithium formate (0.30 g, 5.85 mmol) and DIPEA (0.68 mL, 3.90 mmol) in DMF (3 mL) was added acetic anhydride (0.37 mL, 3.90 mmol). After 30 min, a N2 purged solution of tert-butyl 2-(N-(4-iodobenzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-36 (1.33 g, 1.95 mmol) and PdCl2(dppf) (143 mg, 0.20 mmol) in DMF (2 mL) was added and the mixture heated to 110° C. for 1 h. The reaction mixture was allowed to cool to room temperature, diluted with EA (150 mL) and washed successively with 1N HCl (200 mL) and brine (200 mL). The organics were pre-absorbed onto silica gel then purified by chromatography (EA/isohexanes+1% AcOH) to afford a crude material that was further concentrated from toluene (20 mL). The crude solid was triturated from diethyl ether/isohexanes (10 mL:100 mL) and isolated by filtration to afford 721 mg (60%) of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoic acid INT-37. LCMS-ESI (m/z) calculated for C31H31F3N2O7: 600; found 599 [M−H]−, tR=2.27 min (Method 10). 1H NMR (400 MHz, DMSO) δ 13.86 (s, 1H), 10.33 (s, 1H), 8.00-7.85 (m, 2H), 7.62 (t, J=8.5 Hz, 2H), 7.56-7.29 (m, 5H), 7.28-7.11 (m, 2H), 4.71 (s, 1H), 4.62 (s, 1H), 4.01-3.92 (m, 2H), 3.85 (s, 2H), 3.83 (s, 3H), 1.41(s, 4.5H), 1.31 (s, 4.5H).

Workup

  1. temperatureto cool to room temperature
  2. washwashed successively with 1N HCl (200 mL) and brine (200 mL)
  3. customThe organics were pre-absorbed onto silica gel
  4. customthen purified by chromatography (EA/isohexanes+1% AcOH)
  5. customto afford a crude material that
  6. concentrationwas further concentrated from toluene (20 mL)
  7. customThe crude solid was triturated from diethyl ether/isohexanes (10 mL:100 mL)
  8. customisolated by filtration

Sources & evidence

ORD record
ord-1f89f5338b814730852f533078469a93
Source dataset
uspto-grants-2016_03
Patent number
US09278910B2

Reaction notes

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