Phenylacetyl chloride → 2-Tert-butoxy-2-[4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-6-(2-phenylacetyl)-5,7-dihydro-1,6-naphthyridin-3-yl]acetic acid

HRID 470935Notes

Reaction equation

HRID 470935 reaction equation
[C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][NH:16][CH2:17][C:18]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:39]1([CH2:45][C:46](Cl)=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][N:16]([C:46](=[O:47])[CH2:45][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:17][C:18]=2[C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]

Participants

5

Reactant 3

HCID 7679Phenylacetyl chlorideHCID 8471TriethylamineHCID 717115302-Tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid

Product 1

HCID 717116032-Tert-butoxy-2-[4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-6-(2-phenylacetyl)-5,7-dihydro-1,6-naphthyridin-3-yl]acetic acidYield 11.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1) (9.2 mg, 0.021 mmol) in CH2Cl2 (5 mL) was added Et3N (8.98 μl, 0.064 mmol) followed by 2-phenylacetyl chloride (4.26 μl, 0.032 mmol) and the mixture stirred at room temperature. (Mixture became a clear, colorless solution within 30 min.) After 3 h, the solvent was removed and the residue was taken up in MeOH/DMF and purified by preparative HPLC (10% AcCN/90% H2O/0.1% NH4OAc, Sunfire 19×100 mm, C18, 5 μm). The product was dissolved in MeOH and repurified by preparative HPLC (10% AcCN/90% H2O/0.1% NH4OAc, Sunfire 19×100 mm, C18, 5 μm) to give 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-6-(2-phenylacetyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (1.3 mg, 10% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ ppm 7.38-7.60 (1H, m), 7.00-7.40 (7H, m), 6.97 (1H, d, J=7.02 Hz), 4.75-4.85 (1H, m), 4.35-4.47 (0.5H, m), 4.17-4.34 (1H, m), 3.98 (0.5H, d, J=16.48 Hz), 3.77-3.93 (1.5H, m), 3.57-3.77 (3H, m), 3.53 (0.5H, d, J=13.12 Hz), 1.22-1.42 (9H, m), 1.11-1.22 (3H, m), 0.87-1.04 (9H, m). LCMS (M+H) calcd for C33H40FN2O4: 547.29. found: 547.4.

Workup

  1. customwithin 30 min.
  2. customAfter 3 h
  3. customthe solvent was removed
  4. custompurified by preparative HPLC (10% AcCN/90% H2O/0.1% NH4OAc, Sunfire 19×100 mm, C18, 5 μm)
  5. dissolutionThe product was dissolved in MeOH
  6. customrepurified by preparative HPLC (10% AcCN/90% H2O/0.1% NH4OAc, Sunfire 19×100 mm, C18, 5 μm)

Sources & evidence

ORD record
ord-20a4bf11765c45c5bc1e9c5a9d175ed5
Source dataset
uspto-grants-2014_01
Patent number
US08629276B2

Reaction notes

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